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Patent Analysis of

Multiplex detection of DNA that originates from a specific cell-type

Updated Time 12 June 2019

Patent Registration Data

Publication Number

US10017818

Application Number

US14/707363

Application Date

08 May 2015

Publication Date

10 July 2018

Current Assignee

LIFECODEXX AG

Original Assignee (Applicant)

LIFECODEXX AG

International Classification

C12Q1/68,C12Q1/6881,C12Q1/6883

Cooperative Classification

C12Q1/6881,C12Q1/6883,C12Q2600/16,C12Q2600/154,C12Q2600/158

Inventor

GROMMINGER, SEBASTIAN,HOFMANN, WERA,SAID, HAMED

Patent Images

This patent contains figures and images illustrating the invention and its embodiment.

US10017818 Multiplex detection DNA 1 US10017818 Multiplex detection DNA 2 US10017818 Multiplex detection DNA 3
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Abstract

The present invention relates to methods to detect an amount of DNA that originates from cells of a given type, where the sample comprising such DNA in admixture with DNA that does not originate from such cells. Such methods are based on different methylation, at certain regions, of the DNA that originates from the given type of cells compared to the admixed DNA. Such methods have particular application in the detection, from a biological fluid from a pregnant female, of cell free DNA that originates from a foetus or the placenta of a foetus, or the detection, from a biological fluid from an individual, of cell free DNA that originates from cells of a tumor. Accordingly, such methods have diagnostic, prognostic and/or predictive utility for detecting an increased risk of an individual suffering from or developing a medical condition such as preeclampsia or cancer, and/or to aid subsequent diagnostic, prognostic and/or predictive methods such as the detection of chromosomal trisomy in a foetus, including for twin-pregnancies. The present invention also relates to compositions, kits, computer program products and other aspects that are used in, useful for or related to the practice of such methods.

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Claims

1. A method for quantitatively detecting in a sample from an individual an amount of a species of DNA originating from cells of a given type, which sample comprises said species of DNA in admixture with differently methylated DNA not originating from cells of said type; said method comprising the steps:(a) treating the DNA present in said sample with a reagent that differentially modifies methylated and non-methylated DNA;(b) quantitatively detecting in said sample the presence of methylation in said species of DNA at two or more differentially methylated regions (DMRs) that are differently methylated between said species of DNA and the DNA not originating from cells of said type, the modification of DNA of such DMRs by said reagent is sensitive to methylation of DNA, and wherein the presence of methylated DNA at one or more of said DMRs indicates the presence of said amount of species of DNA in said sample and the absence of methylated DNA at said DMRs indicates the absence of said species of DNA in said sample; and(c) quantitatively detecting an amount of total DNA present in said sample using at least one other region that is not differently methylated between said species of DNA and the DNA not originating from cells of said type, the modification of which region(s) by said reagent is insensitive to methylation of DNA, wherein, said detection in step (b) and said detection in step (c) are made using the same aliquot of DNA of said sample, and in the same reaction/detection vessel, and effectively simultaneously for such DMRs and other region(s), and using: (x) the same detectable label(s) for each of said DMRs; and (y) a different detectable label(s) for said other region(s); and wherein, said detection in step (c) comprises using at least two of said other regions, wherein the number of said other regions is the same as the number of DMRs used in step (b), and wherein one of said other regions is located between about 20 bp and about 20 kb upstream or downstream of a DMR used in step (b) and each other of the said other regions is located between about 20 bp and about 20 kb upstream or downstream of another of said DMRs; and wherein, said detection in step (c) is made using the same detectable label(s) for each of said other regions.

2. The method of claim 1, wherein:(A) prior to or as part of said detection in step (b) and/or step (c), each DNA region comprising said DMRs and/or said other region(s), respectively, is(are) amplified; and/or(B) each detectable label used in step (b) and/or step (c) is fluorescent; and/or(C) said detection in step (b) comprises multiplex real-time probe-based quantitative PCR using at least two labelled probes each of which is specific for one of said DMRs; and/or(D) said detection in step (c) comprises real-time quantitative PCR using at least one labelled probe specific for one of said other region(s).

3. The method of claim 1, wherein: said detection in step (c) comprises multiplex real-time quantitative probe-based PCR using at least two labelled probes each of which is specific for one of said other regions.

4. The method of claim 1, wherein said detection in step (c) and said detection in step (b) comprises multiplex real-time quantitative probe-based PCR using at least one labelled probe specific for each of the said DMRs and other regions.

5. The method of claim 1, wherein said species of DNA originates from cells of a fetus and/or the placenta of a fetus and said sample is from a pregnant female, and wherein said species of DNA is circulating cell-free DNA and said sample is a blood fraction.

6. The method of claim 5, wherein:(A) said DMRs comprise at least one methylation site(s) specific for said reagent, and at least one of said DMRs is located in a portion of the genome and/or gene selected from the group consisting of: RASSF1A, TBX3, HLCS, ZFY, CDC42EP1, MGC15523, SOX14 and SPN; and/or(B) said at least one of said other regions is located in a portion of the genome and/or gene selected from the group consisting of: RASSF1A, TBX3, HLCS, ZFY, CDC42EP1, MGC15523, SOX14 and SPN.

7. The method of claim 6, wherein at least one of said DMRs is located between about positions 4,700 bp and 5,600 bp of RASSF1A or about positions 1,660 bp and 2,400 bp of TBX3.

8. The method of claim 7, wherein said pregnant female is susceptible to a pregnancy-associated medical condition.

9. The method of claim 8, wherein said pregnancy-associated medical condition is preeclampsia.

10. The method of claim 5, further comprising the step of performing on said sample a prenatal diagnosis for an anomaly in the DNA originating from cells of a fetus and/or the placenta of a fetus.

11. The method of claim 10, wherein said anomaly in the DNA originating from cells of a fetus and/or the placenta of a fetus is a chromosomal trisomy.

12. The method of claim 5, wherein one or both of said two or more DMRs is/are located in SEQ ID NOs: 15-199.

13. The method of claim 5, wherein one or both of said two or more DMRs is/are located in SEQ ID NOs: 74-147.

14. The method of claim 1, wherein said species of DNA originates from a cell type associated with a medical condition, wherein said medical condition is one selected from the group consisting of: a cell proliferative disorder, an infection/infectious disease, a wasting disorder, a degenerative disorder, an (auto)immune disorder, kidney disease, liver disease, inflammatory disease, acute toxicity, chronic toxicity, myocardial infarction, and a combination of any of the forgoing, and wherein said species of DNA is circulating cell-free DNA and said sample is a blood fraction.

15. The method of claim 14, wherein said species of DNA originates from cells of a tumor.

16. The method of claim 15, wherein said tumor is a carcinoma or cancer of an organ selected from the group consisting of: liver, lung, breast, colon, oesophagus, prostate, ovary, cervix, uterus, testis, brain, bone marrow and blood.

17. The method of claim 15, wherein said DMRs comprise at least one methylation site(s) specific for said reagent, and at least one of said DMRs is located in a portion of the genome and/or a gene selected from the group consisting of: a tumour suppressor gene, p16, SEPT9, RASSF1A, GSTP1, DAPK, ESR1, APC, HSD17B4 and H1C1.

18. The method of claim 17, wherein at least one of said DMRs is located between about positions 4,700 bp and 5,600 bp of RASSF1A.

19. The method of claim 17, wherein at least one of said other regions is located between about positions 14,220 bp and 13,350 bp of RASSF1A.

20. The method of claim 1, wherein said sample is a tissue sample or a sample of biological fluid, wherein the sample of biological fluid is selected from the group consisting of: whole blood, a blood fraction, urine, saliva, sweat, ejaculate, tears, phlegm, vaginal secretion, vaginal wash and colonic wash.

21. The method of claim 20, wherein said sample is a plasma or serum sample.

22. The method of claim 1, wherein:(A) said reagent that differentially modifies methylated and non-methylated DNA comprises bisulphate; or(B) said reagent that differentially modifies methylated and non-methylated DNA comprises an agent that selectively digests unmethylated over methylated DNA, wherein said agent comprises: at least one methylation sensitive enzyme; at least one methylation sensitive restriction enzyme; and/or an agent selected from the group consisting of: AatII, AciI, AclI, AfeI, AgeI, AgeI-HF, AscI, AsiSI, AvaI, BceAI, BmgBI, BsaAI, BsaHI, BsiEI, BsiWI, BsmBI, BspDI, BsrFI, BssHII, BstBI, BstUI, ClaI, EagI, FauI, FseI, FspI, HaeII, HgaI, HhaI, HinPlI, HpaII, Hpy99I, HpyCH4IV, KasI, MluI, NaeI, NarI, NgoMIV, NotI, NotI-HF, NruI, Nt.BsmAI, Nt.CviPII, PaeR7I, PluTI, PmlI, PvuI, PvuI-HF, RsrII, SacII, SalI, SalI-HF, SfoI, SgrAI, SmaI, SnaBI, TspMI and ZraI.

23. The method of claim 1:(A) wherein each of said detection steps comprises quantitative detection and said detected amount of said species of DNA is expressed as a relative concentration of said species of DNA to the total DNA in said sample; or(B) wherein said method further comprises the steps: detecting an amount of total DNA in a standard sample of DNA of known amount using the same other region(s) as used in step (c); and comparing the signal detected from said standard sample of DNA to the signal detected in step (c); and optionally, wherein each of said detection steps comprises quantitative detection and said detected amount of said species of DNA is expressed as an absolute amount of said species of DNA in said sample.

24. The method of claim 23, further comprising the step: comparing the amount of said species of DNA detected with a threshold amount and/or reference distribution of amounts, wherein: (x) an increase in, or outlying of, the amount of said species of DNA indicates an increased risk of the individual suffering from or developing a medical condition; and/or (y) an amount of said species of DNA in excess to said threshold, or outlying from said distribution, indicates that a diagnosis for an abnormality in the said species of DNA present in said sample may be performed on a separate aliquot of DNA of said sample.

25. The method of claim 1, wherein two of said DMRs are located on separate chromosomes.

26. The method of claim 1, wherein the other region is located upstream or downstream of one of said DMRs within a distance selected from the group consisting of: between about 15 kb to 10 kb, 12 kb to 8 kb, 10 kb to 8 kb, 11 kb to 7 kb, 11 kb to 10 kb, 9 kb to 8 kb, 8 kb to 6 kb, 6 kb to 4 kb, 4 kb to 2 kb, and 2 kb to 500 bp.

27. The method of claim 1, wherein said reagent that differentially modifies methylated and non-methylated DNA comprises at least one methylation sensitive restriction enzyme.

28. The method of claim 1, wherein: said essentially simultaneous quantitative detection of said two or more DMRs comprises multiplex real-time probe-based quantitative PCR using at least two labelled probes, each of which is specific for one of said DMRs; and said essentially simultaneous quantitative detection of said at least two other regions comprises multiplex real-time probe-based quantitative PCR using at least two labelled probes, each of which is specific for one of said other regions.

29. A computer program product comprising: a non-transitory computer readable medium encoded with a plurality of instructions for controlling a computing system to perform and/or manage an operation for determining: (x) an increased risk of an individual suffering from or developing a medical condition and/or (y) if a diagnosis for an anomaly in a species of DNA originating from cells of a given type may be performed, said operation comprising the steps of: receiving: (i) a first signal representing the essentially simultaneous quantitative detection of methylation at two or more differentially methylated regions (DMRs) in a species of DNA originating from cells of a given type in a sample from an individual comprising a species of DNA originating from cells of a given type in admixture with differently methylated DNA not originating from cells of said type, wherein the sample is treated with a reagent that differentially modifies methylated and non-methylated DNA and wherein detection of said two or more DMRs is made using the same detectable label; and (ii) a second signal representing the essentially simultaneous quantitative detection of total DNA in the sample using at least two other regions of DNA that are not differently methylated between said species of DNA and the DNA not originating from cells of said type, wherein the number of said at least two other regions is the same as the number of DMRs, and wherein one of said other regions is located between about 20 bp and about 20 kb upstream or downstream of one of the DMRs and wherein another of said other regions is located between about 20 bp and about 20 kb upstream or downstream of another of said DMRs; wherein said detection of said other regions is made using the same detectable label, and wherein said detectable label for the other regions is different from the detectable label used to detect the DMRs, and wherein said detections of (i) and (ii) are made using the same aliquot of DNA of said sample and in the same reaction/detection vessel and effectively simultaneously for such DMRs and other regions; comparing the first signal with the second signal to thereby obtain a parameter, wherein the parameter represents an enhanced quantitative amount of said species of methylated DNA in the sample, wherein said enhanced quantitative amount is more accurate or precise than a quantitative amount of said species of methylated DNA in the sample obtained using an other region(s) located more than 20 kb upstream or downstream of a DMR(s), wherein each DMR and each other region is detected with a different detectable label and/or in a separate reaction/vessel; comparing the parameter to a threshold amount and/or reference distribution of amounts; and based on such comparison, determining a classification of whether, respectively, (x) an increased risk of an individual suffering from or developing a medical condition exists; and/or (y) a diagnosis for an anomaly in the species of DNA originating from cells of the given type may be performed.

30. The computer program product of claim 29, wherein one of said other regions is located upstream or downstream of one of said DMRs within a distance selected from the group consisting of: between about 15 kb to 10 kb, 12 kb to 8 kb, 10 kb to 8 kb, 11 kb to 7 kb, 11 kb to 10 kb, 9 kb to 8 kb, 8 kb to 6 kb, 6 kb to 4 kb, 4 kb to 2 kb, and 2 kb to 500 bp; and/or another of said other region is located upstream or downstream of another of said DMRs within a distance selected from the group consisting of: between about 15 kb to 10 kb, 12 kb to 8 kb, 10 kb to 8 kb, 11 kb to 7 kb, 11 kb to 10 kb, 9 kb to 8 kb, 8 kb to 6 kb, 6 kb to 4 kb, 4 kb to 2 kb, and 2 kb to 500 bp.

31. The computer program product of claim 29, wherein said species of DNA originates from cells of a fetus and/or the placenta of a fetus and said sample is from a pregnant female, and wherein said species is circulating cell-free DNA and said sample is a plasma or serum sample.

32. The computer program product of claim 31, wherein a classification is determined of whether there is an increased risk of said pregnant female suffering from or developing a pregnancy-associated condition.

33. The computer program product of claim 32, wherein said pregnancy-associated condition is preeclampsia.

34. The computer program product of claim 31, wherein a classification is determined of whether a prenatal diagnosis may be performed for an anomaly in the DNA originating from cells of a fetus and/or the placenta of a fetus.

35. The computer program product of claim 34, wherein said anomaly in the DNA originating from cells of a fetus and/or the placenta of a fetus is a chromosomal trisomy.

36. The computer program product of claim 31, wherein one or both of said two or more DMRs is/are located in SEQ ID NOs: 15-199.

37. The computer program product of claim 31, wherein one or both of said two or more DMRs is/are located in SEQ ID NOs: 74-147.

38. The computer program product of claim 29, wherein said two or more DMRs are located on separate chromosomes.

39. The computer program product of claim 29, wherein said reagent that differentially modifies methylated and non-methylated DNA comprises at least one methylation sensitive restriction enzyme.

40. The computer program product of claim 29, wherein: said essentially simultaneous quantitative detection of said two or more DMRs comprises multiplex real-time probe-based quantitative PCR using at least two labelled probes, each of which is specific for one of said DMRs; and said essentially simultaneous quantitative detection of said at least two other regions comprises multiplex real-time probe-based quantitative PCR using at least two labelled probes, each of which is specific for one of said other regions.

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Claim Tree

  • 1
    1. A method for quantitatively detecting in a sample from an individual an amount of a species of DNA originating from cells of a given type, which sample comprises said species of DNA in admixture with differently methylated DNA not originating from cells of said type; said method comprising the steps:
    • (a) treating the DNA present in said sample with a reagent that differentially modifies methylated and non-methylated DNA;
    • (b) quantitatively detecting in said sample the presence of methylation in said species of DNA at two or more differentially methylated regions (DMRs) that are differently methylated between said species of DNA and the DNA not originating from cells of said type, the modification of DNA of such DMRs by said reagent is sensitive to methylation of DNA, and wherein the presence of methylated DNA at one or more of said DMRs indicates the presence of said amount of species of DNA in said sample and the absence of methylated DNA at said DMRs indicates the absence of said species of DNA in said sample; and
    • (c) quantitatively detecting an amount of total DNA present in said sample using at least one other region that is not differently methylated between said species of DNA and the DNA not originating from cells of said type, the modification of which region(s) by said reagent is insensitive to methylation of DNA, wherein, said detection in step (b) and said detection in step (c) are made using the same aliquot of DNA of said sample, and in the same reaction/detection vessel, and effectively simultaneously for such DMRs and other region(s), and using: (x) the same detectable label(s) for each of said DMRs; and (y) a different detectable label(s) for said other region(s); and wherein, said detection in step (c) comprises using at least two of said other regions, wherein the number of said other regions is the same as the number of DMRs used in step (b), and wherein one of said other regions is located between about 20 bp and about 20 kb upstream or downstream of a DMR used in step (b) and each other of the said other regions is located between about 20 bp and about 20 kb upstream or downstream of another of said DMRs; and wherein, said detection in step (c) is made using the same detectable label(s) for each of said other regions.
    • 2. The method of claim 1, wherein
      • :(A) prior to or as part of said detection in step (b) and/or step (c), each DNA region comprising
    • 3. The method of claim 1, wherein
      • : said detection in step (c) comprises
    • 4. The method of claim 1, wherein
      • said detection in step (c) and said detection in step (b) comprises
    • 5. The method of claim 1, wherein
      • said species of DNA originates from cells of a fetus and/or the placenta of a fetus and said sample is from a pregnant female, and wherein
    • 14. The method of claim 1, wherein
      • said species of DNA originates from a cell type associated with a medical condition, wherein
    • 20. The method of claim 1, wherein
      • said sample is a tissue sample or a sample of biological fluid, wherein
    • 22. The method of claim 1, wherein
      • :(A) said reagent that differentially modifies methylated and non-methylated DNA comprises
    • 23. The method of claim 1:(A) wherein
      • each of said detection steps comprises
    • 25. The method of claim 1, wherein
      • two of said DMRs are located on separate chromosomes.
    • 26. The method of claim 1, wherein
      • the other region is located upstream or downstream of one of said DMRs within a distance selected from the group consisting of:
    • 27. The method of claim 1, wherein
      • said reagent that differentially modifies methylated and non-methylated DNA comprises
    • 28. The method of claim 1, wherein
      • : said essentially simultaneous quantitative detection of said two or more DMRs comprises
  • 29
    29. A computer program product comprising:
    • a non-transitory computer readable medium encoded with a plurality of instructions for controlling a computing system to perform and/or manage an operation for determining: (x) an increased risk of an individual suffering from or developing a medical condition and/or (y) if a diagnosis for an anomaly in a species of DNA originating from cells of a given type may be performed, said operation comprising the steps of: receiving: (i) a first signal representing the essentially simultaneous quantitative detection of methylation at two or more differentially methylated regions (DMRs) in a species of DNA originating from cells of a given type in a sample from an individual comprising a species of DNA originating from cells of a given type in admixture with differently methylated DNA not originating from cells of said type, wherein the sample is treated with a reagent that differentially modifies methylated and non-methylated DNA and wherein detection of said two or more DMRs is made using the same detectable label
    • and (ii) a second signal representing the essentially simultaneous quantitative detection of total DNA in the sample using at least two other regions of DNA that are not differently methylated between said species of DNA and the DNA not originating from cells of said type, wherein the number of said at least two other regions is the same as the number of DMRs, and wherein one of said other regions is located between about 20 bp and about 20 kb upstream or downstream of one of the DMRs and wherein another of said other regions is located between about 20 bp and about 20 kb upstream or downstream of another of said DMRs
    • wherein said detection of said other regions is made using the same detectable label, and wherein said detectable label for the other regions is different from the detectable label used to detect the DMRs, and wherein said detections of (i) and (ii) are made using the same aliquot of DNA of said sample and in the same reaction/detection vessel and effectively simultaneously for such DMRs and other regions
    • comparing the first signal with the second signal to thereby obtain a parameter, wherein the parameter represents an enhanced quantitative amount of said species of methylated DNA in the sample, wherein said enhanced quantitative amount is more accurate or precise than a quantitative amount of said species of methylated DNA in the sample obtained using an other region(s) located more than 20 kb upstream or downstream of a DMR(s), wherein each DMR and each other region is detected with a different detectable label and/or in a separate reaction/vessel
    • comparing the parameter to a threshold amount and/or reference distribution of amounts
    • and based on such comparison, determining a classification of whether, respectively, (x) an increased risk of an individual suffering from or developing a medical condition exists
    • and/or (y) a diagnosis for an anomaly in the species of DNA originating from cells of the given type may be performed.
    • 30. The computer program product of claim 29, wherein
      • one of said other regions is located upstream or downstream of one of said DMRs within a distance selected from the group consisting of:
    • 31. The computer program product of claim 29, wherein
      • said species of DNA originates from cells of a fetus and/or the placenta of a fetus and said sample is from a pregnant female, and wherein
    • 38. The computer program product of claim 29, wherein
      • said two or more DMRs are located on separate chromosomes.
    • 39. The computer program product of claim 29, wherein
      • said reagent that differentially modifies methylated and non-methylated DNA comprises
    • 40. The computer program product of claim 29, wherein
      • : said essentially simultaneous quantitative detection of said two or more DMRs comprises
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Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to European patent application 14 167 769.0 filed 9 May 2014, the entire disclosure of which is hereby incorporated herein by reference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Apr. 27, 2015, is named DFMP-112_SL.txt and is 53 kilobytes in size.

SEQUENCE LISTING

The instant application contains a Substitute Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Sep. 28, 2017, is named DFMP-112-01_ST25 and is 296,000 bytes in size.

The present invention relates to methods to detect an amount of DNA that originates from cells of a given type, where the sample comprising such DNA in admixture with DNA that does not originate from such cells. Such methods are based on different methylation, at certain regions, of the DNA that originates from the given type of cells compared to the admixed DNA. Such methods have particular application in the detection, from a biological fluid from a pregnant female, of cell free DNA that originates from a foetus or the placenta of a foetus, or the detection, from a biological fluid from and individual, of cell free DNA that originates from cells of a tumour. Accordingly, such methods have diagnostic, prognostic and/or predictive utility for detecting an increased risk of an individual suffering from or developing a medical condition such as preeclampsia or cancer, and/or to aid subsequent diagnostic, prognostic and/or predictive methods such as the detection of chromosomal trisomy in a foetus, including for twin-pregnancies. The present invention also relates to compositions, kits, computer program products and other aspects that are used in, useful for or related to the practice of such methods.

Cell-free DNA (cfDNA), especially that found in plasma or serum, has been the subject of considerable research over the past decade. Despite the original finding of circulating cell-free nucleic acids in the bloodstream being described by Mandel and Metais as early as 1948 (Mandel and Metais 1948, CR Acad Sci Paris 142:241), it took until the mid 1990s for proof that tumours shed DNA into the circulatory system (Sorenson et al 1994, Cancer Epidemiol Biomarkers Prev 3:67; Vassioukhin et al 1994, Br J Haematol 86:774), and until 1997 for the discovery of cfDNA originating from a foetus in the circulatory system of the mother (Lo et al 1997, Lancet 350:485).

Among other forms of characteristics shown by circulating cfDNA, numerous studies have described the presence of methylated circulating cfDNA in the plasma/serum and other body fluids of patients with various types of malignancy and the absence of methylated DNA in normal control patients (for review see Muller and Widschwendter 2003, Expert Rev Mol Diagn 3:443). Although other characteristics of circulating cfDNA exist and are important for diagnostic, prognostic or predictive studies (for example, sequence mutations and micro duplications/deletions), such methylation-based epigenetic characteristics have become an increasingly important source of serologic markers for diagnosis, risk assessment and even for therapy monitoring during follow-up of cancer patients.

Likewise, the use of differences in foetal cfDNA present in the maternal circulation has been the main goal for the development of non-invasive prenatal tests (NIPT). Foetal cfDNA is derived from embryonic cell degradation in material peripheral blood (Lo et al 2000, Clin Chem 46:1301) or from apoptotic placental cells (Smid et al 2006, Prenat Diagn 26:785). It has been demonstrated that foetal cfDNA from maternal plasma is cleared immediately (within a few hours) after pregnancy (Lo et al 1999, Am J Hum Genet 64:218). This finding is of great importance, since the presence of foetal cfDNA from previous pregnancies would otherwise interfere with the correct interpretation of subsequent pregnancies.

It is believed that 60% of tissue-specific differentially methylated regions are methylated in embryonic cells, while during the differentiation of embryonic tissues to adult tissues, they undergo de-methylation (Kawai et al 1993, Nucleic Acids Res 21:5604). Based on the evidence that foetal cfDNA in maternal plasma is of placental origin, epigenetic differences between maternal peripheral (whole) blood and placental DNA have been used to detect a hypomethylated gene sequence (maspin/SERPINB5) in maternal plasma derived from the foetus (Masuzaki et al 2004, J Med Genet 41:289; Fiori et al 2004, Hum Reprod 19:723; Chim et al 2005, Proc Natl Acad Sci USA 102:14753). Subsequently, a number of additional differential foetal methylation-based epigenetic molecular markers have been described, including the RASSF1A gene on chromosome 3, as well as a marker on chromosome 21 (Chiu et al 2007, Am J. Pathol 170:941; Old et al 2007, Reprod Biomed Online 15:22; Chim et al 2008, Clin Chem 54:500) and others including T-box 3 (TBX3) (Nygren et al 2010, Clin Chem 65:10, WO 2010/033639; WO 2011/034631).

Various methodologies exist for NIPT based on the analysis of foetal cfDNA. For example, foetal sex determination using eg DYS14 (Lo et al 1997; Lancet 350:485), as well as foetal Rhesus D found in maternal circulation in pregnancies in which the mother was Rhesus D negative (Lo 1998, N Eng J Med 339:1734). Also, and of particular relevance, are those using next generation sequencing (NGS) technologies on cfDNA isolated from maternal plasma with the primary aim of detecting the most common chromosomal aneuploidies as commercially available tests (for example, those using random massively parallel sequencing: www.sequenom.com; www.lifecodexx.com; www.verinata.com). Other technologies include targeted approaches, the aim of which is to enrich specific genomic regions of interest before sequencing to reduce the number of sequence tags needed to perform a reliable statistical analysis (eg www.ariosadx.com or www.natera.com), polymorphism analysis or digital PCR (for review, see Go et al 2011, Human Reprod Update 17:372). However, regardless of the specific technology used, current applications of NIPT rely on the qualitative detection of foetal cfDNA to determine the genetic makeup of the foetus. Such an approach leads to an analytic dilemma, because test results from samples that do not contain any or sufficient foetal DNA or are contaminated with maternal cellular DNA can be misleading. The analogous issue arises in diagnostic, prognostic or predicative tests of tumour derived cfDNA from the circulatory system: the quality of the test result often is dependent on the presence of sufficient, or sufficiently pure, tumour-derived cfDNA in the total DNA from the sample.

The quantitative determination of an amount of DNA originating from such a cell type may, in itself, form a critical part of a diagnostic, prognostic or predicative test. For example, even though studies have demonstrated that the amount of foetal DNA released in maternal circulation increases with pregnancy progression (Lo et al 1998, Am J Hum Genet 62:768), preeclampsia, which results from abnormal trophoblast invasion, is also associated with further elevated foetal cfDNA levels in the maternal circulation. Lo et al (1999, Clin Chem 45:184) demonstrated a fivefold increase in circulating foetal cfDNA concentrations in the plasma of symptomatic preeclamptic women compared with control pregnant subjects, and further studies have investigated if elevated serum foetal cfDNA developed into early-onset preeclampsia (Yu et al 2013, Int J Mol Sci 14:7571), and the potential of cfDNA as a marker for preeclampsia is being increasingly studied (for review, see Hahn et al 2011, Placental 32(Supl):S17). An increased level of circulating cfDNA and/or the level of methylation of such DNA at certain regions is also associated with other medical conditions. For example, hypermethylation of serum cfDNA was found to be common in patients suffering from oesophageal squamous cell carcinoma, and diagnostic accuracy was increased when methylation of multiple genes (RAR-beta, DAPK, CDH1, p16 and RASSF1A) were analysed in combination (Li et al 2011, Epigenetics 6:307). Elevated levels of circulating cfDNA have been reported in patients with acute dengue virus infection (Ha et al 2011, PLoS One 6(10):e25969), in acute Puumala hantavirus infection Outinen et al 2012, PLoS One 7(2):e31455) and high cfDNA has been reported to predict fatal outcome among Staphylococcus aureus bacteraemia patients with intensive care unit treatment (Forsblom et al 2014, PLoS One 10; 9(2):e87741.

It is known that foetal cfDNA present in the maternal circulatory system and tumour derived circulating cfDNA is degraded. For example, studies characterising cfDNA in maternal plasma have found that the size of foetal DNA fragments were estimated to be <0.3 kb, whereas that of maternal DNA was >1 kb (Chan et al 2004, Clin Chem 50:88). Follow-up studies have demonstrated that the release of foetal DNA is due to the apoptosis of no more than three nucleosomal complexes, it has also been shown that the average foetal fragment size is 286+/−28 bp with a maximum foetal cfDNA fragment size ranging from 219 to 313 bp (Kimura et al 2011, Nagoya J Med Sci 73:129), and another study has reported that the most significant difference in the size distribution between foetal and total DNA is that foetal DNA exhibits a reduction in a 166-bp peak size and a relative prominence of the 143-bp peak, the latter likely corresponding to the trimming of a ˜20-bp linker fragment from a nucleosome to its core particle of ˜146 bp (Lo et al 2010, Sci Transl Med 2:61).

In cancer patients, circulating cfDNA in plasma is protein-bound (nucleosomal) DNA and has a short half-life (10 to 15 min) which is removed mainly by the liver (Elshimali et al 2013, Int J Mol Sci 14:18925). Accumulation of cfDNA in the circulation of cancer patients can result from an excessive release of DNA caused by massive cell death, inefficient removal of the dead cells, or a combination of both (Zeerleder 2006, Crit Care 10:142). It should be noted that although cancer patients requiring renal support have higher values of circulating cfDNA, the renal elimination is not the main mechanism of its clearance. The plasma levels of circulating cfDNA do not seem to be dramatically altered in chronic kidney disease, peritoneal dialysis or hemodialysis (Kirsch et al 2008, Ann NY Acad Sci 1137:135).

Although the nucleosome is a very stable protein-DNA complex, it is not static and has been shown to undergo a number of different structural re-arrangements including nucleosome sliding and DNA site exposure. Depending on the context, nucleosomes can inhibit or facilitate transcription factor binding. Also, packaging of DNA into nucleosomes varies depending on the cell cycle stage and by local DNA region (Russell 2010, “iGenetics”. 3rd ed. San Francisco: Pearson Benjamin Cummings, pp 24-27). The degree to which chromatin is condensed is associated with a certain transcriptional state. Unpackaged or loose chromatin is more transcriptionally active than tightly packaged chromatin because it is more accessible to transcriptional machinery. By remodeling chromatin structure and changing the density of DNA packaging, gene expression can thus be modulated. Accordingly, and without being bound by theory, the qualitative and/or quantitative level of chromatin packing of a given region of cfDNA may affect its stability, and hence the amount detected in the circulatory system at any given time. Correspondingly, differences between the level of chromatin packing between different DNA regions (for example, due to differences in each regions state of transcription) may influence the relative quantities of DNA from each of these regions when detected as cfDNA, particularly as two studies have investigated in more detail the kinetics of, and reported the rapid, clearance of cfDNA from the circulatory system (Gauthier et al 1996, J Immunol 156:1151; Lo et al 1999, Am J. Hum Genet 64:218).

Various prior art methods have been described to detect, and quantify, cfDNA from a specific cell type. Quantitative analysis of aberrant p16 methylation was described using probe-based real-time quantitative PCR (Lo et al 1999, Cancer res 59:3899). Analogously, differences in the methylation of the placental mapsin gene found in material plasma has been described, and the methylation signature further analysed using MALDI-TOF mass-spectrometry (Chim et al 2005). Total cfDNA and that from male foetuses (only) were accurately and robustly quantified in maternal plasma from 5 to 41 weeks of gestation using a Y-chromosome specific marker (SRY) (Birch et al 2005, Clin Chem 51:2). Hypermethylation of RASSF1A has been proposed as a universal foetal DNA marker to improve the reliability of NIPT, and was studied in a duplex probe-based real-time PCR reaction compared to the non-differentially methylated region on the beta-actin gene (Chan et al 2006, Clin Chem 52:12). A complex method of quantification has been described (Nygren et al 2010; Clin Chem 56:10, WO 2010/033639; WO 2011/034631): starting from a 13-plex competition-PCR reaction (5 differentially methylated regions (DMRs) including TBX3, 3 regions on different genes for total DNA quantification, 3 for quantification of chromosome Y and 2 for restriction enzyme controls), such a complex reaction is subsequently processed for singe-base extension reactions and finally mass-spectrometry is subsequently conducted to both quantify and identify each of the single alleles my mass differences. Also using a complex process starting from methylated DNA immunoprecipitation, and based on SYBR green based quantitative PCR of a plurality of DMRs, has been claimed to be able to accurately quantitate foetal cfDNA and use such quantitation from eg chromosome 21 DMRs, to prenatally diagnose trisomies (Papageorgiou et al 2011, Nat Med 4:510; WO 2012/092592); although technical concerns about such an approach to diagnose trisomies have been raised (Tong et al 2012; Nat Med 18:1327). High-throughout droplet digital PCR (ddPCR) has been described for absolute quantification of DNA copy number from normal and tumorous breast tissues, and also total and foetal cfDNA in maternal plasma using duplex probe-based quantitative PCR of RASSF1/RNaseP and RASSF1/beta-actin (Hindson et al 2011, Anal Chem 83:8604). Separate SYBR green quantitative PCR reactions of RASSF1A, SRY and DYS14 have been evaluated as an assay to detect RASSf1A to facilitate improved diagnostic reliability of NIPT (White et al 2012; PLOS ONE 7(9):e45073). However, generally considered as the “gold standard” for the quantitative measurement of foetal cfDNA against which other assays are often compared, remains the quantification of Y chromosome-specific genes (eg SFY) of male foetuses eg, as used by Yu and co-workers to determine whether the increased foetal cfDNA in maternal serum level of gravitas developed into early-onset preeclampsia (Yu et al 2013, Int J Mol Sci 14:7571).

Accordingly there is a need, from one or more of the above or perspectives, for improved methods to detect, preferably quantitatively, an amount of a species of DNA that originates from a particular cell type, such as a tumour-, foetal- or a placental cell, in particular to so detect cfDNA eg from the circulatory system of an individual.

Accordingly, it is an object of the present invention to provide alternative, improved, simpler, cheaper and/or integrated means or methods that address one or more of these or other problems. Such an object underlying the present invention is solved by the subject matter as disclosed or defined anywhere herein, for example by the subject matter of the attached claims.

Generally, and by way of brief description, the main aspects of the present invention can be described as follows:

In a first aspect, and as may be further described, defined, claimed or otherwise disclosed herein, the invention relates to a method for detecting in a sample from an individual an amount of a species of DNA originating from cells of a given type, which sample comprises said species of DNA in admixture with differently methylated DNA not originating from cells of said type; said method comprising the steps:

  • (a) treating the DNA present in said sample with a reagent that differentially modifies methylated and non-methylated DNA;
  • (b) detecting in said sample the presence of methylation in said species of DNA at two or more differentially methylated regions (DMRs) that are differently methylated between said species of DNA and the DNA not originating from cells of said type, the modification of DNA of such DMRs by said reagent is sensitive to methylation of DNA, wherein the presence of methylated DNA at one or more of said DMRs indicates the presence of said amount of species of DNA in said sample and the absence of methylated DNA at said DMRs indicates the absence of said species of DNA in said sample; and
  • (c) detecting an amount of total DNA present in said sample using at least one other region that is not differently methylated between said species of DNA and the DNA not originating from cells of said type, the modification of which region(s) by said reagent is insensitive to methylation of DNA,

    wherein, said detection in step (b) and said detection in step (c) are made using the same aliquot of DNA of said sample, and in the same vessel, and effectively simultaneously for such DMRs and other region(s), and using: (x) the same detectable labels(s) for each of said DMRs; and (y) a different detectable label(s) for said other region(s).

In another aspect, the invention also relates to a method for detecting an increased risk of an individual suffering from or developing a medical condition, said method comprising the steps:

  • (i) conducting a method of the first aspect of the invention, wherein each of the detection steps comprises quantitative detection; and
  • (ii) comparing the amount of said species of DNA detected with a threshold amount and/or a reference distribution of amounts,

    wherein an increase in, or outlying of, the amount of said species of DNA indicates an increased risk of the individual suffering from or developing said medical condition.

In other aspects, the invention also relates to a composition, a kit and a computer program product, in each case as may be described, defined, claimed or otherwise disclosed herein, for use within or in connection with a method of the invention.

The figures show:

FIG. 1 depicts a schematic representation of the differentially methylated regions (“DMR”) and the other regions(s) (“OR”) used in the method of the invention.

FIG. 2 depicts a schematic representation of the differentially methylated regions (“DMR”) and other regions (“OR”) used in Example 1.

FIG. 3 depicts the correlation of the amount of male specific DNA (Y chromosomal representation) to the foetal cfDNA fraction measured by a method of the present invention (Example 1) for study twin cases with known foetal genders.

FIG. 4 depicts the improved sensitivity of a method of the invention compared to foetal cfDNA fraction detected using separate reactions of a single DMR. The number of PCR cycles (Cp) required for detection of foetal cfDNA (Example 2) in a sample using either RASSF1A or TBX3 alone as a single DMR, or as a multiplex (using the same labels) of RASSF1A and TBX3.

FIG. 5 depicts a schematic representation of the operations conducted by a computer program product of the invention.

The present invention, and particular non-limiting aspects and/or embodiments thereof, can be described in more detail as follows:

In a first aspect, the invention relates to a method for detecting in a sample from an individual an amount of a species of DNA originating from cells of a given type, which sample comprises said species of DNA in admixture with differently methylated DNA not originating from cells of said type; said method comprising the steps:

  • (a) treating the DNA present in said sample with a reagent that differentially modifies methylated and non-methylated DNA;
  • (b) detecting in said sample the presence of methylation in said species of DNA at two or more differentially methylated regions (DMRs) that are differently methylated between said species of DNA and the DNA not originating from cells of said type, the modification of DNA of such DMRs by said reagent is sensitive to methylation of DNA, wherein the presence f methylated DNA at one or more of said DMRs indicates the presence of said amount of species of DNA in said sample and the absence of methylated DNA at said DMRs indicates the absence of said species of DNA in said sample; and
  • (c) detecting an amount of total DNA present in said sample using at least one other region that is not differently methylated between said species of DNA and the DNA not originating from cells of said type, the modification of which region(s) by said reagent is insensitive to methylation of DNA,

    wherein, said detection in step (b) and said detection in step (c) are made using the same aliquot of DNA of said sample, and in the same vessel, and effectively simultaneously for such DMRs and other region(s), and using: (x) the same detectable labels(s) for each of said DMRs; and (y) a different detectable label(s) for said other region(s).

Terms as set forth herein are generally to be understood by their common meaning unless indicated otherwise. Where the term “comprising” or “comprising of” is used herein, it does not exclude other elements. For the purposes of the present invention, the term “consisting of” is considered to be a particular embodiment of the term “comprising of”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also to be understood to disclose a group that consists of all and/or only of these embodiments. Where used herein, “and/or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example “A and/or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually herein. In the context of the present invention, the terms “about” and “approximately” denote an interval of accuracy that the person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value by ±20%, ±15%, ±10%, and for example ±5%. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than one for a man-made or engineering technical effect. Where an indefinite or definite article is used when referring to a singular noun, e.g. “a”, “an” or “the”, this includes a plural of that noun unless something else is specifically stated.

In certain embodiments of the present invention, the individual is a human or a non-human animal, where such non-human animal may, in particular embodiments, be selected from the group consisting of: horse, sheep, cow, pig, chicken, mouse and rat. In a more specific embodiment, the individual is a pregnant female human or a human individual suspected of being at increased risk of developing or suffering (or suffering from) a medical condition, such as one or more of the medical conditions disclosed herein. Such a method of the present invention is not intended to be practiced on the human or animal body; for example it is intended to be practiced in an in-vitro manner.

In all aspects of the invention, the cell(s) of a given type may be a cell of a particular organ or tissues of the same individual. For example, the cell may be a tumour cell of the individual. Alternatively, such cell(s) may originate from a different individual or organism. For example, in the case of an individual being a pregnant female, the cell of a given type may be a cell of the foetus, including of the placenta of such foetus, and in other embodiments, the cell type may be an infectious agents such as a bacteria or a protozoa.

In certain embodiments of the present invention, said species of DNA and/or said differently methylated DNA is cell-free DNA, and in particular of such embodiments is circulating cell-free DNA. In one particular embodiment, said species of DNA and the differently methylated DNA that is admixed therewith are both circulating cell-free DNA. The term “cell-free DNA” (or “cfDNA”) is art recognised, and includes the meaning of DNA that is found outside of a cell, such as in a biological fluid (eg blood, or a blood fraction) of an individual. “Circulating” is also an art-recognised term, and includes the meaning that an entity or substance (eg cfDNA) is present in, detected or identified in, or isolated from, a circulatory system of the individual, such as the blood system or the lymphatic system. In particular, when cfDNA is “circulating” it is not located in a cell, and hence may be present in the plasma or serum of blood, or it may be present in the lymph of lymphatic fluid.

The term “differentially methylated region” or “DMR” will be recognised by the person of ordinary skill in the art, and is also intended to refer to a region in chromosomal DNA that is differentially methylated (eg at a CpG motif) between said species of DNA and the other DNA with which it is admixed in the sample. For example in one embodiment, the DMRs used in the present invention are differentially methylated between foetal and maternal DNA, or are differentially methylated between tumour-derived and non-tumour-derived DNA from the same individual. In particular embodiments of the present invention, the DMRs are hypermethylated in foetal DNA and hypo methylated in maternal DNA, or are hypermethylated in tumour-derived DNA and hypomethylated in DNA that is derived from non-tumour tissue of the individual. That is, in such regions exhibit a greater degree (ie more) methylation in said species of DNA (eg the foetal or tumour cfDNA) as compared to the other DNA (eg maternal or non-tumour DNA), such as about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% or, or more of, the sites available for methylation at a given DMR are methylated in said species of DNA as compared to the same sites in the other DNA.

A reagent is used in the present invention that differentially (eg selectively) modifies methylated as compared to non-methylated DNA. For example, treatment of DNA with a reagent comprising bisulphite (bisulfite) converts cytosine residues to uracil, but leaves 5-methylcytosine residues unaffected. Thus, bisulphite treatment introduces specific changes in the DNA sequence that depend on the methylation status of individual cytosine residues, yielding single-nucleotide resolution information about the methylation status of a segment of DNA. Various analyses can be performed on the altered sequence to retrieve this information, including the user of PCR primers and/or probes that can distinguish between such single-nucleotide changes.

Such a reagent may alternatively (or in addition) comprise a restriction enzyme that is sensitive to the DNA methylation states. Cleavage of such a restriction enzyme's recognition sequence may be blocked, or impaired, when a particular base in the enzyme's recognition site is modified, eg methylated. In particular embodiments of all aspects of the invention, the reagent comprises a methylation-sensitive restriction enzyme, such as a methylation-sensitive restriction enzyme disclosed herein; including such embodiments that comprise two, three, four, five or more of such methylation-sensitive restriction enzymes.

Prior to step (a), the sample may be processed to isolate, enrich and/or purify, the DNA present therein. For example, a plasma sample may be processed using a cfDNA isolation process or kit to provide a (non-natural) subsequent solution that comprises an admixture of said species of DNA together with the differentially methylated DNA that does not originate from the cell-type. The step of treating in (a) may comprise the step of adding a separate solution that comprises said reagent (eg a methylation sensitive restriction enzyme) to the admixed DNA of the sample (eg, to a non-natural solution comprising such admixed DNA); and/or may comprise maintaining (or changing to) certain conditions. In particular, when said reagent comprises one or more methylation sensitive restriction enzyme, the step of treating in (a) may comprise incubating the DNA and the enzyme(s) together at about 37° C. for between about 5 min and 300 min, such as between about 30 min and 90 min or about 60 min, and optionally may comprise a step of incubating such mixture at a higher temperature (for example, between about 50° C. and 90° Cm such as about 80° C.) so as to deactivate the enzyme(s). In certain embodiments, the composition formed for a treating step of (a) may be non-naturally occurring. For example, particular salts of components of the solution (or buffer); and/or the mixture of (eg human) cfDNA together with one or more bacterial-derived restriction enzymes (or a non-natural mutant thereof) may be a non-natural composition or mixture.

In contrast, an “other region” (“OR”) used in the present invention is not (significantly) differentially methylated between said species of DNA and other DNA with which it is admixed in the sample. For example, under the conditions and nature of the reagent used, there is not detectable difference between modification by such regent at the other region of said species of DNA (eg foetal DNA) as compared to the other region of the admixed DNA (eg the maternal DNA). Such a non-difference may be achieved if the other region comprises no sites for methylation, if there is no difference in the degree of methylation if such sites are present or by the use of a reagent that does not recognise any sites of methylation present in the other region. In particular embodiments, the other region used in the present invention (that is not so differentially methylated) may be non-overlapping with the DMRs used in the present invention. For example, the other region can be located further than about 10 bp, 20 bp, 50 bp, or more than 100 bp, 500 bp, 1 kb or 10 kp, away from either of the DMRs.

One feature of the present invention is that the detection of the various DNA regions, ie the DMRs and the other region(s), occurs in a simplified process. For example, using a single aliquot of DNA from the sample, such DNA regions are detected in a single vessel. This feature simplifies the method, and can provide for more efficient and accurate detection (especially in those embodiments when detection is quantitative). The term “vessel” will be art recognised, and includes embodiments of a vessel (such as a tube, well of a microtitre plate, nano-well, capillary reaction vessel etc) in which a process or procedure comprised in the method occurs, such as a reaction and/or detection process or a step of a method of the present invention. Other such vessels may include droplets in oil/water emulsions, nanoparticles or a hybridisation chamber; as appropriate to the detection technology used. The detectable labels used, in such methods is the same for each DMR and, in certain embodiments, is the same for each other region, provided that the label(s) used for the other region(s) is different (ie, can be separately detected) to the label(s) used for the DMRs. Detectable labels that are “the same”, can also include labels while structurally different, are functionally (essentially) similar as they cannot be significantly differentiated by the detection technology employed. For example, structurally different fluorescent dyes may be considered “the same” if their excitation and emission spectra are (substantially or essentially) similar, or overlap to such a degree that they are able to be excited and detected simultaneously with the same wavelength(s). Suitable labels (and detection modalities) are further described elsewhere herein. In addition, the detection of the DMRs and other region(s) is made effectively simultaneously. For example, within the same (reaction/detection) vessel, all such regions (and hence said species of DNA and total DNA) can be detected within less than about 5 s, 1 s, 0.5 s, 100 ms, 10 ms, 1 ms, 100 us, 10 us or 1 us of each other, and for example without transferring the vessel, or the reaction/mixture, to any subsequent vessel, assay or equipment, or for example, without adapting or recalibrating the detection process for either of the DMRs or the other region(s) separately. The use of two different detectable label(s)—one for said DMRs and one for the other region(s)—utilises components, process and/or steps that are non-natural. For example, a composition of two specific labels together with the specific DNA regions would (generally) not be found in nature. In particular, short probes used in quantitative probe-based PCR, while may comprise a DNA sequence that is a fragment of that found in a natural genome, when linked to a one or more labels (such as fluorescent dye) form a specific labelled fragment that is non-natural.

Collectively, the features of the present invention provide for certain advantages over prior art methods. These can include sensitive detection of methylation (and hence the species of DNA to be detected) and/or accurate quantification of the amount of said species of DNA by reference to the amount of total DNA detected within the same assay, from the same aliquot of admixed DNA and effectively simultaneously with the detection of the two or more DMRs, and optionally using a co-located other region.

By way of graphical description, a schematic representation of the general arrangement of the DMRs, the other region(s) and the detectable label(s), as used for the present invention, is presented in FIG. 1. (1) The presence of methylation in DNA at two or more DMRs, DMR1 and DMR2 (and, optionally, up to DMRn), is in each case detected using the same detectable label(s). (2) Optionally, an other region (“OR”) is located within the same portion of the genome (eg, between about 20 bp and about 20 kb upstream or downstream of) one of the DMRs. (3) The amount of total DNA detected using at least one OR (OR1, and optionally, OR2 or up to ORn) is detected using different detectable label(s) to those used to detect methylation at the DMRs (optionally, the detectable label(s) used is the same for all the ORs). (4) Optionally, methylation at more than two DMRs is so detected, and/or the amount of total DNA is detected at more than one OR.

In certain embodiments, prior to or as part of the detection that occurs as part of a step (b) and/or a step (c) of any method of present invention, each DNA region comprising said DMRs and/or said other region(s), respectively, is(are) amplified. Amplification of DNA may be conducted using any suitable replication process, and in particular of such embodiments, each of the DMRs and/or an other region, is amplified by a polymerase chain reaction (PCR) using primers suitable designed for each DMR and/or other region. The person of ordinary skill will readily be able to design such PCR primers for use in the method of the invention, for example by use of primer design algorithms and programs such as Clone Manager Professional 9 (Sci-Ed Software), Vector NTI (Life Technologies), or web-based tools such as those found from www.ncbi.nlm.nih.gov/tools/primer-blast/ or molbiol-tools.ca/PCR.htm. Those embodiments of the present invention that comprise PCR amplification can further comprises specific steps that are related to the practice of PCR, such as any of those described herein, or in particular the steps of: (A) providing a reaction mixture comprising a double-stranded target DNA, a pair of primers (for example, a pair of primers disclosed herein) designed to amplify a region of such DNA (such as a DMR or an other region as described herein) wherein the first primer is complementary to a sequence on the first strand of the target DNA and the second primer is complementary to a sequence on the second strand of the target DNA, Taq polymerase, and a plurality of free nucleotides comprising adenine, thymine, cytosine and guanine; (B) heating the reaction mixture to a first predetermined temperature for a first predetermined time to separate the strands of the target DNA from each other; (C) cooling the reaction mixture to a second predetermined temperature for a second predetermined time under conditions to allow the first and second primers to hybridise with their complementary sequences on the first and second strands of the target DNA, and to allow the Taq polymerase to extend the primers; and (D) repeating steps (B) and (C) at least 20 times.

In other embodiments, a detectable label used in step (b) and/or step (c) of a method of the invention is independently selected from the group consisting of: fluorescent, protein, small molecule or radioactive label. For example, fluorescent labels that are the same (including, by having similar or overlapping excitation and/or emission spectra) may be used for the DMRs, and a fluorescent label that has an excitation and/or emission spectra (in particular, a different emission spectrum) may be used for detection of the other region(s). The person of ordinary skill will be able to select appropriate such fluorescent label(s) for use in the present invention from, for example, the group consisting of: FAM, TET, JOE, VIC, HEX, NED, PET, ROX, TAMRA, Quasar and Texas Red. In other embodiments, a detectable label may be a protein or small molecule tag that, for example, can be detected using a specific antibody and ELISA-type detection approaches. The use of the same protein or small molecule for each of the DMRs, and a detectably different protein or small molecule for the other region(s), may also be utilised for the detectable label(s) used in the present invention. Different radioactive labels may be distinguished by their emission energy, penetration/excitation characteristics and particle-type (for example, by distinguishing between alpha and beta particles). Other detectable labels (such as nucleic-acid coded tag) may also be employed in the present invention.

In particular embodiments, the detection in step (b) of a method of the example comprises real-time quantitative probe-based PCR, eg by using at least two labelled probes, each of which is specific for one of said DMRs. PCR amplification of said two or more DMRs in the same reaction can be considered as “multiplex” (or “duplex” if only two DMRs are so amplified). Likewise, the detection in step (c) in the methods of the invention may, in addition or alternatively, comprise real-time quantitative probe-based PCR, such as by using at least one labelled probe specific for one of said other region(s).

The term “probe-based” quantitative PCR is art recognised, and encompasses various embodiments described and marketed under different brand names (such as “TaqMan” PCR of Roche), and uses a (eg fluorescent) reporter probe that is specific for the detection of a given amplicon (eg a DMR or an other region). Probe-based quantitative PCR is distinct from quantitative PCR using double-stranded DNA-binding dues (eg SYBR Green) as reporters, as such double-stranded DNA-binding dyes bind non-specially to any double-stranded amplicon and eg cannot be used to distinguish between detection of the DMRs (ie said species of DNA) from detection of the other region(s) (ie detection of total DNA). As the person of ordinary skill will appreciate, a specific amplicon of PCR may be detected using a single probe or by using multiple probes (such as two or three probes) for an amplicon.

Such probe-based quantitative PCR may be conducted in an analogue-approach, using a machine such as a LightCycler in which the intensity of signal (eg over time) is measured and used to quantitatively determine detection. Alternatively, digital PCR (dPCR), ie, PCR conducted in multiple events so as to determine the number of amplification events as method to quantitate an amount of detected DNA. For example, dPCR that is conducted in nano-wells or droplets (ddPCR).

The person of ordinary skill will be able to design suitable primers and probes (and with suitable labels, eg dyes) for probe-based quantitative PCR detection of the DMRs and/or other regions(s); for example by using primer/probe design software as described elsewhere herein. As will be known, the PCR primers may overlap methylation site(s) specific for the methylation-specific modifying reagent used in the methods, in particular when the reagent comprises one or more methylation sensitive restriction enzyme, such as one (or a combination thereof) as disclosed herein. In particular such embodiments, one or other (or when considered together, both) of the PCR primers for a given DMR may overlap two or three such methylation sites (such as two or three restriction sites for methylation-sensitive restriction enzymes, each of which may comprise, or comprises, a methylation site). Alternatively or in addition, the primers for a DMR may be designed to flank one, two, three or more such methylation sites, such as up to 10, 15, 20, 25 or 50 such methylation sites, in particular flanking restriction sites for one, two, three or more such methylation sites, such as up to 10, 15, 20, 25 or 50 methylation-sensitive restriction enzymes, each of which may comprise, or comprises, a methylation site.

In a particular embodiment, the genomic location of the other region used in the present invention is generally located in the same portion of the genome, such as between about 20 bp and about 20 kb upstream or downstream of (including embodiments within the same gene as) the genomic location of at least one of the DMRs used herein. In certain embodiments, the other region does not overlap with the DMR. The inventors find that detection (and particularly quantification) of the species of DNA is enhanced (eg, in terms of sensitivity, accuracy and/or precision) if the other region is so located in the same portion of the genome as one of the DMRs. Without being bound by theory, it is believed that with such similarly located DMR(s) and other region, the effect of variation in chromatin/nucleosome packing across the genome—and hence stability/degradation of different regions of genomic DNA—is mitigated, such that any difference in stability/degradation of a DMR (ie detecting the species of DNA) as compared to the other region (is detecting total DNA) is less, and hence a relative (and absolute) quantification may be made without it being (significantly) confounded by quantitative differences brought about by (significantly) differential chromatin/nucleosome packing across the genome between a DMR and an other region. The combination of this feature (similarly-located DMR(s) and other region) with another feature of the present invention (the use of at least two DMRs, and the detection in step (b) and the detection in step (c) are made using the same aliquot of DNA of the sample, and in the same reaction/detection vessel, and effectively simultaneously for such DMRs and other region, and using: (x) the same detectable labels(s) for each of said DMRs; and (y) a different detectable label for said other region(s)), is a preferred embodiment of the present invention. The use of such a combination of features in the present invention provides opportunity for efficiency improvements and/or synergistic enchantment of outcome. For example, an improved sensitivity and/or accuracy and/or precision of detection (eg, detection of a quantitative amount) of said species of DNA can be obtained by the use of such a combination; the degree of improvement of which can be synergistic, as compared to the use of each feature alone; eg the enhancement obtained by use of the combined features being greater than the sum of each enhancement obtained by the use of each feature individually.

The present invention includes the use of one other region to provide for the detection of an amount of total DNA in the admixture. However, the present invention also encompasses embodiments that use more than one other region. For example, the invention includes such embodiments wherein said detection in step (c) comprises using at least two of said other regions, such as two, three or four of said other regions. In particular embodiments of all aspects of the present invention, the number of said other regions is the same as the number of DMRs used in step (b). For example, if two DMRs are used then two other regions are used in such an embodiment, and if three DMRs are used then three other regions are used (such as depicted in FIG. 1).

As described elsewhere herein, certain embodiments of the present invention include where the other region is generally located in the same portion of the genome, such as between about 20 bp and about 20 kb upstream or downstream of (including embodiments within the same gene as) the genomic location of at least one of the DMRs used herein. In certain embodiments, the other region does not overlap with the DMR. Accordingly, if multiple other regions are used in the present invention, then embodiments are included where two or more of such other regions are similarly located in the genome to the two or more DMRs. For example, one of said other regions may be located between about 20 bp and about 20 kb upstream or downstream of (including embodiments within the same gene as) a DMR used in step (b) and each other of the said other regions (eg, a second other region) is located between about 2 bp and about 20 kb upstream or downstream of (including embodiments within the same gene as) another of said (eg, non-overlapping) DMRs (eg, the second DMR). In certain embodiments an additional other region, may overlap with a DMR.

An other region used in the present invention, when generally located in the same portion of the genome as a DMR, may be located upstream or downstream of one of said DMRs within a distance selected from the group consisting of: between about 16 kb to 20 bp, 14 kb to 20 bp, 12 kb to 20 bp, 10 kb to 20 bp, 8 kb to 20 bp, 6 kb to 20 bp, 5 kb to 20 bp, 4 kb to 20 bp, 3 kb to 2 bp, 16 kb to 20 bp, 1 kb to 20 bp, 500 bp to 20 bp, 200 bp to 20 bp, 20 kb to 15 kb, 15 kb to 10 kb, 12 kb to 8 kb, 10 kb to 8 kb, 11 kb to 7 kb, 11 kb to 10 kb, 9 kb to 8 kb, 8 kb to 6 kb, 6 kb to 4 kb, 4 kb to 2 kb, 2 kb to 500 bp, 1 kb to 100 bp, 500 bp to 50 bp, 400 bp to 200 bp and 500 bp to 100 bp. In particular embodiments, each other region used in the present invention is so generally located to a different of the DMRs used.

If multiple other regions are used, then the present invention includes embodiments where the detection in step (c) is made using the same detectable label for each of said other regions and/or comprises multiplex real-time quantitative PCR using at least two labelled probes each of which is specific for one of said other regions.

In particular embodiments, all detection steps (ie, those required for all DMRs and all other regions) are conducted in an efficient and effective manner using multiplex quantitative probe-based (eg TaqMan) PCR, in one process step or reaction. For example, the detection in step (c) and said detection in step (b) are made using the same aliquot of DNA of said sample, and in the same reaction/detection vessel, and effectively simultaneously with each other, and by multiplex real-time quantitative PCR using at least one labelled probe specific for each of the said DMRs and other region(s). In particular of such embodiments, the reagent comprises one or more methylation sensitive restriction enzyme, such as one (or a combination thereof) as disclosed herein.

The present invention may also include further procedures, such as one or more control procedures. For example, the present invention can include one or more steps directed to the detection of a third class of DNA region that acts as a control for the modification step (eg, as a control for restriction enzyme digestion). Such embodiments may, for example, also be conducted using multiplex real-time quantitative probe-based PCR wherein such control region is amplified and detected by a third set of primer/probe(s) with a third detectable label used for such class of region.

In one embodiment of the present invention of particular relevance, said species of DNA originates from cells of a foetus and/or the placenta of a foetus and said sample is from a pregnant female. In such embodiments, the sample may be obtained in a non-invasive manner. For example, said species of DNA is circulating cell-free DNA that has been detected from the sample being blood or a blood fraction (such as plasma or serum) that has been obtained from the pregnant female by conventional means such as a blood collection tube.

The present invention includes embodiments where the DMRs are hypermethylated in foetal DNA and hypo methylated in maternal DNA. In certain embodiments, such a DMR may be located in a promoter, enhancer region or an exon or a gene, such as a gene disclosed herein. Alternatively, a DMR may be located in an intron of such a gene, or in a non-coding region of the genome. In particular embodiments of all aspects of the present invention, such genome and/or gene is a human genome or gene. Specifically included in the present invention are embodiments wherein said DMRs comprises at least one, preferably at least two, methylation site(s) specific for said reagent, and at least one of said DMRs is located in a portion of the genome and/or gene (eg a human genome or gene) that is RASSF1A and/or TBX3, or selected from the group consisting of: RASSF1A, TBX3, HLCS, ZFY, CDC42EP1, MGC15523, SOX14 and SPN. Also, embodiments are included wherein said DMRs comprises at least one, preferably at least two, methylation site(s) specific for said reagent, and at least one of said DMRs is located in a region and/or gene selected from the group consisting of: AIRE, SIM2, ERG, VAPA-APCDDI, one disclosed in WO 2011/034631 as being hypermethylated in foetal DNA relative to maternal DNA (eg, SEQ ID NOs: 1-59, 90-163; i.e., SEQ ID NOS: 15-147 of the present application, 176, 179, 180, 184, 188, 189, 190, 191, 193, 195, 198, 199, 200, 201, 202, 203, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 221, 223, 225, 226, 231, 232, 233, 235, 239, 241, 257, 258, 259, and/or 261 of WO 2011/034631, i.e., SEQ ID NOS: 148-187 of the present application) and one disclosed in WO 2011/092592 (eg, EP1, EP2, EP3, EP4, EP5, EP6, EP7, EP8, EP9, EP10, EP11 and/or EP12 of WO 2011/092592 (i.e., SEQ ID NOS: 188-199 of the present application), as further investigated in Lim et al 2014, BMC Medical Genomics (7:1).

In particular embodiments of all aspects of the present invention, the two DMRs used are not located in the same portion of the genomic and/or gene. For example, such DMRs may be located on separate chromosomes, or separated by more than about 20 kb, or more than about 15 kb, 10 kb, 8 kb, 6 kb, 4 kb, 2 kb, 1 kb, 500 bp or 200 bp. Alternatively, it is envisioned, that the two (or more) DMRs used in the present invention may, in certain embodiments, be located in the same region or gene (such as one described herein) and, further, may overlap with each other.

In particular embodiments of the present invention, both of said DMRs are (or each, in the case of more than two DMRs are being used, is) located in a portion of the genome and/or gene (preferably that is human) that is RASSF1A and/or TBX3, or is selected from the group consisting of: RASSF1A, TBX3, HLCS, ZFY, CDC42EP1, MGC15523, SOX14 and SPN; and/or at least one of said DMRs is located between about positions 4,700 bp and 5,600 bp of RASSF1A (NCBI Reference Sequence: NG_023270.1: Homo sapiens Ras association (RAlGDS/AF-6) domain family member 1 (RASSF1), RefSeqGene on chromosome 3; SEQ ID NO.: 13) or about positions 1,660 bp and 2,400 bp of TBX3 (NCBI Reference Sequence: NG_008315.1: Homo sapiens T-box 3 (TBX3), RefSeqGene on chromosome 12; SEQ ID NO.: 14). In a more particular embodiment, two (or more) DMRs are used, and a first DMR comprises one located between about positions 4,700 bp and 5,600 bp of RASSF1A and a second DMR comprises one located between about positions 1,660 bp and 2,400 bp of TBX3.

In particular embodiments, a DMR is located in RASSF1A between about positions 4,900 bp and 5,500 bp, 5,000 bp and 5,400 bp, or 5,100 bp and 5,300 bp of RASSF1A; and/or is located in TBX3 between about positions 1,800 bp and 2,260 bp, 1,920 bp and 2,160 bp or 1,920 bp and 2,080 bp of TBX3.

The general arrangement of the DMRs and other regions (“OR”) used in one embodiment of the present invention, is graphically represented by FIG. 2: (1a) DMR1 is found in exon 2 of RASSF1A and OR1 is located within exon 4 of RASSF1A, with DMR1 located between positions 50,340,672 bp and 50,340,784 bp and OR1 located between positions 50,331,604 bp and 50,331,702 bp of the RASS1A genomic sequence (NCBI Reference Sequence: NC_000003.12 Homo sapiens chromosome 3, GRCh38 Primary Assembly), separating DMR1 and OR1 by a distance of 8,969 bp. (1b) DMR2 is found in the promoter region of TBX3, with DMR2 located between positions 114,687,095 bp and 114,687,189 bp and OR2 is located between positions 114,676,384 bp and 114,676,454 bp of the TBX3 genomic sequence (NCBI Reference Sequence: NC_000012.12 Homo sapiens chromosome 12, GRCh38 Primary Assembly), separating DMR2 and OR2 by a distance of 10,640 bp. (2) Methylation in DNA at the two DMRs is detected using probe-based quantitative PCR using the respective forward (F) and reverse (R) PCR primers and region-specific probes, each probe labelled with the same labels (P*). (3) Total DNA is detected at two ORs using probe-based quantitative PCR using the respective forward (F) and reverse (R) PCR primers and region-specific probes, each probe labelled with the same labels for the ORs that is different to the labels used for the two DMRs (P**). Details of primer and probe sequences and probe labels are set out in TABLE 1.

The term “methylation site(s)” will be art-recognised, and has a meaning that encompasses, for example, a CpG motif within a short nucleotide sequence (eg one that is 4, 6, 8, 10 or 12 bp in length) that is, preferably, recognised by a methylation-sensitive restriction enzyme, such as one disclosed elsewhere herein.

Analogously, the other region may be located in particular portions and/or genes of the genome, and may be located in a promoter, enhancer region or an exon of a gene, or alternatively, located in an intron of such a gene, or in a non-coding region of the genome. In particular embodiments of all aspects of the present invention, such genome and/or gene is a human genome or gene. In particular embodiments, an other region used in the present invention is located in a (eg human) housekeeping gene (such as GAPDH, beta-actin, ALB, APOE or RNASEP). Alternatively (and in particular when said species of DNA is foetal cfDNA), said other region may be located in the same portion of the genome and/or gene that feature one or more DMRs (such as those RASSF1A, TBX3, HLCS, ZFY, CDC42EP1, MGC15523, SOX14 or SPN), and preferably does not overlap with a DMR used in the invention. In particular embodiments, said other region comprises a portion of the genome without a methylation site specific for said reagent, and said other region is located in the (eg human) genes RASSF1A or TBX3 (eg SEQ ID NOs.: 13 and 14 respectively), and includes more particular embodiments wherein two or more of said other regions are used in detection step (c) and the first other region is located between about positions 14,220 bp and 13,350 bp of such RASSF1A and the second other region is located between about positions 12,400 bp and 13,000 bp of such TBX3. In particular embodiments, an other region is located in RASSF1A between about positions 14,230 bp and 14,340 bp, 14,230 bp and 14,330 bp, 14,230 bp and 14,320 bp, or 14,230 bp and 14,310 bp of such RASSF1A; and/or is located in TBX3 between about positions 12,400 bp and 12,940 bp, 12,700 bp and 12,850 bp or 12,710 bp and 12,790 bp of such TBX3. Alternatively, an other region may be located in an exon such as between about positions 13,790 bp and 13,880 bp, or 14,490 bp and 14,600 bp of such RASSF1A, or between about positions 8,040 bp and 8,180 bp or 6,230 bp and 6,350 bp of such TBX3; or an other region may be located in an intron such as between about positions 10,500 bp and 11,90 bp of such RASSF1A, or between about positions 10,000 bp and 11,000 bp of such TBX3

There is now strong evidence that the level of foetal cfDNA (and/or total cfDNA) present in the circulatory system (eg in plasma) of a pregnant female is a marker of one or more forms of preeclampsia, such as early-onset preeclampsia, mild and/or severe preeclampsia (see Hahn et al 2011, Placenta 32(Supl):S17). The present invention shows particular utility in the efficient, effective, sensitive and/or low-variability detection/quantification of foetal cfDNA present in plasma of pregnant females, and the present invention has particular utility therein. Accordingly, in particular embodiments of the present invention, the individual is a pregnant female and is susceptible to suffering or developing a pregnancy-associated medical condition; particularly where said pregnancy-associated medical condition is preeclampsia. As used herein, an individual “susceptible to” a medical condition may alternatively be described as “is suspected to” or to “be considered at risk of being susceptible to” suffering or developing a medical condition; and in certain embodiments, the present invention is used to screen and/or diagnose the individual for susceptibility to, risk of suffering or developing, or suffering from or developing, a medical condition.

In alternative embodiments, the individual is a pregnant female and is susceptible to (or considered at risk of being susceptible to) suffering or developing a pregnancy-associated medical condition selected from the group consisting of: preterm labour, intrauterine growth retardation and vanishing twin. In particular, the inventors were surprised that the sensitivity of the present invention was such that discrepancies between cfDNA levels determined by the method of the invention and that determined by counts of Y-chromosome sequences as determined by massively parallel sequencing approaches, was useful in identifying one or more cases of a vanishing twin in (mixed-sex) twin pregnancies that previously were believed to be singleton pregnancies, and/or to follow the relative development and health of one or other of such (mixed-sex) twin pregnancies. The present invention may also be utilised in gender determination of twin pregnancies, by consideration of the relative values for foetal cfDNA compared to counts of Y-chromosome sequences determined from cfDNA (eg by using parallel sequencing approaches). In these regards, it should be noted that approaches that use massively-parallel sequencing of random cfDNA in maternal blood typically always count a very low frequency of “Y-chromosome” sequences (such as between about 0.003% and 0.004% of all sequences, or between about 0.0015% and 0.01% or 0.002% and 0.005% of all sequences) in all female pregnancies due to homology of certain Y-chromosome short sequences to other chromosomes. A cut off of “Y-chromosome” sequence counts of about 0.005%, or between about 0.003%, 0.04%, 0.006% or 0.007%, may therefore be employed for female samples.

As described elsewhere herein, there is also increasing evidence that the presence and amount of methylated DNA at certain DMRs is indicative or prognostic of certain medical conditions that are not associated with pregnancy. Accordingly, in another particular embodiment of the present invention, said species of DNA originates from a cell type associated with such a medical condition, particularly in those embodiments where said species of DNA is circulating cell-free DNA and said sample is a blood fraction such as plasma or serum. For example, the medical condition may be a cell proliferative disorder, such as a tumour or cancer. In particular embodiments, the medical condition is a tumour or a cancer of an organ selected from the list consisting of: liver, lung, breast, colon, oesophagus, prostate, ovary, cervix, uterus, testis, brain, bone marrow and blood; and/or said species of DNA may originate from cells of a tumour; particularly where such tumour is a carcinoma or cancer of an organ selected from the group consisting of: liver, lung, breast, colon, oesophagus, prostate, ovary, cervix, uterus, testis, brain, bone marrow and blood.

When used in the context of a medical condition being a tumour or cancer, the present invention includes embodiment wherein said DMRs comprises at least one, preferably at least two, methylation site(s) specific for said reagent, and at least one of said DMR is located in a portion of the genome and/or a gene (in particular, when such genome and/or gene is a human genome or gene) selected from the group consisting of: a tumour suppressor gene, p16, SEPT9, RASSF1A, GSTP1, DAPK, ESR1, APC, HSD17B4 and H1C1. In particular, one of said two or more DMRs may be located in RASSF1A (eg SEQ ID NO. 13) such as located between about positions 4,700 bp and 5,600 bp of such RASSF1A; and/or said other region is located between about positions 14,220 bp and 13,350 bp of such RASSF1A. Other particular locations of the DMRs and/or other region(s) with RASSF1A for use in this embodiment are disclosed elsewhere herein. Furthermore, the person of ordinary skill will now recognise that other DMRs and/or other regions located in other portions of the genome of in other genes may be identified from the relevant scientific literature (eg, for review, see Elshimali 2013). In particular when used in the context of a medical condition being a tumour or cancer, the present invention includes embodiments where at least one other region (preferably two or more) are located in a (eg human) housekeeping gene (such as GAPDH, beta-actin, ALB, APOE or RNASEP). Alternatively for such context, said other region(s) may be located in the same portion of the genome and/or gene that feature one or more DMRs (such as those p16, SEPT9, RASSF1A, GSTP1, DAPK, ESR1, APC, HSD17B4 and H1C1).

In yet another particular embodiment of the present invention, said species of DNA originates from a cell type associated with a medical condition selected from the group consisting of: an infection/infectious disease, a wasting disorder, a degenerative disorder, an (auto)immune disorder, kidney disease, liver disease, inflammatory disease, acute toxicity, chronic toxicity, myocardial infarction, and a combination of any of the forgoing (such as sepsis) and/or with a cell proliferative disorder, particularly in those embodiments where said species of DNA is circulating cell-free DNA and said sample is a blood fraction such as plasma or serum. For example, the medical condition may be an infection/infectious disease, such as one caused by a bacterial, viral or protozoan pathogen, including a pathogen selected from the group consisting of: a retrovirus (such as HIV), a herpes virus (such as HSV, EBV, CMV, HHV or VSV), dengue virus, mycobacteria (eg Mycobacterium tuberculosis), and hantavirus. In certain embodiments, the medical condition is sepsis and/or excludes kidney disease.

In all aspects of the present invention, there exist embodiments wherein the sample is a tissue sample or a sample of biological fluid. In particular, the sample is whole blood or a blood fraction (eg, such as plasma or serum). In alternative embodiments, the sample is biological fluid selected from the group consisting of: urine, saliva, sweat, ejaculate, tears, phlegm, vaginal secretion, vaginal wash and colonic wash. In more particular embodiments, the sample is a plasma or serum sample from the individual, or is urine from the individual In other embodiments, the sample is largely (or essentially) free from cells, and/or is not a whole blood and/or ejaculate sample. In certain embodiments, the sample is not ejaculate if the individual is female and the sample is not a vaginal wash if the individual is male.

In all aspects of the present invention, the reagent that differently modifies methylated and non-methylated DNA may comprise bisulphite and/or an agent that selectively digests unmethylated over methylated DNA (for example, such agent may digest unmethylated DNA but not methylated DNA). In particular embodiments, the reagent agent comprises: at least one methylation sensitive enzyme; at least one methylation sensitive restriction enzyme; and/or an agent selected from the group consisting of: AatII, AciI, AClI, AfeI, AgeI, AgeI-HF, AscI, AsiSI, AvaI, BceAI, BmgBI, BsaAI, BsaHI, BsiEI, BsiWI, BsmBI, BspDI, BsrFI, BssHII, BstBI, BstUI, ClaI, EagI, FauI, FseI, FspI, HaeII, HgaI, HhaI, HinP1I, HpaII, Hpy99I, HpyCH4IV, KasI, MluI, NaeI, NarI, NgoMIV, NotI, NotI-HF, NruI, Nt.BsmAI, Nt.CviPII, PaeR7I, PluTI, PmlI, PvuI, PvuI-HF, RsrII, SacII, SalI, SalI-HF, SfoI, SgrAI, SmaI, SnaBI, TspMI and ZraI. In particular embodiments, said reagent is one selected from the group consisting of: BstUI, HhaI and HpaII.

In related embodiments, the reagent may comprise two or more of any of the reagents disclosed herein. For example, it may comprise two, three, four, five or more (eg up to seven, eight or ten) methylation sensitive restriction enzymes, including a reagent comprising or essentially consisting of two or three of the methylation sensitive restriction enzymes selected from the group consisting of: BstUI, HhaI and HpaII

The use of bisulphite or methylation-sensitive restriction enzymes to study differential methylation will be well known to the person of ordinary skill, who may apply teachings of standard texts or adaptation of published methods such as Poon et al (2002), Nygren et al (2010) or Yegnasubramanian; et al (2006, Nuc Acid Res 34:319). By way of illustration, the inventors provide examples herein that employ the use of methylation-sensitive restriction enzymes as the reagent that differentially modifies methylated and non-methylated DNA. For further illustration using bisulphite as reagent, it will be apparent to the person of ordinary skill that bisulphite-modified DNA methylation sites may be detected using eg methylation-specific PCR (such as using primers and/or probes that selectively bind to the bisulphite-modified sequences) and/or by the subsequent use of restriction enzymes the recognition site of which is created upon such bisulphite-modification.

In particular embodiments of all aspects of the invention, a quantitative amount of said species of DNA (and/or or said total DNA) is to be detected and/or determined. Accordingly in such embodiments, one or more (eg each) of said detection steps comprises quantitative detection and said detected amount of said species of DNA is expressed as a relative concentration of said species of DNA to the total DNA present in said sample.

If an absolute amount of total DNA is known, then correspondingly an absolute amount (for example, as represented by a concentration such as ug/mL or genome-equivalents such as Eg/mL) of the species of DNA can be determined from such relative concentration. An absolute amount of total DNA for a sample may be determined, for certain embodiments, by including the further steps of: detecting an amount of total DNA in a standard sample of DNA of known amount using the same other region(s) as used in step (c); and comparing the signal detected from said standard sample of DNA to the signal detected in step (c). Such a standard sample of DNA (of known amount/concentration) is readily available from commercial sources, and especially if prepared and analysed using a dilution series, can readily and efficiently be used to determine (by interpolation/estimation from the standard curve) an absolute amount of total DNA present in the sample. Practically, such standard curve may be prepared and analysed essentially as described for the other regions (but in a separate set of standard vessels/reactions), preferably in the same run as the detection of the DMRs/other region(s); and may even use the same reaction master-mix. Accordingly, while the “DMRs” of the DNA control may be detected for such standard DNA, such a signal is not required to generate a standard curve. Accordingly, if the signal from a such a standard DNA sample is used to compare, the in certain embodiments where each of said detection steps comprises quantitative detection, said detected amount of said species of DNA can be expressed as an absolute amount of said species of DNA in said sample.

A determined quantitative amount of said species of DNA has utility in assessing the risk of the individual to certain medial conditions and/or if there is sufficient of such species of DNA in the sample to enable further analysis of such species of DNA to be conducted efficiently, accurately and/or in a cost effective manner.

Accordingly, certain embodiments of the present invention further include the step of: comparing the amount of said species of DNA detected with a threshold amount and/or reference distribution of amounts, wherein an increase in the (or outlying) amount of said species of DNA indicates an increased risk of the individual suffering from or developing a medical condition. Threshold amounts and/or a set of amounts to form a reference distribution may be obtained from published literature and or empirical studies. For example, using published threshold values (Papantoniou et al 2013, Prenat Diag 33:682) if the total cfDNA exceeds an amount of about 7,500 Eg/mL plasma or if the foetal cfDNA fraction exceeds an amount of about 500 Eg/mL plasma, then the woman may be determined to have such an increased risk. Such a risk may instead or additional by assessed by considering: (i) the fold-increase (eg 1.5, 3, 3.5 or 4-fold increase) of foetal cfDNA (determined for such woman compared to a threshold amount), factoring into the determination that for later-term pregnancies a higher fold-increase in foetal cfDNA may be utilized (Zeybek et al 2013, J Obstet Gynaecol Res 39:632); and/or (ii) into which percentile the amount of cfDNA determined from the woman falls, from consideration of a reference distribution of amounts such as those determined from low-risk women or those which did not suffer from or develop preeclampsia, for example if the foetal cfDNA fraction falls within the 90th percentile of such a distribution, then the woman may be considered to have an increased risk of suffering mild or severe preeclampsia (Jakobsen et al 2013, Transfusion 53:1956). Other relevant factors may be considered in determining a suitable threshold amount. For example, a pregnant women who is also suffering from breast cancer, may have a higher bias of methylation of RASSF1A present in her plasma due to both factors.

Analogously, certain embodiments of the present invention further include the step of: comparing the amount of said species of DNA detected with a threshold amount and/or reference distribution of amounts, wherein an amount of said species of DNA in excess to said threshold (or is not an outlier compared to said population) indicates that a diagnosis for an abnormality in the said species of DNA present in said sample may be performed on, preferably a separate aliquot of DNA of, said sample. For example, if foetal cfDNA fraction is greater than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or 0.5% of total cfDNA present in maternal plasma, then there would be sufficient fraction or foetal cfDNA to effectively conduct a subsequent test to investigate one or more characteristics of the foetal cfDNA, for example to investigate the chance of existence of a chromosomal anomaly of mutation comprised within such foetal cfDNA (such as using NIPT based on massively parallel sequencing). In the case of twin pregnancies, the inventors determine that a minimum foetal fraction of cfDNA for NIPT of a twin pregnancy could be considered to be 8%, or about 5%, 6%, 7%, 9% or 10%, and for monochorionic twin pregnancies with concordant genotypes (apart from rare exceptions, Chen et al, 2013, Am J Med Genet A, 161A:1817), a foetal cfDNA fraction of 4%, or about 2%, 3% or 5%, would be sufficient.

Therefore, the present invention also includes embodiments where comprising a further step of: performing on, preferably with a separate aliquot of DNA of, said sample an in-vitro diagnosis for an abnormality in said species of DNA present in said sample; preferably wherein, said species of DNA originates from cells of a foetus and/or the placenta of a foetus, said sample is from a pregnant female and said diagnosis is a prenatal diagnosis. Such diagnosis directed at said species of DNA present may comprise a step that uses a detection technology selected from the group consisting of: DNA sequencing, SNP analysis, digital PCR and hybridization, and in particular embodiments said detection technology is massively parallel sequencing of DNA, such as massively parallel sequencing of random and/or (exon) enriched DNA.

Such a diagnosis or test may be directed at the foetal DNA to identify a genetic mutation or chromosomal abnormality of the foetal DNA. Accordingly in certain embodiments, said species of DNA originates from cells of a foetus and/or the placenta of a foetus, said sample is from a pregnant female and said abnormality is a genetic mutation or a chromosomal abnormality, such as a chromosomal trisomy, associated with a foetal abnormality and/or a congenital disorder. In particular such embodiments, the genetic mutation is selected from the group consisting of: colour blindness, cystic fibrosis, hemochromatosis, haemophilia, phenylketonuria, polycystic kidney disease, sickle-cell and disease, Tay-Sachs disease; and/or the chromosomal abnormality is selected from the group consisting of: a trisomy (such as trisomy 21, trisomy 18, or trisomy 13), a sex-chromosome abnormality (such as Turners syndrome, Klinefelter syndrome, Noonan syndrome, Tripe X syndrome, XXY syndrome, or Fragile X syndrome), a chromosomal deletion (such as Prader-Willi syndrome, Cris-du-chat syndrome, Wolf-Hirschhorn syndrome, or 22q11 deletion syndrome, Duchene muscular dystrophy), Beckwith-Wiedemann syndrome, Canvan syndrome, and neurofibromatosis. In other embodiments, the genetic mutation or chromosomal abnormality may be one or more selected from those having a clinical utility gene cards (CUGCs) of the EuroGentest2 initiative (www.eurogentest.org). In particular embodiments, the chromosomal abnormality is a trisomy (such as trisomy 21, trisomy 18, or trisomy 13), a sex-chromosome abnormality or a chromosomal deletion.

Such diagnosis or test may be directed at a species DNA to identify a genetic mutation or chromosomal abnormality of such DNA that is derived from a cell or cell-type associated with a medical condition. Accordingly in one of such embodiments, said species of DNA originates from cells of a tumour and said abnormality is a genetic mutation or a chromosomal abnormality associated with the diagnosis, prognosis or predictive treatment of a carcinoma or cancer. In particular such embodiments, the genetic mutation is selected from the group consisting of: a mutation in a tumour suppressor gene (such as TP53 (p53), BRCA1, BRCA2, APC or RB1), a mutation in a proto-oncogene (such as RAS, WNT, MYC, ERK, or TRK) and a DNA repair gene (such as HMGA1, HMGA2, MGMT or PMS2); and/or the chromosomal abnormality is a translocation (such as t(9;22)(q34;q11) [ie, Philadelphia chromosome or BCL-ABL], t(8;14)(q24;q32), t(11;14)(q13;q32), t(14;18)(q32;q21), t(10;(various))(q11;(various)), t(2;3)(q13;p25), t(8;21)(q22;q22), t(15;17)(q22;q21), t(12;15)(p13;q25), t(9;12)(p24;p13), t(12;21)(p12;q22), t(11;18)(q21;q21), t(2;5)(p23;q35), t(11;22)(q24;q11.2-12), t(17;22), t(1;12)(q21;p13), t(X;18)(p11.2;q11.2), t(1;19)(q10;p10), t(7,16)(q32-34;p11), t(11,16)(p11;p11), t(8,22)(q24;q11) or t(2;8)(p11;q24)).

A related aspect of the present invention relates to an alternative method for detecting in a sample from an individual an amount of a species of DNA originating from cells of a given type, which sample comprises said species of DNA in admixture with differentially methylated DNA not originating from cells of said type; said method comprising the steps:

  • (a) treating the DNA present in said sample with a reagent that differentially modifies methylated and non-methylated DNA; and
  • (b) detecting in said sample the presence of methylation in said species of DNA at two or more DMRs that are differently methylated between said species of DNA and the DNA not originating from cells of said type the modification of DNA of such DMRs by said reagent is sensitive to methylation of DNA, wherein the presence of methylated DNA at one or more of said DMRs indicates the presence of said amount of species of DNA in said sample and the absence of methylated DNA at said DMRs indicates the absence of said species of DNA in said sample,

    wherein, said detection in step (b) is made using the same aliquot of DNA of said sample, and in the same reaction/detection vessel, and effectively simultaneously for such DMRs, and using (x) multiplex real-time quantitative PCR; and (y) at least two labelled probes each of which specific for one of said DMRs and that are labelled with the same detectable label(s) for each of said DMRs. Such an alternative method of the present invention is not intended to be practiced on the human or animal body; for example it is intended to be practiced in an in-vitro manner. Further characterisation of any of the features of this alternative method of the present invention (or any combination of such features) can include the characterisations (and their combinations) as described elsewhere herein in respect of the first aspect of the invention. In particular embodiments of this alternative method of the present invention, the reagent comprises one or more methylation sensitive restriction enzyme, such as one (or a combination thereof) as disclosed herein.

In a second aspect, the invention relates to a method for detecting an increased risk of an individual suffering from or developing a medical condition, said method comprising the steps:

  • (i) conducting a method of the present invention that determines a quantitative amount said species of DNA (and/or total DNA) in the sample; and
  • (ii) comparing the amount of said species of DNA detected with a threshold amount and/or a reference distribution of amounts,

    wherein an increase in the (or outlying of) amount of said species of DNA (and/or total DNA) indicates an increased risk of the individual suffering from or developing said medical condition.

A third aspect of the invention relates to a composition (eg, one that is useful for, or used in, a method of the present invention), said inventive composition comprising:

    • two pairs of PCR primers, each pair for amplifying one of said two or more DMRs as set forth anywhere herein;
    • one pair of PCR primers for amplifying said other region as set forth anywhere herein;
    • two labelled probes for quantitative probe-based PCR, each of which specific for one of said DMRs, and labelled with the same detectable labels(s) for each of said probe; and
    • one labelled probe for quantitative probe-based PCR specific for said other region and labelled with different detectable label(s) to the probes used for said DMRs.

Such a composition of the present invention may further comprising:

    • a further pair of PCR primers for amplifying a second other region as set forth anywhere herein; and
    • a further labelled probe for quantitative probe-based PCR specific for said other region and labelled with detectable label(s) that is different to those used probes for said DMRs; and optionally that is the same as that used for the probe(s) specific the first other region.

A fourth aspect of the invention relates to a kit (for example a kit of separate components; such as a kit of holders or vessels, each holding a different component of the kit), such kit comprising a set of primers and probes as comprised in a composition of the present invention. A kit of the present invention may comprise additional components. For example, the kit may additionally comprise: (i) a printed manual or computer readable memory comprising instructions to use said primers and probes, including to use them to practice a method of the present invention and/or to produce or use a composition of the present invention; and/or (ii) one or more other item, component or reagent useful for the practice of a method of the present invention; and/or the production or use of the composition of the present invention, including any such item, component or reagent disclosed herein, such as a reagent that differently modifies methylated and non-methylated DNA as set forth anywhere herein.

A further aspect of the invention relates to a computer program product comprising a computer readable medium encoded with a plurality of instructions for controlling a computing system to perform and/or manage an operation for determining: (x) an increased risk of an individual suffering from or developing a medical condition and/or (y) if a diagnosis for an anomaly in a species of DNA originating from cells of a given type may be performed, in each case from a sample from an individual comprising a species of DNA originating from cells of a given type in admixture with differently methylated DNA not originating from cells of said type, the DNA in present in said sample being treated with a reagent that differentially modifies methylated and non-methylated DNA as set forth herein; said operation comprising the steps of:

    • receiving: (i) one signal representing the essentially simultaneous quantitative detection of methylation at two or more DMRs as set forth in step (b) as described anywhere herein; and (ii) one signal representing the essentially simultaneous quantitative detection of total DNA using at least one other region as set forth in step (c) as described anywhere herein;
    • determining a parameter from the signals (i) and (ii), wherein the parameter represents a quantitative amount of said species of DNA (and/or said total DNA);
    • comparing the parameter to with a threshold amount and/or reference distribution of amounts; and
    • based on such comparison, determining a classification of whether, respectively, (x) an increased risk of an individual suffering from or developing a medical condition exists; and/or (y) a diagnosis for an anomaly in a species of DNA originating from cells of a given type may be performed.

In certain embodiments, a computer program product of the present invention the operation further comprises steps of: receiving a further signal representing the quantitative detection of total DNA in a standard sample of DNA as set forth anywhere else herein; and comparing said signal with the signal representing the essentially simultaneous quantitative detection of total DNA using at least one other region, so as to determine said parameter that represents an absolute quantitative amount of said species of DNA.

In particular embodiments, the computer program product of the present invention is for an operation for determining if a diagnosis for an anomaly in said species of DNA may be performed, and said operation further comprises the step of determining from said parameter a number of random and/or enriched DNA molecules to be sequenced from, preferably from a separate aliquot of DNA of, said sample as part of said diagnosis.

One embodiment of operations performed and/or controlled by the computer program product of the invention is depicted in FIG. 5. Operation (A) receives signals (1) and (2) that represent, respectively, the methylation at the DMRs and the total DNA, and optionally signal (3) then represents an amount of total DNA from a standard sample. Operation (A) determines a parameter (4) from signals (1), (2) and optional (3) that represents a relative or absolute amount of DNA (eg from foetal vs total DNA). This parameter (4) is compared by operation (B) against a threshold amount (5) and/or a reference population of amounts (6) so as to classify (7) the risk of an individual suffering from a medical condition and/or if a diagnosis for an anomaly in either of the DNA in the sample may be performed.

It is to be understood that application of the teachings of the present invention to a specific problem or environment, and the inclusion of variations of the present invention or additional features thereto (such as further aspects and embodiments), will be within the capabilities of one having ordinary skill in the art in light of the teachings contained herein.

Unless context dictates otherwise, the descriptions and definitions of the features set out above are not limited to any particular aspect or embodiment of the invention and apply equally to all aspects and embodiments which are described.

All references, patents, and publications cited herein are hereby incorporated by reference in their entirety.

Certain aspects and embodiments of the invention will now be illustrated by way of example and with reference to the description, figures and tables set out herein. Such examples of the methods, uses and other aspects of the present invention are representative only, and should not be taken to limit the scope of the present invention to only such representative examples.

Example 1: Use of the Method of the Invention in NIPT in Multiple Pregnancies, Including in Cases of Vanishing Twins

Sample Collection, Processing and DNA Extraction:

36 blood samples from women pregnant with multiple gestations (mono-, di- and trichorionic twin and triplet pregnancies) were collected between Nov. 6, 2012 and Nov. 16, 2013, for research & development (R&D) purposes and as part of routine non-invasive prenatal testing (NIPT) laboratory procedure. One blood sample came from a woman pregnant with triplets, the remaining 35 samples came from twin pregnancies. From each pregnant woman carrying a multiple pregnancy two samples each with 7-10 ml venous blood were collected using Streck cell-free DNA blood collection tubes (Streck). The blood samples were shipped to the diagnostic laboratory with a maximum delivery time of 4 days. Other blood samples from pregnant females analysed herein were similarly collected.

Plasma preparation was performed by centrifugation (1600 g for 10 min at 4° C.) and plasma separation followed by a second centrifugation step (16000 g for 10 min at 4° C.). Extraction of total cell-free DNA (cfDNA) was performed with QIAamp Circulating Nucleic Acid Kit (Qiagen) according to the manufacturer protocol using 3.0-4.0 ml plasma with a final elution volume of 60 ul AVE-buffer (Qiagen).

DNA Quantification:

Foetal cell-free DNA (foetal cfDNA) was detected and quantified in relation to total cell-free DNA (total cfDNA) in order to determine the foetal cfDNA fraction as both a relative concentration and absolute amount using a method of the present invention. From the eluted cell-free DNA, 11 ul were digested with the CpG-methylation sensitive enzymes HhaI (0.4 U/ul), HpaII (0.3 U/ul) and BstUI (0.3 U/ul) in a 22 ul reaction using CutSmart™ Buffer (New England Biolabs). The reaction was incubated for 60 min at 37° C. and 60 min at 60° C. 10 ul from the digestion reaction was used as template DNA for quantitative probe-based PCR (reactions were conducted in duplicate), described briefly as follows.

A 25 ul PCR reaction using a 2-fold concentrated PCR master mix (QuantiFast Multiplex PCR Kit, Qiagen) was conducted. Primers that span CpG methylation sensitive restriction enzyme sites of the respective region that is differentially methylated between foetal and maternal DNA (as a DMR) were used in combination with FAM-labelled probes for such DMRs, and primers that do not span any restriction enzyme sites, an other region that is not differentially methylated between foetal and maternal DNA (as an OR) are used in combination with VIC-labelled probes for such ORs. The sequences of the primers and labelled probes used in this example are described in TABLE 1, and the thermocycler profiles used for the quantitative probe-based (TaqMan) PCR (LightCycler 480 II Instrument; Roche) are described in TABLE 2. In this example, the probes used to detect the presence of the two DMRs, are each labelled with the same detectable fluorescein amidite (FAM) fluorescent moiety, and each with the same minor binding grove (MGB) non-fluorescent quencher (NFQ) moiety, and the probes used to detect the presence of the two ORs, are each labelled with the same detectable VIC (life Technologies) fluorescent moiety, and each with the same MGBNFQ moiety.


TABLE 1
Quantitative (prose based) PCR components
SEQ
Final
ID
Stock
ul for
uM
Region
Component
Sequence (5'-3')*
No.
Conc
1x
Conc
Master-mix
N/A
2x
12.5
1x
RASSF1A
DMR1-For
ATT GAG CTG CGG GAG CTG GC
1
100 uM
0.35
1.4
DMR
DMR1-Rev
TGC CGT GTG GGG TTG CAC
2
100 uM
0.35
1.4
DMR1-Probe
[FAM]-ACC CGG CTG GAG CGT-[MGBNFQ]
3
100 uM
0.035
0.14
RASSF1A
OR1-For
GGT CAT CCA CCA CCA AGA AC
4
100 uM
0.35
1.4
Other
OR1-Rev
TGC CCA AGG ATG CTG TCA AG
5
100 uM
0.35
1.4
region
OR1-Probe
[VIC]-GGG CCT CAA TGA CTT CAC GT-[MGBNFQ]
6
100 uM
0.035
0.14
TBX3
DMR2-For
GGT GCG AAC TCC TCT TTG TC
7
100 uM
0.35
1.4
DMR
DMR2-Rev
TTA ATC ACC CAG CGC ATG GC
8
100 uM
0.35
1.4
DMR2-Probe
[FAM]-CCC TCC CGG TGG GTG ATA AA-[MGBNFQ]
9
100 uM
0.035
0.14
TBX3
OR2-For
TGT TCA CTG GAG GAC TCA TC
10
100 uM
0.35
1.4
Other
OR2-Rev
CAG TCC ATG AGG GTG TTT G
11
100 uM
0.35
1.4
region
OR2-Probe
[VIC]-GAG GTC CCA TTC TCC TTT-[MGBNFQ]
12
100 uM
0.035
0.14
General
DMSO
N/A
100%
0.025
0.625
reagents
MgCl2
N/A
 50 mM
2
1
DNA sample
N/A
10
Water
Total
25
*The dyes used for each probe are shown in “[ ]” parentheses


TABLE 2
Thermocycler profiles
Step
Temperature
Time
Cycles
Analysis mode
Pre-incubation
95° C.
5
min
1
None
Denaturation
95° C.
10
sec
45
Quantification
Annealing
60° C.
10
sec
None
Elongation
72° C.
8
sec
Single
Cooling
40° C.
None

The assay design used in this example on two marker DMRs which are described to be hypomethylated in maternal DNA and hypermethylated in foetal DNA (Nygren, et al, 2010: Clin Chem 56, 1627; Chan et al, 2006: Clin Chem 42, 2211; Chiu et al, 2007: Am J Pathol 170, 941), and two other regions (ORs) not differentially methylated between maternal and foetal DNA which are each located between about 20 bp and 20 kb of their DMR. In particular, the methylation insensitive locus located in RASSF1A is located between 8 kb and 9 kb (8.97 kb) downstream of the methylation sensitive locus located in RASSF1A, and the methylation insensitive locus located in TBX3 is located between 10 kb and 11 kp (10.64 kb) downstream of the methylation sensitive locus located in TBX3. FIG. 2 depicts the respective arrangements and detection modalities of the two DMRs and the two other regions used in this example.

Parallel probe-based quantitative PCR reactions were performed (in separate reactions within the same PCR run) using for template a serial dilution of male genomic DNA (Promega) having known concentrations as a standard. The foetal cfDNA fraction was calculated by relative quantification of signals in the FAM channel (DMR; ie detecting foetal cfDNA) versus the VIC channel (ORs; ie detecting total cfDNA), and the absolute total cfDNA amount was calculated by absolute quantification of signals in the VIC channel obtained from the sample compared to the VIC channel obtained from the dilution series of standard DNA of known concentration. Such relative and absolute quantifications were conducted using LightCycler 480 Software release 1.5.0 (Roche).

Maternal Plasma DNA Sequencing and Data Analysis to Identify Foetal Aneuploidy:

DNA sequencing libraries were prepared using NEBNext Ultra™ DNA Library Prep Kit from Illumina. Libraries were prepared according to the manufacturer protocol automated on a Hamilton STARplus robot. Library quality and quantity was measured using a Bioanalyzer instrument (Agilent) and a Qbit Fluorometer (Invitrogen). Based on the library quantification dilutions and equimolar pools of 12 samples per pool were prepared. The pooled samples were sequenced on one lane of an Illumina v3 flow cell on an Illumina HiSeq2000 sequencer. Clonal clusters were generated using TruSeq SR Cluster Kit v3-cBot-HS on a cBot Cluster generation System according to the manufacturer protocol. Bioinformatic analysis to identify foetal chromosomal aneuploidy was carried out as described previously, with z-scores≥3 indicating the presence of a foetal trisomy 21 (Stumm et al 2014, Europ Prenat Diag 34:185). In cases of a positive test result for foetal aneuploidy from this method, the result was confirmed by invasive diagnostic methods.

Results:

Characteristics, % foetal fraction of cfDNA and aneuploidy test results for the blood samples are given in TABLE 3. There were two positive test results indicating foetal trisomy 21. Both were confirmed by karyoptyping after amniocentesis; thus, the false positive rate in this study was 0%. One blood sample represented monochorionic twins with concordant karyoptypes [47, XY, +21] and the other one represent dichorionic twins with discordant karyotypes [47, XY, +21 and 46, XX]. In both samples the foetal fraction was as high as 18.0 and 24.8%, respectively. All other NIPT results were negative for trisomies 21, 18 and 13. There is no evidence for false-negative NIPT results so far in the pregnancies included in this study. Nevertheless, a number of pregnancies are still on-going (with the last birth of the patients expected in mid May 2014) and therefore, the final detection rate is still uncertain.


TABLE 3
Characteristics and NIPT results for the collected blood samples
Foetal DNA
Gestational
Chr13
Chr18
Chr21
fraction
age
No. of foetuses, chorinicity
Sample
z-score
z-score
z-score
(%)
(p.m.)
amnionicity
NIPT result
LCMPC05
1.3
−1.0
−0.8
16.7
11 + 5
3, trichorionic, triamniotic
negative
LCMPC06
−0.4
1.1
8.5
18.0
13 + 2
2, monochorionic, n.a.
T21 positive
LCMPC07
−1.0
0.3
0.9
7.9
19 + 0
2, dichorionic, diamniotic
negative
LCMPC08
0.7
1.2
0.0
16.5
18 + 1
2, dichorionic, diamniotic
negative
LCMPC09
0.6
−0.8
0.7
8.9
11 + 5
2, monochorionic, diamniotic
negative
LCMPC10
0.3
0.7
−0.7
17.6
20 + 4
2, dichorionic, diamniotic
negative
LCMPC11
−0.9
−0.8
0.7
11.5
23 + 0
2, dichorionic, diamniotic
negative
LCMPC12
−0.9
−0.7
−2.0
13.3
11 + 1
2, monochorionic, diamniotic
negative
LCMPC13
1.3
0.1
0.3
21.4
16 + 0
2, dichorionic, diamniotic
negative
LCMPC14
0.2
−0.3
0.0
6.8
12 + 5
2, n.a., n.a.
negative
LCMPC15
2.2
0.1
14.7
24.8
16 + 0
2, dichorionic, diamniotic
T21 positive
LCMPC16
1.1
1.7
0.5
5.4
12 + 5
2, n.a., n.a.
negative
LCMPC17
0.7
1.4
0.5
16.5
14 + 2
2, n.a., n.a.
negative
LCMPC18
0.3
2.6
0.0
18.5
18 + 3
2, n.a., n.a.
negative
LCMPC19
−0.2
0.8
0.3
16.6
14 + 0
2, dichorionic, diamniotic
negative
LCMPC20
−0.7
−0.9
0.1
13.1
15 + 4
2, dichorionic, diamniotic
negative
LCMPC21
1.0
−0.7
1.2
8.4
 9 + 3
2, dichorionic, diamniotic
negative
LCMPC22
−1.1
−0.2
0.3
5.6
16 + 2
2, monochorionic, n.a.
negative
LCMPC23
−2.2
2.2
−0.8
20.6
19 + 5
2, monochorionic, n.a.
negative
LCMPC24
−1.6
−0.4
−0.5
14.7
22 + 2
2, monochorionic, diamniotic
negative
LCMPC25
−0.8
−0.2
−1.5
12.1
11 + 5
2, n.a., n.a.
negative
LCMPC26
−0.4
−0.6
−1.3
7.5
13 + 0
2, dichorionic, diamniotic
negative
LCMPC27
0.5
−0.8
−0.4
16.3
12 + 6
2, n.a., n.a.
negative
LCMPC28
−1.2
−0.3
−0.7
19.4
10 + 1
2, dichorionic, diamniotic
negative
LCMPC29
−0.8
0.7
−0.4
14.2
13 + 2
2, monochorionic, n.a.
negative
LCMPC30
0.7
0.3
0.9
14.9
12 + 2
2, monochorionic, monoamniotic
negative
LCMPC31
−0.2
0.3
−0.9
19.3
19 + 1
2, dichorionic, diamniotic
negative
LCMPC32
−1.1
2.5
−2.2
11.6
20 + 0
2, dichorionic, diamniotic
negative
LCMPC33
0.2
2.2
−1.6
8.6
11 + 0
2, dichorionic, diamniotic
negative
LCMPC34
−1.0
1.2
0.0
15.1
15 + 4
2, dichorionic, diamniotic
negative
LCMPC35
−0.3
−0.8
−0.3
19.2
12 + 0
2, dichorionic, diamniotic
negative
LCMPC36
−1.4
−0.5
−0.8
13.9
12 + 0
2, dichorionic, diamniotic
negative
LCMPC37
1.8
−0.7
0.1
13.8
17 + 6
2, dichorionic, diamniotic
negative
LCMPC38
−0.1
1.1
−0.7
13.4
13 + 1
2, dichorionic, diamniotic
negative
LCMPC39
−1.9
0.2
−2.2
15.0
17 + 0
2, dichorionic, diamniotic
negative
LCMPC40
0.6
−0.4
0.8
16.2
18 + 3
2, dichorionic, diamniotic
negative

The reliable detection of foetal aneuploidy in twin pregnancies by NIPT is dependent on a sufficiently high amount of foetal cfDNA from each foetus in the maternal blood. Different data and considerations have been published on how the lower limit of foetal cfDNA fraction should be defined to ensure that each twin's contribution is above the detection threshold (Leung et al 2013, Prenat Diag 33:675; Qu et al 2007, Am J Pathol 170:941; Struble et al 2013, Fetal Diagn Ther December 7 Epub ahead of print). This is especially important for dichorionic twin pregnancies with discordant karyotypes. In the study described above, supporting information was used for the definition of the minimum foetal cfDNA fraction for twin pregnancies derived from the Y-chromosomal representation, if only one of the two foetuses is male. Using the method of the present invention, the total foetal cfDNA fraction can be determined, which reflects the summary of foetal cfDNA derived from both foetuses. Using the Y-chromosomal representation from the next generation sequencing, the foetal cfDNA amount can be determined for male foetuses (as described in Stumm et al 2014). Thus, in the case of mixed foetal gender the contributing amount of each foetus can be determined by subtraction of the amount of foetal cfDNA determined by the Y-chromosomal representation from the foetal cfDNA fraction measured by method of the present invention. The foetal cfDNA fractions determined by the method of the present invention were compared with the values obtained from Y-chromosomal reads from next generation sequencing for cases with known gender (see FIG. 3). There is a correlation of the amount of male specific cfDNA (y axis) to the foetal cfDNA fraction measured by method of the present invention (x axis). Thus, for twin pregnancies with male/male gender approximately true is: [y=x], for female/male genders it is: [y=0.5x] and for female/female: [y=1]. The genders of cases with similar values are male/male and in case of differing values with low Y-chromosomal representation the genders are female/female. The intermediate cases, which show about half the percentage of foetal fraction as Y-chromosomal representation, are of mixed gender. The data presented in FIG. 3 show that it is not only possible to determine the foetal genders using NIPT results for twin pregnancies, but also that the measurement of the amount of foetal fraction of cfDNA determined by the method of the present invention is surprisingly accurate as compared to frequency counting of Y chromosome sequences. On the other hand, these data support the hypothesis that each foetus of a twin pregnancy contributes roughly about half of the total foetal cfDNA fraction. This leads to the conclusion that for twin pregnancies, twice the amount of foetal cfDNA would be required, and thus a recommended minimum foetal fraction of cfDNA for NIPT of a twin pregnancy could be considered to be 8%.

For monochorionic twin pregnancies with concordant genotypes (apart from rare exceptions, Chen et al 2013, Am J Med Genet A 161A:1817), a foetal cfDNA fraction of 4% would be enough to detect a foetal aneuploidy, just as for single pregnancies. However, for routine laboratory NIPT service one major issue speaks against the implication of such different quality criteria for mono- and dichorionic pregnancies: the determination of chorionicity is dependent on the gestational age and the practical experience of the physician performing the ultrasound examination. The chorionicity is clearly detectable in the first trimester of a multiple pregnancy, but in later stages detection becomes more difficult (Sperling et al 2001, Acta Obstet Gynecol Scand 80:287). Therefore, it is a safer strategy to generally define a minimum foetal cfDNA fraction for twin pregnancies, which is applicable for monochorionic as well as for dichorionic multiple pregnancies.

Identification of Vanishing Twins:

In two cases of NIPT aneuploidy testing in which the foetal cfDNA fraction was measured using the method of the present invention, identified a trisomy 21 (z-scores 13.5 and 3.4 respectively), but also a striking discrepancy between the total foetal cfDNA fraction measured by the method of the invention and the cf-Foetal-DNA amount measured by Y-chromosome representation were observed.

For case A, two analyses of blood samples (first and back-up samples) estimated the total foetal cfDNA fraction measured the method of the present invention was 20.7% and 24.8%, respectively, whereas the foetal cfDNA according to the Y-chromosomal representation from next generation sequencing was 9.2% and 9.3%, respectively. It was speculated, and reported to the physician, that the pregnancy may be a mixed-sex twin pregnancy, who confirmed that a deceased twin had been observed during ultrasound scan at week 10. A further blood sample taken in the third trimester of the pregnancy (38+2) turned out to be negative for trisomy 21 and the foetal cfDNA amount measured by Y-chromosomal representation correlated with the foetal amount measured by QuantYfeX (21.7% and 21.4), which matched the male gender determined by karyotyping of the living foetus. At birth a foetus papyraceus was found in the placental tissue from which a sufficient amount of cells could be isolated for cell culture and following GTG banding, a trisomy 21 positive, female karyotype was confirmed (47, XX, +21).

For case B, a slightly increased Y-chromosomal representation was monitored indicating male specific cf-Foetal-DNA of 3.0% and 2.7% respectively. As the foetal cfDNA fraction estimates measured by the method of the invention were far above that (13.4% and 10.0%) we hypothesized from this discrepancy in the foetal fraction measured, that two foetuses with discordant gender contribute to the foetal fraction and the male foetus being the one affected by trisomy 21. This suggestion was derived from the correlation of Y-chromosome specific foetal cfDNA amount of roughly 3% with the elevated z-score around the cut-off value of 3.0. Since the examination was clearly requested for a singleton pregnancy, the male specific foetal cfDNA was suspected to stem from a vanishing twin—maybe the carrier of a trisomy 21—that was either not recognized or not indicated on the consent form for NIPT. Thus, the result was reported to be indecisive for chromosome 21 and the conflicting data was reported to the responsible physician, including a notice regarding the potential vanishing twin, for further clarification via ultrasound. The responsible physician subsequently confirmed that the pregnancy had started as twin and later continued as a singleton pregnancy. The gender of the living and apparently healthy foetus was confirmed to be female and thus, the foetal cfDNA that caused the increased z-score for trisomy 21 can clearly be assigned to a deceased male foetus. The pregnancy is still on-going and further analysis of placental tissue and blood of the living foetus is not yet possible.

Example 2: Improved Detection Sensitivity Using Two Differentially Methylated Regions Using the Same Detectable Moiety/Moieties for Each Differentially Methylated Region

The inventors were surprised to observe that a complex and multiplex reaction detecting two DMRs using the same detectable moiety/moieties for each of said DMR (as well as two other regions (OR) not differentially methylated) was more sensitive to detect foetal cfDNA fraction than previous detection reactions that each detected—in separate PCR reactions—a single DMR (as well as a single OR) (FIG. 4).

In a method of the present invention, two DMRs (those found in RASSF1A and TBX3, as described in Example 1) were detected (over 4 dilutions) with the same aliquot of DNA and reaction—effectively simultaneously (using quantitative probe-based (TaqMan) PCR) with two ORs (those found in RASSF1A and TBX3, as described in Example 1), using: (x) the same detectable moiety/moieties for each of said DMR; and (y) a detectable moiety/moieties for said at least one OR that is/are different to the detectable moiety/moieties used for said DMRs. In comparison, detection of foetal cfDNA fraction was less sensitive, as shown by detection at higher cycle numbers (Cp), if each DMR (and corresponding OR) was detected independently in separate reactions. The regions/markers, primers/probes and detection methodology was substantially as described in Example 1, except that for the single locus reactions, only the DMR and OR from a given gene (RASSF1A or TBX3) were detected simultaneously in a single reaction.

In contrast, detection of foetal cf DNA fraction using a multiplex reaction of the two DMRs using different detectable moieties (eg FAM for the RASSF1A locus and VIC for the TBX3 locus) is determined to be even less sensitive, and further is difficult to detect simultaneously with any OR; without being bound by theory, believed due to the higher complexity of colour compensation, the limited number of separately detectable fluorescent markers and/or the “bleaching” effects from so many fluorescent markers being present in the same reaction.

Given the exponential nature of quantitative PCR detection, a higher sensitivity of detection (ie lower cycle numbers) would also equate to higher accuracy of quantification, as the correction to standard curves, and interpolation between data points, would be subject to less error than that arising with the amounts of DNA correlating to detection at higher cycle numbers.

Example 3: Detection of an Increased Risk of a Pregnant Woman Suffering From or Developing Preeclampsia (Prophetic Example)

Using a method of the present example, pregnant women are assessed for their risk of suffering from or developing preeclampsia as follows. Firstly, a blood sample is collected from the woman for whom such risk to be assessed and total cfDNA extracted from the plasma of such sample substantially in accordance with the procedures described in Example 1. Secondly, using a method substantially as described in Example 1, a relative and/or absolute amount of foetal cfDNA and total cfDNA present in the plasma is determined, wherein the absolute amount of foetal and/or total cfDNA can be expressed as the amount of genome equivalents (“Eq”). Thirdly, such determined amount of cfDNA and/or total cfDNA is compared to a threshold amount or a reference distribution of amounts, and the women is determined to be at increased risk of suffering from or developing preeclampsia if the amount of foetal cfDNA or total cfDNA exceeds such threshold value and/or is an outlier in such distribution.

For example, using published threshold values (Papantoniou et al 2013, Prenat Diag 33:682) if the total cfDNA exceeds an amount of about 7,500 Eg/mL plasma or if the foetal cfDNA fraction exceeds an amount of about 500 Eg/mL plasma, then the woman is determined to have such an increased risk. Such a risk may instead or additional be assessed by considering: (i) the fold-increase (eg 1.5, 3, 3.5 or 4-fold increase) of foetal cfDNA (determined for such woman compared to a threshold amount), factoring into the determination that for later-term pregnancies a higher fold-increase in foetal cfDNA may be utilised (Zeybek et al 2013, J Obstet Gynaecol Res 39:632); and/or (ii) into which percentile the amount of cfDNA determined from the woman falls, from consideration of a reference distribution of amounts determined from low-risk women or women who did not suffer from or develop preeclampsia, for example if the foetal cfDNA fraction falls within the 90th percentile of such a distribution, then the woman is considered to have an increased risk of suffering mild or severe preeclampsia (Jakobsen et al 2013, Transfusion 53:1956).

In this example, t detection of a risk is conducted using a computer program product that performs the operations represented by FIG. 5. Operation (A) receives signals (1) and (2) representing, respectively, foetal and total cfDNA are used by the computer program product to determine a parameter (4) that represents the relative and/or absolute amount of foetal (or total) cfDNA present in the plasma of the woman. This operation may optional receive a signal (3) representing an absolute amount of standard DNA. A second operation (B) compares such determined parameter (4) against a threshold amount (5) and/or a reference population of amounts (6) so as to determine and report (7) whether or not—and based on such comparison—the woman is determined to be at increase risk of suffering or developing preeclampsia.

Example 4: Detection of Tumour-Associated DNA in Samples From Cancer Patients (Prophetic Example)

Methylation of RASSF1A and at least one other DMR such as ER-beta (oestrogen receptor beta), RAR-beta2 (retinoic acid receptor beta 2) and/or Cyclin D2 is used to detect cfDNA derived from a tumour and to assess the risk of women suffering from breast cancer. Specific methylation at such DMRs is a characteristic of tumour-derived cfDNA, and a method of the present invention is used to detect and to quantify the amount tumour derived cfDNA in the plasma of women, and those determined to have elevated (or outlying amounts of tumour-derived cfDNA are determined to be at increased risk from suffering from or developing breast cancer. Essentially, the process described in Example 3 is followed except that DMR2 and OR2 are located in one of ER-beta, RAR-beta2 or Cyclin D2, rather than TBX3. Primers and probes to detect such DMR2 and OR2 for use in this embodiment of the present invention are designable by the person of ordinary skill.

In this example, a similar computer program product as described in Example 3 can be used to assess the risk for a given woman is based on the amount of tumour-derived cfDNA present in her blood, but in this example this parameter is compared against a threshold amount or distribution of amounts that is derived from a study of the amount of tumour-derived cfDNA present in control and breast cancer patients; and those women having an elevated (or outlying) amount of tumour-derived cfDNA are considered to have an increased risk of suffering from or developing breast cancer.

In view of the above, it will be appreciated that the present invention also relates to the following items:

  • 1. A method for detecting in a sample from an individual an amount of a species of DNA originating from cells of a given type, which sample comprises said species of DNA in admixture with differently methylated DNA not originating from cells of said type; said method comprising the steps:
    • (a) treating the DNA present in said sample with a reagent that differentially modifies methylated and non-methylated DNA;
    • (b) detecting in said sample the presence of methylation in said species of DNA at two or more differentially methylated regions (DMRs) that are differently methylated between said species of DNA and the DNA not originating from cells of said type, the modification of DNA of such DMRs by said reagent is sensitive to methylation of DNA, wherein the presence of methylated DNA at one or more of said DMRs indicates the presence of said amount of species of DNA in said sample and the absence of methylated DNA at said DMRs indicates the absence of said species of DNA in said sample; and
    • (c) detecting an amount of total DNA present in said sample using at least one other region that is not differently methylated between said species of DNA and the DNA not originating from cells of said type, the modification of which region(s) by said reagent is insensitive to methylation of DNA,
    • wherein, said detection in step (b) and said detection in step (c) are made using the same aliquot of DNA of said sample, and in the same vessel, and effectively simultaneously for such DMRs and other region(s), and using: (x) the same detectable labels(s) for each of said DMRs; and (y) a different detectable label(s) for said other region(s).
  • 2. The method of item 1, wherein prior to or as part of said detection in step (b) and/or step (c), each DNA region comprising said DMRs and/or said other region(s), respectively, is(are) amplified.
  • 3. The method of item 1 or 2, wherein each detectable label used in step (b) and/or step (c) is independently selected from the group consisting of: fluorescent, protein, small molecule or radioactive label.
  • 4. The method of any one of items 1 to 3, wherein said detection in step (b) comprises multiplex real-time probe-based quantitative probe-based PCR using at least two labelled probes each of which specific for one of said DMRs.
  • 5. The method of any one of items 1 to 4, wherein said detection in step (c) comprises real-time quantitative PCR using at least one labelled probe specific for one of said other region(s).
  • 6. The method of any one of items 1 to 5, wherein said other region is located between about 20 bp and about 20 kb upstream or downstream of, and/or within the same gene as, at least one of said DMRs.
  • 7. The method of any one of items 1 to 6, wherein said detection in step (c) comprises using at least two of said other regions; preferably wherein, the number of said other regions is the same as the number of DMRs used in step (b); more preferably wherein, one of said other regions is located between about 20 bp and about 20 kb upstream or downstream of a DMR used in step (b) and each other of the said other regions is located between about 20 bp and about 20 kb upstream or downstream of another of said DMRs.
  • 8. The method of item 7, wherein said detection in step (c) is made using the same detectable label(s) for each of said other regions.
  • 9. The method of item 7 or 8, wherein said detection in step (c) comprises multiplex real-time quantitative probe-based PCR using at least two labelled probes each of which is specific for one of said other regions.
  • 10. The method of any one of items 1 to 9, wherein said detection in step (c) and said detection in step (b) are made using the same aliquot of DNA of said sample, and in the same reaction/detection vessel, and effectively simultaneously with each other, and by multiplex real-time quantitative probe-based PCR using at least one labelled probe specific for each of the said DMRs and other region(s).
  • 11. The method any one of items 1 to 10, wherein said species of DNA originates from cells of a foetus and/or the placenta of a foetus and said sample is from a pregnant female; preferably wherein, said species of DNA is circulating cell-free DNA and said sample is a blood fraction such as plasma or serum.
  • 12. The method of item 11, wherein said DMRs comprises at least one, preferably at least two, methylation site(s) specific for said reagent, and at least one of said DMRs is located in a portion of the genome and/or gene selected from the group consisting of: RASSF1A, TBX3, HLCS, ZFY, CDC42EP1, MGC15523, SOX14 and SPN; preferably wherein,
    • each of said DMRs is located in a portion of the genome and/or gene selected from the group consisting of: RASSF1A, TBX3, HLCS, ZFY, CDC42EP1, MGC15523, SOX14 and SPN; and/or
    • at least one of said DMRs is located between about positions 4,700 bp and 5,600 bp of RASSF1A or about positions 1,660 bp and 2,400 bp of TBX3; more preferably wherein,
    • said two or more DMRs comprise those located between about positions 4,700 bp and 5,600 bp of RASSF1A and about positions 1,660 bp and 2,400 bp of TBX3.
  • 13. The method of item 11 or 12, wherein said other region is located in a portion of the genome and/or gene selected from the group consisting of: GAPDH, beta-actin, ALB, APOE, RNASEP, RASSF1A, TBX3, HLCS, ZFY, CDC42EP1, MGC15523, SOX14 and SPN; preferably wherein,
    • said other region comprises a region without a methylation site specific for said reagent and said locus is located in the genes RASSF1A or TBX3, more preferably wherein,
    • two or more of said other regions are used in detection step (c) and comprise those located between about positions 14,220 bp and 13,350 bp of RASSF1A and about positions 12,400 bp and 13,000 bp of TBX3.
  • 14. The method any one of items 11 to 13, wherein said pregnant female is susceptible to a pregnancy-associated medical condition; preferably wherein, said pregnancy-associated medical condition is selected from the group consisting of: preeclampsia, preterm labour, intrauterine growth retardation and vanishing twin.
  • 15. The method of any one of items 1 to 10, wherein said species of DNA originates from a cell type associated with a medical condition; preferably wherein, said medical condition is one selected from the group consisting of: a cell proliferative disorder, an infection/infectious disease, a wasting disorder, a degenerative disorder, an (auto)immune disorder, kidney disease, liver disease, inflammatory disease acute toxicity, chronic toxicity, myocardial infarction, and a combination of any of the forgoing; more preferably wherein, said species of DNA is circulating cell-free DNA and said sample is a blood fraction such as plasma or serum.
  • 16. The method of item 15, wherein said species of DNA originates from cells of a tumour; preferably wherein, said tumour is a carcinoma or cancer of an organ selected from the group consisting of: liver, lung, breast, colon, oesophagus, prostate, ovary, cervix, uterus, testis, brain, bone marrow and blood.
  • 17. The method of item 16, wherein said DMRs comprises at least one, preferably at least two, methylation site(s) specific for said reagent, and at least one of said DMR is located in a portion of the genome and/or a gene selected from the group consisting of: a tumour suppressor gene, p16, SEPT9, RASSF1A, GSTP1, DAPK, ESR1, APC, HSD17B4 and H1C1; preferably wherein, one of said two or more DMRs is located in RASSF1A; more preferably wherein, one of said two or more DMRs is located between about positions 4,700 bp and 5,600 bp of RASSF1A; and/or more preferably wherein, said other region is located between about positions 14,220 bp and 13,350 bp of RASSF1A.
  • 18. The method of any one of items 1 to 17, wherein said sample is a tissue sample or a sample of biological fluid; preferably wherein, said sample is a sample of biological fluid selected from the group consisting of: whole blood, a blood fraction, urine, saliva, sweat, ejaculate, tears, phlegm, vaginal secretion, vaginal wash and colonic wash; more preferably wherein, said sample is a plasma or serum sample.
  • 19. the method of any one of items 1 to 18, wherein said reagent that differentially modifies methylated and non-methylated DNA comprises bisulphite.
  • 20. The method of any one of items 1 to 18, wherein said reagent that differentially modifies methylated and non-methylated DNA comprises an agent that selectively digests unmethylated over methylated DNA, preferably wherein, said agent comprises:
    • at least one methylation sensitive enzyme;
    • at least one methylation sensitive restriction enzyme; and/or
    • an agent selected from the group consisting of: AatII, AciI, AClI, AfeI, AgeI, AgeI-HF, AscI, AsiSI, AvaI, BceAI, BmgBI, BsaAI, BsaHI, BsiEI, BsiWI, BsmBI, BspDI, BsrFI, BssHII, BstBI, BstUI, ClaI, EagI, FauI, FseI, FspI, HaeII, HgaI, HhaI, HinP1I, HpaII, Hpy99I, HpyCH4IV, KasI, MluI, NaeI, NarI, NgoMIV, NotI, NotI-HF, NruI, Nt.BsmAI, Nt.CviPII, PaeR7I, PluTI, PmlI, PvuI, PvuI-HF, RsrII, SacII, SalI, SalI-HF, SfoI, SgrAI, SmaI, SnaBI, TspMI and ZraI.
  • 21. The method of any one of items 1 to 20, wherein each of said detection steps comprises quantitative detection and said detected amount of said species of DNA is expressed as a relative concentration of said species of DNA to the total DNA in said sample.
  • 22. The method of any one of items 1 to 20, further comprising the steps:
    • detecting an amount of total DNA in a standard sample of DNA of known amount using the same other regions(s) as used in step (c); and
    • comparing the signal detected from said standard sample of DNA to the signal detected in step (c).
  • 23. The method of item 22, wherein each of said detection steps comprises quantitative detection and said detected amount of said species of DNA is expressed as an absolute amount of said species of DNA in said sample.
  • 24. The method of item 21 or 23, further comprising the step:
    • comparing the amount of said species of DNA detected with a threshold amount and/or reference distribution of amounts, wherein: (x) an increase in, or outlying of, the amount of said species of DNA indicates an increased risk of the individual suffering from or developing a medical condition; and/or (y) an amount of said species of DNA in excess to said threshold, or outlying from said distribution, indicates that a diagnosis for an abnormality in the said species of DNA present in said sample may be performed on, preferably a separate aliquot of DNA of, said sample.
  • 25. The method of any one of items 21 to 24, further comprising the step:
    • performing on, preferably with a separate aliquot of DNA of, said sample, a diagnosis for an abnormality in said species of DNA present in said sample; preferably wherein, said species of DNA originates from cells of a foetus and/or the placenta of a foetus, said sample is from a pregnant female and said diagnosis is a prenatal diagnosis.
  • 26. The method of item 25, wherein said diagnosis comprises a step that uses a detection technology selected from the group consisting of: DNA sequencing, SNP analysis, digital PCR and hybridisation; preferably wherein, said detection technology is massively parallel sequencing of DNA; more preferably wherein said detection technology is massively parallel sequencing of random and/or enriched DNA.
  • 27. The method of item 25 or 26, wherein:
    • (x) said species of DNA originates from cells of a foetus and/or the placenta of a foetus, said sample is from a pregnant female and said abnormality is a genetic mutation or a chromosomal abnormality, such as a chromosomal trisomy, associated with a foetal abnormality and/or a congenital disorder; preferably wherein:
      • said genetic mutation is selected from the group consisting of: colour blindness, cystic fibrosis, hemochromatosis, haemophilia, phenylketonuria, polycystic kidney disease, sickle-cell and disease, Tay-Sachs disease; and/or
      • said chromosomal abnormality is selected from the group consisting of: a trisomy (such as trisomy 21, trisomy 18, or trisomy 13), a sex-chromosome abnormality (such as Turners syndrome, Klinefelter syndrome, Noonan syndrome, Triple X syndrome, XXY syndrome, or Fragile X syndrome), a chromosomal deletion (such as Prader-Willi syndrome, Cris-du-chat syndrome, Wolf-Hirschhorn syndrome, or 22q11 deletion syndrome, Duchene muscular dystrophy), Beckwith-Wiedemann syndrome, Canvan syndrome, and neurofibromatosis; or
    • (y) said species of DNA originates from cells of a tumour and said abnormality is a genetic mutation or a chromosomal abnormality associated with the diagnosis, prognosis or predictive treatment of a carcinoma or cancer; preferably wherein:
      • said genetic mutation is selected from the group consisting of: a mutation in a tumour suppressor gene (such as TP53 (p53), BRCA1, BRCA2, APC or RB1), a mutation in a proto-oncogene (such as RAS, WNT, MYC, ERK, or TRK) and a DNA repair gene (such as HMGA1, HMGA2, MGMT or PMS2); and/or
    • said chromosomal abnormality is a translocation (such as t(9;22)(q34;q11) [ie, Philadelphia chromosome or BCL-ABL], t(8;14)(q24;q32), t(11;14)(q13;q32), t(14;18)(q32;q21), t(10;(various))(q11;(various)), t(2;3)(q13;p25), t(8;21)(q22;q22), t(15;17)(q22;q21), t(12;15)(p13;q25), t(9;12)(p24;p13), t(12;21)(p12;q22), t(11;18)(q21;q21), t(2;5)(p23;q35), t(11;22)(q24;q11.2-12), t(17;22), t(1;12)(q21;p13), t(X;18)(p11.2;q11.2), t(1;19)(q10;p10), t(7,16)(q32-34;p11), t(11,16)(p11;p11), t(8,22)(q24;q11) or t(2;8)(p11;q24)).
  • 28. A method for detecting an increased risk of an individual suffering from or developing a medical condition; said method comprising the steps:
    • (i) conducting the method of item 21 or 23; and
    • (ii) comparing the amount of said species of DNA detected with a threshold amount and/or a reference distribution of amounts,
    • wherein an increase in, or outlying of, the amount of said species of DNA indicates an increased risk of the individual suffering from or developing said medical condition.
  • 29. A composition comprising:
    • two pairs of PCR primers, each pair for amplifying one of said two of more DMRs as set forth in any of items 1 to 28;
    • one pair of PCR primers for amplifying said other region as set forth in any of items 1 to 28;
    • two labelled probes as set forth in item 4; and
    • one labelled probe as set forth in item 5.
  • 30. The composition of item 29, further comprising:
    • a further pair of PCR primers for amplifying a second other region as set forth in any of items 9 to 28; and
    • a further labelled probe as set forth in item 9.
  • 31. A kit comprising:
    • the primers and probes as set forth in item 29 or 30; and
    • optionally, further comprising: (i) a printed manual or computer readable memory comprising instructions to use said primers and probes to practice a method of any one of items 1 to 28 and/or to produce or use the composition of item 29 or 30; and/or (ii) one or more other item, component or reagent useful for the practice of a method of any one of items 1 to 28 and/or the production or use of the composition of item 29 or 30, including any such item, component or reagent disclosed herein, such as the reagent that differently modifies methylated and non-methylated DNA as set forth in any one of items 1 to 28.
  • 32. A computer program product comprising a computer readable medium encoded with a plurality of instructions for controlling a computing system to perform and/or manage an operation for determining: (x) an increased risk of an individual suffering from or developing a medical condition and/or (y) if a diagnosis for an anomaly in a species of DNA originating from cells of a given type may be performed, in each case from a sample from an individual comprising a species of DNA originating from cells of a given type in admixture with differently methylated DNA not originating from cells of said type, the DNA in present in said sample being treated with a reagent that differentially modifies methylated and non-methylated DNA as set forth in any one of items 1 to 28; said operation comprising the steps of:
    • receiving: (i) one signal representing the essentially simultaneous quantitative detection of methylation at two or more DMRs as set forth in step (b) of any one of items 1 to 28; and (ii) one signal representing the essentially simultaneous quantitative detection of total DNA using at least one other region as set forth in step (c) any of items 1 to 28;
    • determining a parameter from the signals (i) and (ii), wherein the parameter represents a quantitative amount of said species of DNA;
    • comparing the parameter to with a threshold amount and/or reference distribution of amounts; and
    • based on such comparison, determining a classification of whether, respectively, (x) an increased risk of an individual suffering from or developing a medical condition exists; and/or (y) a diagnosis for an anomaly in a species of DNA originating from cells of a given type may be performed.
  • 33. The computer program product of item 32, wherein said operation further comprises the steps:
    • receiving a further signal representing the quantitative detection of total DNA in a standard sample of DNA as set forth in item 22; and
    • comparing said signal with the signal set forth in (ii) of item 32, so as to determine said parameter that represents an absolute quantitative amount of said species of DNA.
  • 34. The computer program product of item 32, or 33, wherein said operation is for determining if a diagnosis for an anomaly in said species of DNA may be performed, and further comprises the step of determining from said parameter a number of random and/or enriched DNA molecules to be sequenced from, preferably from a separate aliquot of DNA of, said sample as part of said diagnosis.
  • 35. A method for detecting in a sample from an individual an amount of a species of DNA originating from cells of a given type, which sample comprises said species of DNA in admixture with differentially methylated DNA not originating from cells of said type; said method comprising the steps:
    • (a) treating the DNA present in said sample with a reagent that differentially modifies methylated and non-methylated DNA; and
    • (b) detecting in said sample the presence of methylation in said species of DNA at two or more DMRs that are differently methylated between said species of DNA and the DNA not originating from cells of said type the modification of DNA of such DMRs by said reagent is sensitive to methylation of DNA, wherein the presence of methylated DNA at one or more of said DMRs indicates the presence of said amount of species of DNA in said sample and the absence of methylated DNA at said DMRs indicates the absence of said species of DNA in said sample,
    • wherein, said detection in step (b) is made using the same aliquot of DNA of said sample, and in the same reaction/detection vessel, and effectively simultaneously for such DMRs, and using (x) multiplex real-time quantitative PCR; and (y) at least two labelled probes each of which specific for one of said DMRs and that are labelled with the same detectable label(s) for each of said DMRs; preferably wherein, said reagent comprises agent as set forth in item 20.

<160> NUMBER OF SEQ ID NOS: 199

<210> SEQ ID NO: 1

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Primer

<400> SEQENCE: 1

attgagctgc gggagctggc 20

<210> SEQ ID NO: 2

<211> LENGTH: 18

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Primer

<400> SEQENCE: 2

tgccgtgtgg ggttgcac 18

<210> SEQ ID NO: 3

<211> LENGTH: 15

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Probe

<400> SEQENCE: 3

acccggctgg agcgt 15

<210> SEQ ID NO: 4

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Primer

<400> SEQENCE: 4

ggtcatccac caccaagaac 20

<210> SEQ ID NO: 5

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Primer

<400> SEQENCE: 5

tgcccaagga tgctgtcaag 20

<210> SEQ ID NO: 6

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Probe

<400> SEQENCE: 6

gggcctcaat gacttcacgt 20

<210> SEQ ID NO: 7

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Primer

<400> SEQENCE: 7

ggtgcgaact cctctttgtc 20

<210> SEQ ID NO: 8

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Primer

<400> SEQENCE: 8

ttaatcaccc agcgcatggc 20

<210> SEQ ID NO: 9

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Probe

<400> SEQENCE: 9

ccctcccggt gggtgataaa 20

<210> SEQ ID NO: 10

<211> LENGTH: 20

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Primer

<400> SEQENCE: 10

tgttcactgg aggactcatc 20

<210> SEQ ID NO: 11

<211> LENGTH: 19

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Primer

<400> SEQENCE: 11

cagtccatga gggtgtttg 19

<210> SEQ ID NO: 12

<211> LENGTH: 18

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Probe

<400> SEQENCE: 12

gaggtcccat tctccttt 18

<210> SEQ ID NO: 13

<211> LENGTH: 18151

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: misc_feature

<223> OTHER INFORMATION: RASSF1

<400> SEQENCE: 13

gacttggcgt ctgaggacag agtccagacc acaaggatct ggagctcagg agagactcgt 60

gggccacagc ccgagaaagc gctgggaatc caaatactat ggcgattggc agtcgcgtag 120

gcgaggcggg ctagagaccc gcccggattt aggcgcgagc cacctccagg ggcggggccc 180

aggccgcact gcgcaggcgc ggctaacccg tttccatggc tgcgagaact gacgctcccc 240

aaccgtcccg caactgtcct gtcccagact ttggcaccgt cggggtccgt cgtccccgaa 300

tgtgacagca tccccacccc ggctgctgcc caggatccgc cggaccccgg cctcgatatg 360

ggagacctgg aactgctgct gcccggggaa gctgaagtgc tggtgcgggg tctgcgcagc 420

ttcccgctac gcgagatggg ctccgaaggg tgaggcaccc gggtcaggcg gagtcccgga 480

gtcattgtcc ttgagtcggg gagctggggc ctgactcggg ggaggggctg cccagtgtgg 540

aggggctccc aaatggggga gcagagcgtt ccgagacagg agtattactg ctcctgagcc 600

ccctgtgtcc cctcaggatc aggttaggct tcagtaggat ccagccccca tccccactcc 660

taatgcacac acgtggacgc acatgcactt accctctgag gcaggtggaa ccagcagcat 720

gagaacctgg agaagctgaa catgcaagcc atcctcgatg ccacagtcag ccagggcgag 780

cccattcagg agctgctggt cacccatggg aaggtacccc gaggtcacag gcagggttcc 840

tgccttcccc catacctcac ctactctacc cctccggagt cccctgtgtg cccttcccct 900

ctggcctggt acacctgttc tccctgaagg acaaagagga atgtgttaca tgtttcattt 960

tgtatcccta ttggacagga ctctggcaca ccaggctggg tgcagggcat gagttgatta 1020

gggagaaagc tgtaggtcct agaacagctt aggcttcaag gggaaggccc aaatgctaaa 1080

ggcatctgtg aattgactgt aaggctggtg gtggggaagg ggtggggagg ggttggggag 1140

ggcgggaggg aggggagata acctaactgg aggtggaact tcggcatgga aggaagcagc 1200

cttcccaaca tgaaaggggg aagttagaaa ccagggagat gcctggctgg aacatggacc 1260

agggagtgtc accagcagat gacctgagat atcaattgac caaaaaaaaa aaaaaaaaag 1320

ccgggcatgg tagctcatgc ctgttatccc agcattttgg gaggccaaga cgggtggatc 1380

atctgaggtc aggagttcaa ggccagcctg gccaacatgg tgaaacccca cctctactaa 1440

aaatacaaaa atttgcagag catggtggtg cacacctgta atcccagcta ctcgggaggc 1500

tgaggcagga gaatcgcttg aacctgggag gcagaggtta cagagagcca agatcatgcc 1560

actgcactcc agcctgggtg acaagagtga aactccgtct caaaaaaaaa aaaaaaaaaa 1620

agaaaggtcc tttgcaaaag aaagatggaa ctcatactag gggataggat aggaacaggg 1680

cactgtgaag ggtcctgagt aggagtgagg ccaaggcaca caagagcttt ggaggaccac 1740

agacagggac tagagggagg gcatgaggag aagggctggc ttgaaaggga tgcctgaatg 1800

ggcgggcaga ggataagggt gcaggtgcag gcagggcaag gcagtctggg aactgggcag 1860

gagccagtca cataagcatg agggacatcc acagaggtgt tgggagcagc tggtaatgaa 1920

ggtccaaggt gcaagagaga agtcaggaag gatactcatg ggtctggaat agtttagggg 1980

cccagcagtg tttggggata tcagggttga gctgagccgg ggatgggagg gttgccaggc 2040

aaaggtaggc ccatctcatc cctgtccttt accctaccct tcaaaggtcc caacactggt 2100

ggaggagctg atcgcagtgg agatgtggaa gcagaaggtg ttccctgtgt tctgcagggt 2160

ggaggacttc aagccccaga acaccttccc catctacatg gtggtgagct gggcccctgg 2220

ttcatacctc ttctcactcc ttcagagggc tctggaccgg ggaggagagc tggtagcccc 2280

tatcccttcc tcaggccctg tccttctctt tatctgacag gtgcaccacg aggcctccat 2340

catcaacctc ttggagacag tgttcttcca caaggtgagg gactatctct gcccatgggc 2400

cacagttccg ggtcagggcc tggcaggaag ggagattgtg tctgtgtggg gaaggcatca 2460

gacacagaaa gtttccctcc tccttttccc aggaggtgtg tgagtcagca gaagacactg 2520

tcttggactt ggtagactat tgccaccgca aactgaccct gctggtggcc cagagtggct 2580

gtggtggccc ccctgagggg gagggatccc aggacagcaa ccccatgcag gtgggttgag 2640

gttacctagg gttgtgaaag cctaggtctg ggttccccaa ggcctgcgca ggtgagggtg 2700

gcccagcgtg aacactgtgt gacctcccag gagctgcaga agcaggcaga gctgatggaa 2760

tttgagattg cactgaaggc cctctcagta ctacgctaca tcacagactg tgtggacagg 2820

tgagcagtcc gactgggcct gggcctactg tggagggctg gaagaccggg cctgtagcct 2880

gcctctactc acctccttca caacgtccct gcccctagcc tctctctcag caccttgagc 2940

cgtatgctta gcacacacaa cctgccctgc ctcctggtgg aactgctgga gcatagtccc 3000

tggagccggc gggaaggagg tagggtcctc ccccaccagc ctaagcccca ggctactgct 3060

tcagggtatc tttttgatag aggggggcag cttgcacaca cgaagacaaa ccctgtcccc 3120

aagcccactg aggataccag gatgcctcag ccaaggttgg cctagacctg agctctgcag 3180

caggccaggc ccatgtgtcc actactgagg ctcaccctgc tctggggtca gcagccctat 3240

agcctgggca agtcctgcag cccaggttct cccattccca ggcagtggtc agtctcccag 3300

cccccacagc tggctcactt gaagagaatt caacgtctgc acccagtgtg ctggttcctc 3360

tccccaggca agctgcagca gttcgagggc agccgttggc atactgtggc cccctcagag 3420

cagcaaaagc tgagcaagtt ggacgggcaa gtgtggatcg ccctgtacaa cctgctgcta 3480

agccctgagg ctcaggcgcg ctactgcctc acaagttttg ccaagggacg gctactcaag 3540

gtcagactcc ctccgcacca gcccccacag ccccagtacc gccctcccca tcctaccccg 3600

actgcgtccc tgctgtttat ctttgcccac ccacctcaac cccagtgctc ttttcagtcc 3660

ttgggcctca ggtgacacac cagctagtgg gacatgggcc cccacaggca ttctcagccc 3720

aacccagccc cttccttttc cttggccccc tggccagcac ctgcatcaca ctggcctcca 3780

ctggacaccc ttgcagcttc gggccttcct cacagacaca ctgctggacc agctgcccaa 3840

cctggcccac ttgcagagtt tcctggccca tctgacccta actgaaaccc agcctcctaa 3900

gaaggacctg gtgttggaac aggtaggcac tggaaagtta gctgctcagg accactgtcc 3960

cactttacca gcaccttcct gccactctcc acttctctct cctagatccc agaaatctgg 4020

gagcggctgg agcgagaaaa cagaggcaag tggcaggcaa ttgccaagca ccagctccag 4080

catgtgttca gcccctcaga gcaggacctg cggctgcagg cgcgaaggta aggcctgtgg 4140

aaatggcagg gagggtggag gggatgcagg aggcatggat gtgggtgggg tgcccccacc 4200

ttccagggcc agtcagacct tcctgacttt cccccaggtg ggctgagacc tacaggctgg 4260

atgtgctaga ggcagtggct ccagagcggc cccgctgtgc ttactgcagt gcagaggctt 4320

ctaagcgctg ctcacgatgc cagaatgagt ggtattgctg caggtgaggg tatcctagaa 4380

ccttggacct ctaagcccta ctcccacatc ccccacatgc attgccatcc tcaataccca 4440

cctgcctgca gggagtgcca agtcaagcac tgggaaaagc atggaaagac ttgtgtcctg 4500

gcagcccagg gtgacagagc caaatgaggg ctgcagttgc tgagggccga ccacccatgc 4560

caagggaatc cacccagaat gcacccctga acctcaagat cacggtccag cctctgccgg 4620

agccccagtc tccgcagtgg agagcagagc gggcggtaaa gctgctgacc gatctccctc 4680

ctcctcaccc caagtgaagg ctcgagactt cctgccccac ccagtgggta ggccaagtgt 4740

gttgcttcag caaaccggac caggagggcc agggccggat gtggggaccc tcttcctcta 4800

gcacagtaaa gctggcctcc agaaacacgg gtatctccgc gtggtgcttt gcggtcgccg 4860

tcgttgtggc cgtccggggt ggggtgtgag gaggggacga aggagggaag gaagggcaag 4920

gcgggggggg ctctgcgaga gcgcgcccag ccccgccttc gggccccaca gtccctgcac 4980

ccaggtttcc attgcgcggc tctcctcagc tccttcccgc cgcccagtct ggatcctggg 5040

ggaggcgctg aagtcggggc ccgccctgtg gccccgcccg gcccgcgctt gctagcgccc 5100

aaagccagcg aagcacgggc ccaaccgggc catgtcgggg gagcctgagc tcattgagct 5160

gcgggagctg gcacccgctg ggcgcgctgg gaagggccgc acccggctgg agcgtgccaa 5220

cgcgctgcgc atcgcgcggg gcaccgcgtg caaccccaca cggcagctgg tccctggccg 5280

tggccaccgc ttccagcccg cggggcccgc cacgcacacg tggtgcgacc tctgtggcga 5340

cttcatctgg ggcgtcgtgc gcaaaggcct gcagtgcgcg cgtgagtagt ggccccgcgc 5400

gcctacgaga gcggaagggg cagccaaggg gcagcgcagt cgccgcgggt caagtcgcgg 5460

cagagggggt cggcggggac agctcccgag gactaggtcc gttactttcg ccccatcgct 5520

gaagagtgcg cgaaaatggt ttatcccttg tcgcactcca ctcgtatctg ggccacagat 5580

gagcagaggt ggctgcttat atgtaaaaat acgctgattt taagtttctt atctttaaaa 5640

tgccttggcc cttcttgaga aagggtttgt gcctactgtc ctcggagtcc atcttcccag 5700

gcttgcctct tctcaaacac tcatgacccc ctccagaacc tttagggtga agggaaatta 5760

ccacctatgg gagggagcct ggaaaaattt agaacctttg gtgggccccc tgcaagcagg 5820

agttttgttg agtctttatt tagcaaacac ccttttctga cccagtgaat cagatgctaa 5880

aatatgcacg cagccacaca cccagcagtc cttctgcacc cctgggaatc gccagcaagc 5940

aaaggttgct ctcccctggg tagacaccag ctggaatcac caggggtgct tttacagtcc 6000

tccccgctag cctggatccc accgcagacc tgttgaatca actgctggga gtggacccta 6060

ggcatcagta aattttaaaa actccccaaa ttattgtaac atggagtctg ggttgagcat 6120

cactgctctg gcctatttag gaacttgtgg atggatagtg tcccaggtct gtgtgtgcat 6180

ggagaccctc tcatccggta caagaggaca tcacaaattc agctgggggg agcacaaagt 6240

tgtgacagaa tgcaaagaat gaacaagggg ccgagcgcgg tggctcatgc ctgtaatccc 6300

agcacttcgg aaggcggagg cgggtggatc acctgaggtc aggagttcaa gaccagcctg 6360

gccaacatgg tgaaacctca tgtctactaa aaaataaaaa aaaatgagcc aggcgtagtg 6420

gcgggtgcct gtaatcccag ctactcggga ggctgaggtg ggagaattgc ttgaacacag 6480

gaggcggagg ttgcagtgag ccgagatcgt gccactgccc tccagccttg gcgacagagt 6540

gagactctgt ctcaaaaaaa aaaaaaaaaa aaaaaagaac aaggctggga cattgcagcg 6600

ttctcaaaga gaaataaagt agccatggag ataagaagca ggatgatttg ggcatgttta 6660

tcagaggtag agacaaggga gaaatcaaag ataagtttgg gcttttgtct ccagtaactg 6720

ggagcctagt ggccattttt gctgcaaaga ggaagctggg caagtgtagc agtgaggctg 6780

aagaaaaggg aattaaattt tggccatgtt cacttgaaac gtcttttaga catcctagtg 6840

aaggtactgg cacggaggat ctagtctgag ggtttaggtc agtgtttcag ccgtggatct 6900

ggggcagatg aatgtagaca gaccaggcca gtgatcagga ctgagcccag acttcatcgt 6960

gagatatgga agttgagtca gaatctgcaa aggagctgag caggagctgc agggggtagg 7020

aggaaaactg ggagagtgta gcccctggga gtcaaaggga gcaagcttca aatgatgctg 7080

agggggtgag aatggagaat ggaacactgg attccatttg gtagtacaca gatcgctgag 7140

gaccctgtcc cgggcagttt cctggaggaa gaggcaagcc tggctggagt gggtagaggg 7200

gagagtgaag gcgaaggatt agagtgtata gagaccagtg tcttggtctg aggggagtag 7260

agacaggtga caaccacagg gcagacgtag gttaaaggtg tttagttttt ccttcaagta 7320

aatgggcaga tgtattccat atacgttccc agtgaagggc cgggtgcggt ggctcaagcc 7380

tgtagtccca gcactttgga aggccgaggc gggtggatca cctgagatca ggagtttgag 7440

accagcctgg ctaacatggt gaaaccccgt ctctactaaa aatacaaaaa ttagctgggc 7500

atggtggcgg gcgcctgtaa tcctaggtac tcaggaggct gaggcagaag aatcgcttga 7560

acccaggagg cggaggttgc ggtgagccga aatcgcgcca ttgcactcca gcctgggtga 7620

caaaagcaag acgcagtttt ttgttgttgt ttttttaatt gccaatgagg aaaggggaag 7680

ttctgtgcta ggcgatagag atccaactgt tgagcaggcc tctctgcctg tggccttccg 7740

gccggtttcc agacgcccag gtggccaaca ttagagtccg cgtagcagtg tgaggtaacc 7800

cactgagata ggtcgggcct gcggagcctg gcgagcagcg gccctctccc tggggcttcc 7860

cttcaatctc cgggacattt ccccgacctg gagctcctcc gcctcaccgc caggcctctc 7920

tgcagattgc aagttcacct gccactaccg ctgccgcgcg ctcgtctgcc tggactgttg 7980

cgggccccgg gacctgggct gggaacccgc ggtggagcgg gacacgaacg tggtgagcgc 8040

ggggccgagg gcgtatggga agggcgagga tgggcaggcc acagtgcagg cattctcgag 8100

ggctgcctgg gtgccgcgcg caaggagcgt tctaattgcc gatttcccgg cggcacagag 8160

aggctaattc tgcgcggggg ctgggagggg agcctggatt gccggctccg caagtactcc 8220

acccgctgca agcggacccg ggcccaggct gacccaggct ccgcgcacgc gcacttcccg 8280

caccttcccg ccctcgcctc cggccagagg ccactcttgt gcgcttgccc ggacgctggc 8340

acccgccccc gttccctgtg gtaggtgggg tctgtgagtg gagctccgga gcgatgaggt 8400

cattcctggg ggcgaagcgt gcgtgtcccc gccccggcgt tcctgcccca atgagacaag 8460

agctagatcc cggcgatcta cgtttcagtc ttaacggttg cggcgcggct ctggcccggg 8520

cgcacgcgca cactgacacg cgtacacgca cgcacgcgac cggggcggtg gttggcggct 8580

acggacgcgc aggactgggg gacgggcggg tacggctatg ggcgaggcgg aggcgccttc 8640

tttcgaaatg acctggagca gcacgacgag cagtggctac tgcagccaag aggactcgga 8700

ctcggagctc gagcagtact tcaccgcgcg aacctcgcta gctcgcaggc cgcgccggga 8760

ccaggtggga gccagggggt gccggcgggc gggaggggaa gcggtcgctg gagctccgcc 8820

ctccccggtc cgttgccgcg tcctgggtcg gtgggcagcc ccaccctcct ggctacgtgg 8880

ctccccgcgg gtcctggccg gggacctgcc cgcggaaccg tgcgtaagac cccgattcca 8940

ccgcctagat gctgggtgcc ggggccccct tggtttctgt cacagacagg ttgaacacgg 9000

aaaaagcagc tgtatggctt gtggtagacc tgagccgggc attatccagc tatgactaaa 9060

gccgaccgag cagtttggac tagcacctcg atttccgcgt tcgaatgctc ctgctccctc 9120

cttggggaga ctaggggagg atgtggagag ggaagagtcc tcgccaggaa ttgagaagta 9180

tgtttaggaa aacttgagag gcagagagag atcctgctcc tccatctgca ctcctgtatg 9240

gagccagctg agccctcacc tcttccctgt tctggcctgt caccagctgc tggaatgtgg 9300

aagattctgt tcccttcctc tagggtggat ctggagaaag atttgggaat agataggaaa 9360

gaagtcttgt tttggaccat aagcattcag gagcacttta cccacaggaa gggggaaagc 9420

tagattataa aatgcctaaa gaggtggaaa aagagatcca ggttactaac ccaggactgt 9480

aaggtgtctc ggaacctcct aggtatcccc attatcggag aactgtgtgc cagatgccat 9540

tggtgtgacc accaggctca gagaaccagg cctaggcacc aggaaaaaga aacagggact 9600

gtgaagctca gtatgcctgg cagaaatggg gcggaaatcc ttatttaagt aaagaaagtg 9660

gagttgtgag tgatgcttca gataaaattt tacaaaattc cttacaaaat gggtggtgct 9720

cagcacgcca aaatcttagc ccagagcttg ggtgcaaggg ttgagttgag tgtagacccc 9780

tgggcttgtc ttcatgtcag tcagtcctga gccattttcc actgtggaaa ggtgggaaaa 9840

ccacaagaca ctaaccaatt gaaaaggagg gctagccacg gaggtgcaca cctgtaatcc 9900

cagctacttg ggagggtgag gcagaaggat cacttgaacc tgggaggcag aggttgcagt 9960

gagccaagat cgtgccactg cactccagcc tgagtgacag agtgagactc tgtctcaaaa 10020

atagaaaagg aagccaagta cggtggctca cacctctaat gccaatgctt tgggaggcca 10080

aggcaggtgg atcatttgca atcaggaatt cgaggtcagc ctggccaaca tggtgaaacc 10140

ctatctctac taaacataca aaaattagcc gggcatggtg gtgtgtgact gtagtcccag 10200

ctacttggga gactgaatca cttcaaccgg gaggcaaagg ttgcagtgag ccaagatcgt 10260

gccactgcac tccaacctgg gtgacagggt gaggctctgt ctcaaaaaaa agaaagaagg 10320

ctgggcttgg tgactcatgc ctgtaatctc agcattttgg gaggccaagg caggcagatc 10380

acttgaggcc aagagttcga gacctgccag gccaacatag caaaaccccg tctgtactga 10440

aaatacaaaa aaattatctg gccatggtgg tgtgtgcctg taatcccagc tactggggag 10500

gctgaggcag gagtatcact tgaacccaga agacagaggt tgcagtgagt cgagactggg 10560

ccactgcatt ccagcctgga tgagagagca agactctgtc tcaaaaaaaa aaaaaaaaaa 10620

aaagaaagaa taggaggctg agaagtccca agttatatgt taaaaaaaaa gaaaaaaaca 10680

tcagttttag gccaggtgca gtggctcaca cctttaatcc cagcactttg gaaagccgag 10740

gtgggtggat catgaggtca ggagttcaag accagcctgg ccaaaatggt gaaaccccgt 10800

ctcgactaaa aatacaaaaa attagccagt tgtggtggca ggcacctgta atcccagcta 10860

cttgggaggc tgaagcagag aattgcttga acccaggagg cagagattgc aatgagccaa 10920

gatcgcacca ctgcactcca gcctggaaaa cagagcgaga ctctgtctca aaaaaaaaac 10980

catcagtttt tatggacagt ggtagagtgg agggtgggtc cctatggtgc agaagggaaa 11040

ttccatggtc ctgctgtgca tccgactggg atggctgttg aaatcctctt ccagcaggca 11100

gctttggaaa cagaaaaaga aactcttcct cctttagaat cctggaaggg ctgtgcagtg 11160

cctctaatcc aagtctgttt tctgagtgaa gatagggagg ttcatcacca gaagggaagg 11220

ggctggaaat gaggtcactg catcccagcc cagggctcct gggtcatcca ggaagggaag 11280

aaggagcaag ctttctcatt gttaggtagg agctcagagc catcacaaga acaagttagc 11340

accatccctg tgccctccct gttctgcaaa caaaatgatc ttccttcttg ccctggcact 11400

agagtctgtc tggcatttct cctgccccta gtactcctcc catctgggta cttcttcccg 11460

ttggtgtact gaacaaacac atccactgct ttattcacag cctccagccc tcattttcca 11520

gggcccacac catttgtttt tactaacccg acaaggttgc ccactgtccc cagtaaggtt 11580

tgtactgggg tttttactcc agtgctcttc tccatccagg agacctttgg atacttgggg 11640

aagaaaatga gcttaaattc ccacccctcc ccctttacct ttttcctgta aggccctggc 11700

cttagttctt agccccacat ccttgctggc tgcagaatag cagcgggttc tgggtaagga 11760

gcattctgct aaaacgctcc accctgctcc ctcatctgtc ctctccattt gtccccatca 11820

gatggtttaa gtgcttaagg ggactccagg gcggagtcag ggagaaccct ggctctcctg 11880

ggctaggcac aagatcattc tacaggaaac cttgtgggaa ttcttctggg acaaagtatt 11940

ggtcagcgct gagcttagct gtgtctgtga cactcgcatt ctaactaggg cctatctgac 12000

gtcaacagga agtaaggctg atgcagtggg gccaagggag tctgggagaa gaaagtcggt 12060

tcagagccct ggctgccctg tcccacactc cacccttccg gcaagaatcc agtccctaga 12120

tgaggtgggg agtgagtggt cgagttaaaa atctctgggt cgggtacgat ggttcacgcc 12180

tgtaatccca gcactttggg aggtgaaggc aggcggatca cttgaggtca ggagttcaag 12240

accaacctgg ccaatgtggt gaaatcccat ctctactaaa aatacaaaaa ttagccgggt 12300

gttgttgtgg cacgcgcctg tagtcccagc tactcgggag tctgaggcag gagaatcgct 12360

tgaacccagg aggcagaact tgcagtgagc caagatccag ccactgcact acagcctggg 12420

cgacagagtg aggcttcgtc tcaaaaaaaa aaaaaatctt tgggccaaat ctccagacag 12480

cacaggcagg tgcagaaacc caccaggaag ctgcctgtgt acctctggca gattggagcc 12540

tggcctaaag ctgcctttta tgcagcttgg gtcaaggtta aacatcatgt cacagtgatt 12600

tttctcacta tgtgtgagac atggagaact ggctccaagt actactctgt ccactggtgg 12660

ctggactact gatgtgcacc actctccact cctctcaccc tgcagtgggt catggccccg 12720

tgccggggca gaggagaaaa atgggctgcc ttctccagga caaaccctca ctccaactca 12780

actagggtgc tgtgatcaga atgtgcaatt gaggtgtgat tttactgatt tttttttttt 12840

ttgagaccga gtttcgctct tgttgcccag gctggagtgc gatggcacga tctcagttca 12900

ctgcaacctc cacctcccga gtttgagcaa ttctcctgcc tcagcctcct aagtagctgg 12960

gattacaggc atgtgccacc acgcctggct aattttgtat ttttagtaga gacggggttt 13020

ctccatgttg gtcaggctgg tctcaaactc ctgacctcag gtgatccacc cgcctcggcc 13080

tcccaaagtg ctagaattac aggcgtgagc caacgtgccc agcctgtttt tgttttttgt 13140

gttttgaagc agggtctcac tcagttcccc aggctggagt gcagtgacac gataatagct 13200

tactgtagct gcaatctccc gggctcaaac gatcctccca cctcagcctc ctgaacagtt 13260

gggactacag gcacaccacc acacctggct aatttttttt tttctttttt tagtagagat 13320

gaggtcttgc tatgttgccc aagctggtct caaactcctg aggatcaagt gatcctccta 13380

ccttagcctc ccaaaatgct gggattgcag atgtgagcca ccacacccag cctgatttta 13440

ctttaaatga gagtccctct tcagagtccc tcagctgttc ctggcccctg gccatgtgcc 13500

ttcagttgcc cctgcttctg tggtatcctt aaggctacat tcagtgctga ggccctaggc 13560

aggcagcaga gagaagccaa atgattctgt ctttccctta tccacccaga gcatgcaaaa 13620

ccaggagcag tggtgggttc agggtgggca ccagctatgt atatgtacat cagggacagg 13680

gggccaaagg cagtcagttt ccaaagactg ccccagaggc catttttcag agaagccctg 13740

ggttcctcaa gggccctgtg tccatgctgg cccatcttgc aggacgagcc tgtggagtgg 13800

gagacacctg acctttctca agctgagatt gagcagaaga tcaaggagta caatgcccag 13860

atcaacagca acctcttcat gagcttggtg agttgactgc tcaggaaggg ggcgtgggga 13920

ggagcaggta cccagctatg tgcctgatac tcagagggtc acaactgagg ttatcttggg 13980

tgggcgcaag cagtaatttg tgcataccca gcctagcccc aagtagactg acatctcacc 14040

tggaacctat tatcaaggtt tggtttctct atttctttag aacaaggacg gttcttacac 14100

aggcttcatc aaggttcagc tgaagctggt gcgccctgtc tctgtgccct ccagcaagaa 14160

gccaccctcc ttgcaggatg cccggcgggg cccaggacgg ggcacaagtg tcaggcgccg 14220

cacttccttt tacctgccca aggatgctgt caagcacctg catgtgctgt cacgcacaag 14280

ggcacgtgaa gtcattgagg ccctgctgcg aaagttcttg gtggtggatg acccccgcaa 14340

gtttgcactc tttgagcgcg ctgagcgtca cggccaaggt gggcttccca ccccaccctg 14400

ccctatgtga gggtatatac gcatgcacct gagcatgcag gggctgagca gctggccctg 14460

tctctgatca ttacttcccc ttcacagtgt acttgcggaa gctgttggat gatgagcagc 14520

ccctgcggct gcggctcctg gcagggccca gtgacaaggc cctgagcttt gtcctgaagg 14580

aaaatgactc tggggaggtg aacgtgagta catagttctt agtttcttgg ttgtcactag 14640

acaggactga tgggctgtag ctacagtaag gcttggagga ggaattgtgc tggaagacaa 14700

gccctgcaaa acagttccag gagtgtatag gcattgtaac taaagcaaag gcttccagac 14760

cactcatgcc aaagcctagg gttgtcccaa gaagccagga agaattgcct tggtgctttg 14820

atctttcctg gtgtggaaaa tcttctggag atgcaggagt ccatctaatg acatgaggag 14880

gcccccttca gactttttac ctggaagctt tctggctcca aggtattagg cctgtggagt 14940

gaaattagac tcagaatatg cctgacctgt ccacaggtaa ttggggaaca tctgacttgg 15000

ttgtctcagt aaggtgaccg ttttgtaggg cccatcttcc atacaaactg ctgtcaggga 15060

tcctaccaga gatcattcag ccaagagcct gacatcagaa agcccagtcc tagcttgtgt 15120

gaacatgagg tgctagtctt ctctggggag ggtctgctgg cttggccatc ccttctgcag 15180

cctgtacact ccccttttgc cccttgcagt gggacgcctt cagcatgcct gaactacata 15240

acttcctacg tatcctgcag cgggaggagg aggagcacct ccgccagatc ctgcagaagt 15300

actcctattg ccgccagaag atccaagagg ccctgcacgc ctgccccctt gggtgacctc 15360

ttgtaccccc aggtggaagg cagacagcag gcagcgccaa gtgcgtgccg tgtgagtgtg 15420

acagggccag tggggcctgt ggaatgagtg tgcatggagg ccctcctgtg ctgggggaat 15480

gagcccagag aacagcgaag tagcttgctc cctgtgtcca cctgtgggtg tagccaggta 15540

tggctctgca cccctctgcc ctcattactg ggccttagtg ggccagggct gccctgagaa 15600

gctgctccag gcctgcagca ggagtggtgc agacagaagt ctcctcaatt tttgtctcag 15660

aagtgaaaat cttggagacc ctgcaaacag aacagggtca tgtttgcagg ggtgacggcc 15720

ctcatctatg aggaaaggtt ttggatcttg aatgtggtct caggatatcc ttatcagagc 15780

taagggtggg tgctcagaat aaggcaggca ttgaggaaga gtcttggttt ctctctacag 15840

tgccaactcc tcacacaccc tgaggtcagg gagtgctggc tcacagtaca gcatgtgcct 15900

taatgcttca tatgaggagg atgtccctgg gccagggtct gtgtgaatgt gggcactggc 15960

ccaggttcat accttatttg ctaatcaaag ccagggtctc tccctcaggt gttttttatg 16020

aagtgcgtga atgtatgtaa tgtgtggtgg cctcagctga atgcctcctg tggggaaagg 16080

ggttggggtg acagtcatca tcagggcctg gggcctgaga gaattggctc aataaagatt 16140

tcaagatcct cctgctgttg gaatctttta tacatataaa gtttttgtag agacatgagt 16200

ctctctgtgt tgcccaggat cctcccaact tggcctccca aagtgttggg attacaggtg 16260

tgagccaccc tgcccagcct ggactcttta ttattatagg cgcagagctg cagttgcccc 16320

tcatggtgcc agaagttgcc aagggtgatg gacaggctcc caggtgtctt gcaaagtcac 16380

catggaccaa tttgtgaaga tgtagtatgc atacatactt ggtcatcact cagctccctg 16440

gggctcaggt tgtggtggag acaaaaatgg actgcagtta gaacttaggg aaactggctg 16500

ggcatagtgg ctcacacctg taatcccaac actttggttg ggctaggtgg gcagatcact 16560

tgaggccagg agttcgaggc cagcctggcc agcatggcga aaccccatct ctaccaaaaa 16620

tacaaaaaaa atttagctgg gcgtggtggt gggcgcttgt agtcccagct actcagaagg 16680

ctgaggcagg agaatcgctt gaacccggca ggcagaggtt gcagtgagtg gagatcacac 16740

cactgcactc cgatagagca agactccaac tcaaaaaaaa aaaaaacggc cgggcgcagt 16800

ggctcaggcc tgtaatccca gcactttggg aggccaaggc gggtggatca cctgaggtcc 16860

ggagttcaag actgcctgac caacatggtg aaaccccgtc tctactagaa atacaaaaaa 16920

attagccggc atggtggcag atgcctgtaa tcccaagtac tcgggaggct gaggcaggag 16980

aatcgcttga accctggagg cagaggctgc agtgagccga gatcgtgcca ctgcacatta 17040

tcctgggcga caagagtgaa actccatctc aaaaaaaaaa aaaaacaaaa ccatcccttc 17100

aacacacaca caccacgctc tgggagaagg tgtggcataa ctccttcacc aaatacagag 17160

ctgccaccgt ggaccagaca ctgctcgtga taccgagggt atagctgtta acaattcttg 17220

ctttcattaa gcatggactc tgctgggttt gaaaacactg aattcgaagt tcttcagaac 17280

tgaatgtaac tatgtgaatc tggccagttc cttaattttc tttcaacttg gttagttcac 17340

ataagcgtgg caatcgcaaa aatacagctg tgaaaataga agccagatgg gcacccggcg 17400

gtctggcctt aggccctgaa gtgcaggttt gaggattggt gcttgcgaag tcctgctagg 17460

cctgaactca ggtgttgggg gacgtcagag ccgccaaata cacccaaaag accgggagga 17520

ctcacggcca ccactttcct cggtgggagc tgtcccagct ggtcagatcg cgcttgctgg 17580

gacctgggat ctcgcaacgc atgctgggat gcccagcatc taagggcgcc cattggtccc 17640

gcccccacga cttgagcaac agccaatcag aggtggcagc gtgcggaagc ggaagtgagg 17700

tttccgtgga gacagccgag cctgcggaag gcggcggcgg cggcacctgc gatcagcggc 17760

tggggcaggt tatggtagtg cggactgcgg tgtgagcaga gcggccacgg ggcccgccat 17820

gcgccggcgg ccctgacatg ggcgccagcg ggtccaaagc tcggggcctg tggcccttcg 17880

cctcggcggc cggaggcggc ggctcagagg cagcaggagc tgagcaagct ttggtgcggc 17940

ctcggggccg agctgtgccc cccttcgtat tcacgcgccg cgggtaaggg catgggttcc 18000

accctggcgg ggggaacagg cgggcggcca ggcgtcccgc gccacggggg aacttccacc 18060

gctgtacccc actacagcca agccaggacg acccccatat tttgagcctc attggagctg 18120

ggggtggaga aagccgggca gtggtctcct g 18151

<210> SEQ ID NO: 14

<211> LENGTH: 20911

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: misc_feature

<223> OTHER INFORMATION: TBX3

<400> SEQENCE: 14

agggatctcc aggctgtcat ggttgctggg aaagatgagg gagggaaagg gggcagagta 60

cggaggcacc aggtcagaaa gacaggagag aattcagaca ggaccaaaac agccagaaaa 120

aataggataa agaaggtaga aaaaaaaaaa aaacaaaaca aaacatgaga agttaaagcc 180

tgggaaatag atacaagaca agaaagagaa atagaaacca agaacaagat tgatgaaagg 240

aggagaagag aaagtagaag gaaaaagaat aagaaagatt ccagacacgc attcaaataa 300

tcctaaatgg ggatgagcag aaagacaagg agaccaaaag aaaagggggg gggggggtgg 360

tggggaggag aaagaaagga atggaaaaag aaacaaaagg tgaatgtcct gccctgtctg 420

tctggtccaa ccaagaagct agtgtctgcc ctggagggag gaaaggtggg ggagtccagc 480

ctgtctccaa gggactgaca ggcagcttct ggaccagaga ggaactaagc tctcaaagca 540

agctttgggg aggaggaagg gatgggggtg catggtgagt ggagactcct ggaggaagag 600

caagcctcca ctgggttcag cactgccagg gggagagtca gggttcaggg tagcatagca 660

gtgctaatgt atgtacccca gaggggtagg gggtgctagg gcaatttgca ggaggaccac 720

aaacagtaaa ctagagagct acttccctgg gatccgtgat aagaaaatca cttcctcagg 780

tgggagaatt gagcccgaaa gagaatggga gcccttgggg ggcaggcacc tggtcagttt 840

caaagctcgt caatatcaaa agaggctggg atcctgagat caaatgggct ggggcactgg 900

gcagaaacga ggagccattg ccaaactgcc aggatgacca gaacgcccct cccccaggaa 960

aagttcatat atgaacccac ccctgtatga aacttcttaa ttaggtctca tacccccggt 1020

gaatcttgga tgcccttctg tcaacagaat tcccaattta gtgacacctc ggactgaaaa 1080

gagctctgcg gcaaacgggg gtgaaagttt aagagggaat aagcatataa tactcccttg 1140

ccagacctca cacatgctga agggaatatt tacagcaaac tggccaaagc aaacgacccc 1200

gcctacccac catcctttta ccctcctccc cgcccttttt gtaaactcca gataaacacc 1260

atttgatcac aaaagggtcg gtttgtcccc tttatagttt gaggcaggca gtgcggcagg 1320

gaaaagtggc gtgggctaag cttccgtctc gggcaaggcc agcttctttg ctggcaccgt 1380

ggcctgggct aaggacagtt gatttggttt tgtttccccc gacccccacc ccgaccccac 1440

ccccacaaag gaacattatt ttcagggtcc tccccccacc cagctttaac actcgcctac 1500

ttgcacccgc actactttaa atgctgcggg cattgcagat agagaggttt ttcagttaat 1560

ttactttttt aattctagag ctacaattaa gtgaaaactc tttttgcgaa aaggtggagg 1620

aatatttcag agacgccaga aattatctgg gtcttttctg acccggaatc tgccctcttt 1680

ctcccttctc ctccccttaa gtcacccttt tctgggactc tgttgaaggg caggctcttt 1740

caacgtctct agtctgtctt ttgttgagtg tgagaccgaa ggaaagagga tcgaggggtc 1800

tgcagagaga aaaagaccgc agatagccgg cagctggcgc ctaatgccgg ggtccgggga 1860

gcgctggcct cgtgggttct cctggaggcc aggcccagca caagccttcg gaacacgctg 1920

gccaatgttt aacccgaatg cagtggccac caggccgctt ttgtttgttc gcaaattaat 1980

cacccagcgc atggccggcg ccagagtggg tttatcaccc accgggaggg gggcgcgccg 2040

ggcacgcaga gacaaagagg agttcgcacc ttcccgcttt tgatcccaga attacggcgg 2100

cctccctgcc taatacgagc ctcctggggc cgagtctggg aggtcagtca taattggcgg 2160

aagtttgcag accattagca agatgtcgac attttcgatt cgaaccccgc aaactttcct 2220

ctcgttctct gcttcgcgcg ctggaggttg gtgtgggaga ggagatgggg gtcagaagta 2280

gcgatctggg gtgatcacag ggttaagtta gagctatggg caaaaaatag gcaattgagg 2340

gaggaggaca gtgtgagggg cagaactccc tctcagtcca cccgcggagc caaaaacaaa 2400

tctagacatt tttaagtaaa atccgcaagc tcccctccca tttccaaagc tgacagctgg 2460

ccagaatgca gaggaatgtc tctctgctgt gcgtgggacg cttgggggca ccgagtgggt 2520

gaggaggagg tcggtcacag tgtggttgta gaactacttt gcttccaccc caagtagtgg 2580

ggcagagatt ggcctgcgag ggcaggcagg caaaaccaga tcgctgggat ttggggccgc 2640

tcttgaaaga gcagcgaagg ggccccaggc cccggaggcg agcagtctgg gggagggggt 2700

gcactttttt tttctatttc tttcttttct tttctttttc ttttttttgg ggcgggggtc 2760

cccagagact catgaaaccc tgcagtgact tccgtgttct gtgtaaggcg ggaaatggcc 2820

tggcctttcg cacccttcag gtggggagga ggggatgcgg gagggggtgt tatgagccaa 2880

cactctgggg caccaccacc tcgtaatttt ccctctctct cctttctcta ttttaaccac 2940

tggcagagac agagaggacg ccagagaaag acagactgaa agggaaagaa aggggcgaga 3000

tggcgagcca gacggagttc gcagaaccac actattctct ctggtgactt cagggaattc 3060

tcaacgctgg cgccaagctc tcttaaccat gtgcgtcaaa aatgcgaggc tggagaagcc 3120

tgtcgcctca aaagatcctc ccctatctca gcgtggttgg cccacaagag cacttcattt 3180

tcacccttcc cttggtgcca cgttggggtt tcggggttgc tgggggttgc gcgggtgcac 3240

aaggcaaaat gcgagagagg cctgtgctgg cctacagaga cacacacatc caaagccctg 3300

agtctcttaa acccctaagc ccccagatca gccctttctc cgttcccttt ccatcgaaga 3360

agctttcatc tcaggaaaga taaaagaaca ttgttttcaa gatttccctc catctaagca 3420

aggatggtcc aagacattgg cccccagaat caagaactgt gggcttaggc gaatcctctg 3480

accccgaccg ggcgctgcgg taacagagtt ggtaattcgg cgattggtaa gatccggtcg 3540

tttccctccc gtccgcctaa gaggaggccc ccaccctacc cgtactaaaa acagtcaact 3600

cgcctctgag gtgggggcgt ttcacggttt gttttacaaa ttcaccctcc ctccccgact 3660

tctggccaga ttaagtcccc ggggtggaga aagaactgag gcaccgagag ataagtgcga 3720

tgcctagaga agataccagg ctggcgcgcc tcccccaacc caatcgccca ccccttaccc 3780

tgtgctgtgc acccagccgg gcctcgaggt gagggcagcg gcttggaggg gacaggctca 3840

gaacccagtc tctcgctgtg ctcgctttgt ccagatcctc cattctcttc tctacaccca 3900

cacccacatc caggtggaat atgggggccc gcatgcaaat gaaagacgag atccaaaagg 3960

gctggtaaat gcatttcata aaaatcccaa atccatcttc cccaggagct caggcagggc 4020

cagccgcgca ggctgtgtac gtgtttgtgt gtacgtgttt ttcggtgtgt gtttcagtcc 4080

cagtgtgttg gcgcgtgttc gagtacagat acaccggggg tgtttgggta cccgcacatg 4140

gctgcgggtg gggcgcagtg gagaggaagc ccacacatgc gtgtgctgag atatggccgc 4200

atccttgtgc tcccccagcc cagacgcagg ggagaccagc accgagacac ccgagctcgg 4260

gagcccttca gcggcggccg ggcggagctt ggctccacgt ggggctggag agcacgcaag 4320

cctggagtct cggcgctcgc ttctcggctg ccgccggctt ttgtagaacc gagtggccgg 4380

atggcagctc gcggggaggc tcggccaccc gcccggctcg cccggggcgg ggagaagaag 4440

gagagctgga gagagaaccg gccgcggcgg tcggagaggc gagcggagtg caagagaggc 4500

gagcgcccct gcccggcgcc cgggcgcgct ctccgccttc cccgcccggc tcgcctgctc 4560

gctggctccc tccctctctc cctccccctt cctccttggc cctgcctcct ccctcgatcc 4620

ccggctggat gactgaggca tttcagacgt gggctgaacc agagcgagcg agcgagctca 4680

ggggctgcag cgatctctcg ataagccacc tagaggcgac tctgtgcgcg cgcgctcccc 4740

agtggctccc gcccgccctc tgatcatgtt gacatattca caggacaggc agtagtaccg 4800

atgcggcgct gcgacgttac agtttccgac accttctttt tataactcag ctctatcccc 4860

cagcactcga cctgtgaaaa ccacgcctat gcagcaacac aattggtccg aaagcgtcaa 4920

agagccaatc aagaggcctc cggctccccg cagcccacag cgcagcccga ccttctagag 4980

ccgccgagca gacgcccggt gaattctaga ggcggcggag ggtggcgagg agctctcgct 5040

ttctctcgct ccctccctct ccgactccgt ctctctctct ctctctctct ctcccctccc 5100

tctctttccc tctgttccat tttttccccc tctaaatcct ccctgccctg cgcgcctgga 5160

cacagattta ggaagcgaat tcgctcacgt tttaggacaa ggaagagaga gaggcacggg 5220

agaagagccc agcaagattt ggattgaaac cgagacaccc tccggaggct cggagcagag 5280

gaaggaggag gagggcggcg aacggaagcc agtttgcaat tcaagttttg atagcgctgg 5340

tagaaggggg tttaaatcag attttttttt ttttaaagga gagagacttt ttccgctctc 5400

tcgctccctg ttaaagccgg gtctagcaca gctgcagacg ccaccagcga gaaagaggga 5460

gaggaagaca gatagggggc gggggaagaa gaaaaagaaa ggtaaaaagt cttctaggag 5520

aacctttcac atttgcaaca aaagacctag gggctggaga gagattcctg ggacgcaggg 5580

ctggagtgtc tatttcgagc tcagcggcag ggctcgggcg cgagtcgaga ccctgctcgc 5640

tcctctcgct tctgaaaccg acgttcagga gcggcttttt aaaaacgcaa ggcacaagga 5700

cggtcacccg cgcgactatg tttgctgatt tttcgccttg ccctctttaa aagcggcctc 5760

ccattctcca aaagacactt cccctcctcc ctttgaagtg cattagttgt gatttctgcc 5820

tccttttctt ttttctttct tttttgtttt gctttttccc cccttttgaa ttatgtgctg 5880

ctgttaaaca acaacaaaaa aacaacaaaa cacagcagct gcggacttgt ccccggctgg 5940

agcccagcgc cccgcctgga gtggatgagc ctctccatga gagatccggt cattcctggg 6000

acaagcatgg cctaccatcc gttcctacct caccgggcgc cggacttcgc catgagcgcg 6060

gtgctgggtc accagccgcc gttcttcccc gcgctgacgc tgcctcccaa cggcgcggcg 6120

gcgctctcgc tgccgggcgc cctggccaag ccgatcatgg atcaattggt gggggcggcc 6180

gagaccggca tcccgttctc ctccctgggg ccccaggcgc atctgaggcc tttgaagacc 6240

atggagcccg aagaagaggt ggaggacgac cccaaggtgc acctggaggc taaagaactt 6300

tgggatcagt ttcacaagcg gggcaccgag atggtcatta ccaagtcggg aaggtaagca 6360

gtgggggcct cctcccctaa gctgttggag agttttttcc tccctttatt tctctgctcc 6420

cagaacagtc ggttggtcgg ttattacggc ttggacgaaa agttagttcc cctagaaatg 6480

tatgcacaga cttccaggcc ctgccccggt ggcaggaaat ttcagcttac ctgggcatct 6540

gcatgggtct tgcatttggt ctgcatcctg ggttccctcc cgaacagaca gaatttttca 6600

gtggagcaca gacatccctg cagggagcag gaaagaaaaa aaaaaaaggc actctactgc 6660

aagaaactca ctcttcaaac cctcctggaa catccttatt tctttgttga tgttgtgttg 6720

tctgttttat tttgttctca gagagaaaaa cttaaagccc tttccttttg tgtgggtatt 6780

gggaggcctg acaccattcc ccggcccttt ctgccctcca gtctagcctc tgggtctaaa 6840

ggggcctgct gctgccctgg tcagagagaa atcgaagggc attttggttt gtttgcccac 6900

actacttcac gtgtctgtaa cccaagggcg agttcagcag gcaattttgc ataatttaag 6960

attatgtttg cagacttaag gagccagtga ggagacacac accttttttt taatgtgtga 7020

atattatcaa ccatatttta cataatgttt aaaggtcctt gcctgaccaa aacctgcctg 7080

gaagagaaga tcctgtaata gtcatttaaa atcactgatt ttttttttgt aatagcattg 7140

aagcctgtaa aggcataaag ttgatacaaa aataaaatcc ccttcatgat atcttaagcg 7200

ttctgtctcc ttccaagcta aatgaggcca aagtttggca taaaatcctc ctcaaactca 7260

caagacattt agtcagtttt ccagcaaagt gcttccttgc ttccttttaa gtcaagacta 7320

cagaatgcca acccttctgt gaaattaaca gcaatgtggt ggcacagtct tgcggttttg 7380

gactggccta agaagtgggg gaatgtgtta gcagctccac gggcagatcg gttatcaggc 7440

ccaggagtgc accgaagtct gcaaaattcg ttctgggaac tcactgaagt ccagtttcac 7500

ttcgcccaca gcgggattgc tattctgcag cagggagggg tgcaacttga cgttcatttc 7560

cttgataagt ttaacatttt ctcatcaatg ggtggtggaa aattctagtc ttaactgacc 7620

gcgctttaca aaaatcttac cccaacctgt ttagatctag atacccacag aaaaagacat 7680

gggcaagaat ttgctctcag gagggcaatc tgtaaagtca agcaaggaca aaaaaaatat 7740

tgaagaaatt gttagacaat gtagagaatt gcagtgccac aatgcatttg ttttgaacct 7800

tgggacgtct aaatatggcg aaactgagaa tatttaatac gttagttgtg gaagaaaacg 7860

attttgcaac cagttgcctc actctgaaac atgtaagctt atcagtcaca atataaagtc 7920

ttagacttgg tttcaatatt atgtgataca taggaaatca aacccaagat tacgggtggt 7980

ttatctttct ttttcttttc tattctttcg ttttataggc gaatgtttcc tccatttaaa 8040

gtgagatgtt ctgggctgga taaaaaagcc aaatacattt tattgatgga cattatagct 8100

gctgatgact gtcgttataa atttcacaat tctcggtgga tggtggctgg taaggccgac 8160

cccgaaatgc caaagaggat gtacattcac ccggacagcc ccgctactgg ggaacagtgg 8220

atgtccaaag tcgtcacttt ccacaaactg aaactcacca acaacatttc agacaaacat 8280

ggatttgtaa gtttcattgc tctcttcagt aaaattttct cctccttcac tcagtcaaag 8340

gcagtgcttc ccatttcatg agtttcagcc cagacttctc ctttgcttct ccctaagcat 8400

agcaaacttg tcctcgtctg gaaaaaggat tcggggtgtt tctctccaaa taatggaagg 8460

cctggcgttc taaaagaaat ggggcaagaa aacttaccgg cttgtgttct atagcaattc 8520

cagctctttg gtagattcct gacctgagag tgaagttaaa aaccattttt taagagctaa 8580

aatcaatttc aaggctatgt attcctaaag gatttgtttt gttttaaaat atcatacttc 8640

tgttttgaaa ccagtgatat tattttctca ggagagttta cgtttcggag ccttgactct 8700

gttggttaaa tggtgtgaat acatttttaa aaactcgttc ttttactaaa aaaagaattg 8760

ggcttaggtg ggagtccggc ttaccctaaa tgaggcttag atcttcagaa aaaaatggtt 8820

tgtgtgttgg gagtgtatat atggattcag tgacagtgct tagaaactta gaaaactttc 8880

attgcttgta gatatcaggc aaaggacctt ttgcgccttt tcctacccct ccccaacatt 8940

tcaataaaat aaacagcgtg ataagcaagg agtaagcaga aagattaggc ccaggaagac 9000

gcgaatggcg cggaaatatc ttcagcgggc aggaattgca tttgaagccc ttgatttgat 9060

taaggcataa atattcctct ctagagttca gcctttcagg gctttaagtg gattgggctc 9120

gtcaattagt gggcgcttaa agtactgaat cattttgtaa attaaaatgc atgtttttct 9180

ctatctttta agactttggc cttcccaagt gatcacgcta cgtggcaggg gaattatagt 9240

tttggtactc aggtaggcta gggttcaagg tatgaatgat ccttagatgg tgagggtggg 9300

gggggccctt tggcaactga ggagcaattt ggattctcca gaagataaca tctgtggagc 9360

gaaacgtacc cagggggtac tccaaggagg tgggctcggt acaagcgtgg taccctgcgg 9420

tggggaagat ttcagcctgg caggggtcct aagatcccgt ttgttctgct aaatccttgt 9480

tttatgtatg tctcctcttc cctgcccctg cagactatat tgaactccat gcacaaatac 9540

cagccccggt tccacattgt aagagccaat gacatcttga aactccctta tagtacattt 9600

cggacatact tgttccccga aactgaattc atcgctgtga ctgcatacca gaatgataag 9660

gtaaactcaa ggggctttcc tttttaatgg tgatattttg ccttcccctt aaaagctgct 9720

ttaagtcagg atgagaaagt tacaagagag tggagacgag agtcttgagt tgtcttttgt 9780

gatttgtgga gcatttgggg ggaaaggaca atgacacctc gaggagacag aaaaacacct 9840

tgactaggta ggaacaatgc tgagcaaaaa aacgccatac taattttgcc acagagaaac 9900

tcctagaact gctgtcattg atgccaccca ctcctccccc cctcttgggc tttgtcctgt 9960

ctgttttaag gttcatcttc ttccccttgg ggaagaagga tcaagaagtc acattcaaaa 10020

ggaaccagct aaaaatttaa ggcaaaagcc atttgggatc ctgggaggag aatcctagta 10080

gagaccagct tttctcccct agccagaaat cctgagtagc tggtctggtt tttattacct 10140

tttatgctgc tgtgttatga tgtgtgtgtg tgtgtgcatg tgtgtgcatg catgcgtgtg 10200

gttggaaaaa cctaccctga tcacagggtc atattaatcg agttgtctga ggcttttgag 10260

ttggggtggc caaagtcacc acttcatttg aattcccccc ctcccccagg cctgaatctg 10320

gaggttagaa ggatccccaa aagggaaagc acctgatatc tagagctatg gtggcctgaa 10380

ggtcatgggc acagaaaaag tgacccttac tgctgattca ccagttccca gattggctgt 10440

tagcagttat ggggtgggag gagggactga agacccctgc tctgcaatcc tggacttcaa 10500

agagagtcca ttttacctga caacacactt cattttgaac tcactgtcat tgtcactgtc 10560

cttgggtcct ctgtggactt catgatgggg atgttccagc taaatttctt tagtgtgaat 10620

accaaaacat gatcttctct ccctgtgaaa cctgaagtct tcaatagagc aatttattcc 10680

aagaacatga atccaaccaa gggtccccct ttccacctct gagtaactct gtgtatataa 10740

cttcttcttc ccaccaaggg gaagggattt gaaagattac acactatagc atttttctca 10800

aagtgcaaaa tgcatgtgcc ctctagaccc agaatcctgt gaaatgaagt tgttaatgta 10860

ataataaaat gtagcatttt tgatcagaca aaaaggccat gggccttctc cacctaatgg 10920

ccatggcaga gcatataaat gaaaacagat gtttccagtg gtcattcagt actgtaactg 10980

tcaatattgt aatttcctca aaccaccccc caggcaaaga aaaaaaaaat taaactcact 11040

cccgcactca ctcccgcaca agggtagtga aaccccataa atcatttatt ggattcatgg 11100

aaaaggagtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgaaggga gtatgctata 11160

atttatgatt aattgcactg tataaaaatc aaaatgaaag cataatttta agatctacag 11220

gttttccctc ttgatgactt tgacaacact tccatgtcta aacccaaact gttggctgcc 11280

caaagaaaag aatttctttg aataatttca tccccaaatc cctggtttgg cctcatatag 11340

gagatacaag ccctgccaca gtttccttat tatctccttt ccctggcata tctatatgac 11400

ttctgttggc agtcacatct ctagacttgt tgagttggga aaaacaccct caaaacattc 11460

tagaaaatga gaacaatgtc tctgtcttgc ttgtgtctct tccaatagat aacccagtta 11520

aaaatagaca acaacccttt tgcaaaaggt ttccgggaca ctggaaatgg ccgaagagaa 11580

aaaaggtgag ttgaaacaat tatttattag atagtttaga aaaatccctt tttttaggat 11640

ccaactctga agtgttagaa gtgagatgca ggcacttatc ctaagagcgg gtggaaatca 11700

ttcactttcc ccactgctac atgcttgccg ctatcagtat acccaggaca agtacttttc 11760

ctacctcctt acctttaagg aaattaacta ggctacacca tacttatctc tggaagagaa 11820

gcatcaggga taatagatta tacagggatg cctattaatt cctaattaat ttaagttcat 11880

cctaggcagg tcccagaaag aaccatgcca ttgagaaaat acttgggaat ttttgcaatc 11940

ctgtcttcca aataccatca gacagagctg gggacttcgg aaagatgtat ggctctctcc 12000

ctccttcgtg gggacatgta tcattttgca ttacgtagac agctggagag tatatgaaag 12060

agggtctccc ctcccccacc ccctttcaaa gaatttctaa aatccagaaa atcaccccca 12120

aatttttaac ctatcccctt ggggcgggca ttaaaaaata attgctaaca gctaaatata 12180

tttttattcc aattaatttg ttagtaaaac gattacagta aagtgcagca tgaaataacc 12240

acttcctccc aatcttagcc accatccaaa atttgggtat gctggggaca gacagcgttg 12300

tgtttgcagg attggacacc cggttctccc tatataaggc tggcagtcca gctgtctctg 12360

actagatcca gcctcttctc ctgcttttaa ataaaatttc acagcccaag caaatgcctt 12420

ttcctaatga aaccccatct tgaataaatg caactgaagc ctccttcctt tctccctaac 12480

cctctgccac actcttcagc ccagttagag ggtcaaggac aaagcttggg tctatgtggc 12540

tgccctgggg caagcagatt tcagtgaatt agcgttgtcc ctgggcagca ggcagggtgt 12600

gaggtatgtg tgtgccgctt tggaaagggt aagggaaaca aagaggggaa atgtatgtta 12660

cattctgtaa cctgggtgtg ggcttctgcc acagaaaaca gctcaccctg cagtccatga 12720

gggtgtttga tgaaagacac aaaaaggaga atgggacctc tgatgagtcc tccagtgaac 12780

aagcagcttt caactgcttc gcccaggctt cttctccagc cgcctccact gtagggacat 12840

cgaacctcaa aggtaaacca tgtcaccttt gtgatcactg gactccagtc cctcgtggcc 12900

tggaagagtt gaagggggat ggggcaccaa ccagggcact tgccctttaa aagctagaag 12960

ccttctaaac atccttaaac agaagccaga gttcaaaaag ggctatcagg tgtgtctccc 13020

cttccccgct aaggcagtag aaggagagca cagaggcctt tctcccagat ccttatttgg 13080

ctggtgggga ggggaggtgg gtgtctgttt gcatactacc tcttggcaag cagctttgaa 13140

aacttgcttg aagcgcttct ctcttttctc tctgtctctg tttctttctc ctcccattct 13200

ctccaaccaa cagaggctcc aactgctgac ttttcactgt ctttgaactc taggttacaa 13260

tgtgttggac tgggtggggg ggaagcaagg gactctgcca cctggaaccg agaaggtggc 13320

ctagaaaaca tccagctata aagcaacaat tgacctggga gaggaggtgg agcactgggg 13380

atctgcggtg ggggtagagc tgggggaggt gggtgaggag tggacaagat ggctcaaatc 13440

ccccctcagt tacctgtgtt taaagagcaa gcagtattta tttggaaaga cacacacaca 13500

cacacacaca cacacacaca cacacacaca ctctcaacgg gaagaaacct gttttttagt 13560

gaaataaaat gcaagtcctt tatgtcttca atccatttaa gctttaaaca taaaatagga 13620

tccctttttc ttttcttctg gtggaacacc cacagagggt gtggtaaaag cgaaaaaaga 13680

atctatgatc gtccccgggc tgtgagccat ctgtccgaca ctcatctctc tctgcaggga 13740

ctggggcaaa tacaaacggt tcaactgagt actggtgttg aaggacaggt gtccgttctg 13800

ccattatcaa ttcagatgtc agggttcttg ccaaacaaat ccttccagag taattcacaa 13860

atttgtggaa ggtgctgctc tctgtcattc actgattttt tgatagtaat tagaatatgt 13920

tccagctgtg agttttaatg ttacttttta cttttaaaaa gttaatttgc aatcgaatgg 13980

ggagatgcat gtgaaatctg ccactgtagg aactcaaaaa aagaagtaaa attcattaaa 14040

ataagaagag ctactgatta ggggattgtc catctaaggg aaagtttaaa ctctgggtaa 14100

atactttaaa ttcataatcg cttattgaat tttccagcaa tgttgttggg cacgattatc 14160

cccattttgc agatgacaac actgaggtgc agagaggcta aggggctttc cccgggatta 14220

cacagccact aagccacgag ctgggattcc aacttgggaa ctggagttcc gttggctcat 14280

actggagata acgcccttct gccttggttt tttccttcgc ctgtggtaga tttatgtccc 14340

agcgagggtg agagcgacgc cgaggccgag agcaaagagg agcatggccc cgaggcctgc 14400

gacgcggcca agatctccac caccacgtcg gaggagccct gccgtgacaa gggcagcccc 14460

gcggtcaagg ctcacctttt cgctgctgag cggccccggg acagcgggcg gctggacaaa 14520

gcgtcgcccg actcacgcca tagccccgcc accatctcgt ccagcactcg cggcctgggc 14580

gcggaggagc gcaggagccc ggttcgcgag ggcacagcgc cggccaaggt ggaagaggcg 14640

cgcgcgctcc cgggcaagga ggccttcgcg ccgctcacgg tgcagacgga cgcggccgcc 14700

gcgcacctgg cccagggccc cctgcctggc ctcggcttcg ccccgggcct ggcgggccaa 14760

cagttcttca acgggcaccc gctcttcctg caccccagcc agtttgccat ggggggcgcc 14820

ttctccagca tggcggccgc tggcatgggt cccctcctgg ccacggtttc tggggcctcc 14880

accggtgtct cgggcctgga ttccacggcc atggcctctg ccgctgcggc gcagggactg 14940

tccggggcgt ccgcggccac cctgcccttc cacctccagc agcacgtcct ggcctctcag 15000

gtatggatcc ttcttcctgc ctccaccagt ctttccacct ttcgtccagt ttccctgtcc 15060

tttgccagca gaccctcacc cgatcccttt ggcctagtag ctgtaataat ttttactgag 15120

ccattaccgg gttcaaggct tagctcatgg agttattatg acttcattct ccccattcac 15180

cccaaaaatc tttaaaattt ttccgaagtt aaaggctgtt tccagcagag tagataggta 15240

gtaacaaaga taacagctgg acacagcact tactttcagg cattcttcta agtgcttgct 15300

ctgtattgac tcatttgacc taacccttca ggggtactat tatcacctcc actttacaga 15360

tgaaggcgaa gacgcccaga gatgttgagt gacttgtcca aggtcacaca gcgggtacat 15420

ggtggagctg agactcaacc ccaggctatc tgactccagg gcctctttga gggtttctga 15480

ttttagcttc agagctgaca tgtctcttaa gtgtctcata gccaaccctt ccccaggaat 15540

gggactctag gcctggggag gggaagtgac tacttcctga gtaggagttc agtcttgatt 15600

cctccagcct ttcctcccag ttcgaagctc ttctccccac ccccaacccc aagcaggcca 15660

gcctattcct cgaagggtta atggtttgtg cacacgtggg aaatgtcaga ggacagggat 15720

aagcagggac tggggcaggc ctggaggcct gtgtgtggct cagacagctg tgctgggggg 15780

aggtctcagg cggctggaaa caccctgaac tcgatgaaaa ggttctatga ggttttgcat 15840

gctgttgcct tttgttttgt ctgagcacat tcgtctggtc tcccttccct gcgccaagaa 15900

accagattgg cctccccact ccagggagga gggagctgag gaaaggcttg gcttctggca 15960

tttctcaatt cctcccatct cctctgctgg cttctccggg agaccctgtc ctaggtgggc 16020

aggtggttgg tacaccaagg actacctgaa cagacaaaac cttaagggca cctcaaggca 16080

tgatgcagag aactggccca ggccagggtg cctgcatctt aaatgctgct tctgccaatt 16140

cccagcttag tgcactcctg aactcctgcg gcctacctcg gcttctcacc tggaacacca 16200

gtgaatcatg ctggacgatt tctttgtctc tgtttataac aaatgccctt tttccctccc 16260

ccagccccag tttccttttg cttaagatct tcactgtctg ttttttttgt tttgttttgt 16320

tttgtttgga gaaacttcta ggattggggt gggaggatgg gggttgggga agaagaaaga 16380

tttaaaaaat tattcctact aatttatgtc ctccggcttc cccttggtta cctctgtggg 16440

gtaaactgaa tctgtatccc catttaacag gtgcaaggag atttcctggg ggctgcacac 16500

actgtgtgca gcatattgca ggctttcact catttaatat ctacaaagtc ctcaataagt 16560

atatgaatta cttatgattt ccctgttttt tcttcctata aggaagctga ggcacaagtt 16620

aatcaaagtc tcttggccta gggtgacaca gctaagattt gtacctagag atttctgagt 16680

gttgacttct ctcctgcccc cacctatctc cccccccaaa aaaaaaaaca caacaacaac 16740

aacaacagaa cataccaggg attcatggct tgcccaatgt tggaggggga gaagagagga 16800

gagggatgag ataagctcct cccacccggc tgactcgctg tgtgtctctt ttctcacccc 16860

agggcctggc catgtcccct ttcggaagcc tgttccctta cccctacacg tacatggccg 16920

cagcggcggc cgcctcctct gcggcagcct ccagctcggt gcaccgccac cccttcctca 16980

atctgaacac catgcgcccg cggctgcgct acagccccta ctccatcccg gtgccggtcc 17040

cggacggcag cagtctgctc accaccgccc tgccctccat ggcggcggcc gcggggcccc 17100

tggacggcaa agtcgccgcc ctggccgcca gcccggcctc ggtggcagtg gactcgggct 17160

ctgaactcaa cagccgctcc tccacgctct cctccagctc catgtccttg tcgcccaaac 17220

tctgcgcgga gaaagaggcg gccaccagcg aactgcagag catccagcgg ttggttagcg 17280

gcttggaagc caagccggac aggtcccgca gcgcgtcccc gtagacccgt cccagacacg 17340

tcttttcatt ccagtccagt tcaggctgcc gtgcactttg tcggatataa aataaaccac 17400

gggcccgcca tggcgttagc ccttcctttt gcagttgcgt ctgggaaggg gccccggact 17460

ccctcgagag aatgtgctag agacagcccc tgtcttcttg gcgtggttta tatgtccggg 17520

atctggatca gattctgggg gctcagaaac gtcggttgca ttgagctact gggggtagga 17580

gttccaacat ttatgtccag agcaacttcc agcaaggctg gtctgggtct ctgcccacca 17640

ggcggggagg tgttcaaaga catctccctc agtgcggatt tatatatata tttttccttc 17700

actgtgtcaa gtggaaacaa aaacaaaatc tttcaaaaaa aaaatcggga caagtgaaca 17760

cattaacatg attctgtttg tgcagattaa aaactttata gggacttgca ttatcggttc 17820

tcaataaatt actgagcagc tttgtttggg gagggaagtc cctaccatcc ttgtttagtc 17880

tatattaaga aaatctgtgt ctttttaata ttcttgtgat gttttcagag ccgctgtagg 17940

tctcttcttg catgtccaca gtaatgtatt tgtggttttt attttgaacg cttgctttta 18000

gagagaaaac aatatagccc cctacccttt tcccaatcct ttgccctcaa atcagtgacc 18060

caagggaggg ggggatttaa agggaaggag tgggcaaaac acataaaatg aatttattat 18120

atctaagctc tgtagcagga ttcatgtcgt tctttgacag ttctttctct ttcctgtata 18180

tgcaataaca aggttttaaa aaaataataa agaagtgaga ctattagaca aagtatttat 18240

gtaattattt gataactctt gtaaataggt ggaatatgaa tgcttggaaa attaaacttt 18300

aatttattga cattgtacat agctctgtgt aaatagaatt gcaactgtca ggttttgtgt 18360

tcttgttttc ctttagttgg gtttatttcc aggtcacaga attgctgtta acactagaaa 18420

acacacttcc tgcaccaaca ccaataccct ttcaaaagag ttgtctgcaa catttttgtt 18480

ttctttttta atgtccaaaa gtgggggaaa gtgctatttc ctattttcac caaaattggg 18540

gaaggagtgc cactttccag ctccacttca aattccttaa aatataactg agattgctgt 18600

ggggagggag gagggcagag gctgcggttt gactttttaa tttttctttt gttatttgta 18660

tttgctagtc tctgatttcc tcaaaacgaa gtggaattta ctactgttgt cagtatcggt 18720

gttttgaatt ggtgcctgcc tatagagata tattcacagt tcaaaagtca ggtgctgaga 18780

gatggtttaa agacaaattc atgaaggtat attttgtgtt atagttgttg atgagttctt 18840

tggttttctg tatttttccc cctctcttta aaacatcact gaaatttcaa taaattttta 18900

ttgaaatgtc tttgggcctt gtgttaaatg ttttttcttt gggaaccttt cctgaagatg 18960

gacagtcagg ggagggttta gtatcttctt gttctgagtt tacccccttc ccttcgcctt 19020

taaataatta agaccgcccc cagcgaacca aaatgagatg tcactcaagt tacaaagcta 19080

aaaacaaaag tcccttactt gagcgaaggg agccacttca atctgaaatt acttttcctt 19140

taaattaggg agcaaagcag ggagacggaa aggggcctga tgagaataca gaaagaaggg 19200

taatttcaga tacttttaag ttttaatgga aaaagactga tgtgctccct aagtcaggtt 19260

ttcccacccg aatccgacca aaagtaagct cggcaagtac gaatgttttt cgttttaagc 19320

tcgccctcag ttttgacatc aatctggcga atccaagtcg aaaatacctt cttgcaccag 19380

tgtgtttggc tcggggaaaa ggccagcaga atgccccagc agtccgagcg ggcttggcta 19440

ggcagcaacc ctccaggttg tagaagtgga caagacgcaa cgcctttcca ctcggcaacc 19500

ccccacacag cctgcagtcc ctggtgcctc aaattgaacc cggctggccc aaggcgcccc 19560

tacgaggccc catccatccc gagttgtgcg tgcaaagcgc ggccagctcc gcgaaaactt 19620

agctgtgtca cgcgagggag gagggaaatt atccccgaaa ggggaaaggt aattccaggg 19680

tgcacatttc accccctcca cggcaaaagt cacccaggag gctgacatcc tcccctagtc 19740

tccccttcaa acccgtctcc aggctgttcg gggagttgcc ttttgaagtt caatttatct 19800

ttgaaacatt caataaaaaa tgatgaggca ctgtcagtct tttggtctcc cgacccccag 19860

cctcgcctcc gaggtgtgtg tctgttgggg ggcgggggcg gcacgggaag gttcgagggt 19920

tagtccttag cccttttctt gccctggggg ccatgacgtg aagacccagc tggagcctgc 19980

ctggcggctg cctccctccc caccccccac ccgccacccc ctggagcccg ccagcccggc 20040

cccaagtccc tgtcaccttc aggcctcttg aatgaccgga gaggaggacg ccccctccct 20100

tccctcatcc tgtacttgga agggatcgag gtcgagacct tttggagagc ggggcaaagc 20160

cccttccatc tctggccagg cacgtgggga cccctacagc ctcctctgcg atgtctccgg 20220

gggtgggagg gaagacagac aaccagagta tgttggtgcg gagtcgcggg gggggggagg 20280

ggcggggtgc gctgcggggg tggcagggcc tgagctgaga cgggccctgg ggacctttga 20340

ggctggggct cccccgagga ctgggagatt tccagggcgc gctccttctg cgcagcggct 20400

acagcctgaa gggggcagct ctggatccag cgacaacgcg cggtgtccgc gcctctgaga 20460

aggtggtagt tggctggttg cgctctcccg aattggggaa aaaagaactc agcctccaaa 20520

agggaagaaa tgctttgctt ttctcttctt tctcagtcca aatttgctta cctcctccct 20580

tctctccccc cgcccccgat ttggggaccc tgctcagact tgtgtccagc ctctcttact 20640

ggcgttcctc tttttttttt tttttttttt ttaatctcct gtgtatctca tttgtatatt 20700

gtgatgttaa tgagtaactc ctgtagcgct gatgggcggg gggtggaggg gatgaacggc 20760

tcgcagtctc tctggatttt gctgcctatt actcacctgg cgccggtcgc aatctcgccg 20820

caggctttat ggtggctgcg gccgccccag aggccactca gggcaggcgc cttcgccttt 20880

tttctgggct tcgagtgcca cctatctgtc t 20911

<210> SEQ ID NO: 15

<211> LENGTH: 305

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 15

cagcaggcgc gctcccggcg aatctgcctg aatcgccgtg aatgcggtgg ggtgcagggc 60

aggggctggt tttctcagcc ggtcttggct tttctctttc tctcctgctc caccagcagc 120

ccctccgcgg gtcccatggg ctccgcgctc agaacagccc ggaaccaggc gccgctcgcc 180

gctcgctggg ggccacccgc ctctccccgg aacagcctcc cgcgggcctc ttggcctcgc 240

actggcgccc tcacccacac atcgtccctt tatccgctca gacgctgcaa agggccttct 300

gtctc 305

<210> SEQ ID NO: 16

<211> LENGTH: 336

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 16

gctttggatt tatcctcatt ggctaaatcc ctcctgaaac atgaaactga aacaaagccc 60

tgaaccccct caggctgaaa agacaaaccc cgcctgaggc cgggtcccgc tccccacctg 120

gagggaccca attctgggcg ccttctggcg acggtccctg ctagggacgc tgcgctctcc 180

gagtgcgagt tttcgccaaa ctgataaagc acgcagaacc gcaatcccca aactaacact 240

gaacccggac ccgcgatccc caaactgaca agggacccgg aacagcgacc cccaaaccga 300

cacgggactc gggaaccgct atctccaaag ggcagc 336

<210> SEQ ID NO: 17

<211> LENGTH: 139

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 17

tttccacaac agggagccag cattgaggcg cccagatggc atctgctgga aatcacgggc 60

cgctggtgaa gcaccacgcc ttacccgacg tggggaggtg atcccccacc tcatcccacc 120

cccttctgtc tgtctcctt 139

<210> SEQ ID NO: 18

<211> LENGTH: 292

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 18

gctggacaag gagcgctcac tgtagctctg ctgtggattg tgttggggcg aagagatggg 60

taagaggtca aagtcgtagg attctggcga ccgcctacca agggattggg tccacagcac 120

agaggtctga tcgcttcctt ctctgctctg ccacctccag acagcagctc taaccagctg 180

cccagcagca agaggatgcg cacggctttc accagcacgc agctgctaga gctggagcgc 240

gagttcgctt ctaatatgta cctgtcccgc ctacgtcgca tcgagatcgc ga 292

<210> SEQ ID NO: 19

<211> LENGTH: 190

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 19

tgcctgacac tgaccccagg cgcagccagg aggggctttg tgcgggagag ggagggggac 60

cccagcttgc ctggggtcca cgggactctc ttcttcctag ttcactttct tgctaaggcg 120

aaggtcctga ggcaggacga gggctgaact gcgctgcaat cgtccccacc tccagcgaaa 180

cccagttgac 190

<210> SEQ ID NO: 20

<211> LENGTH: 706

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 20

tcggcggaga gacctcgagg agagtatggg gaaaggaatg aatgctgcgg agcgcccctc 60

tgggctccac ccaagcctcg gaggcgggac ggtgggctcc gtcccgaccc cttaggcagc 120

tggaccgata cctcctggat cagaccccac aggaagactc gcgtggggcc cgatatgtgt 180

acttcaaact ctgagcggcc accctcagcc aactggccag tggatgcgaa tcgtgggccc 240

tgaggggcga gggcgctcgg aactgcatgc ctgtgcacgg tgccgggctc tccagagtga 300

gggggccgta aggagatctc caaggaagcc gaaaaaagca gccagttggg cttcgggaaa 360

gacttttctg caaaggaagt gatctggtcc cagaactcca gggttgaccc cagtacctga 420

cttctccggg agctgtcagc tctcctctgt tcttcgggct tggcgcgctc ctttcataat 480

ggacagacac cagtggcctt caaaaggtct ggggtggggg aacggaggaa gtggccttgg 540

gtgcagagga agagcagagc tcctgccaaa gctgaacgca gttagcccta cccaagtgcg 600

cgctggctcg gcatatgcgc tccagagccg gcaggacagc ccggccctgc tcaccccgag 660

gagaaatcca acagcgcagc ctcctgcacc tccttgcccc agagac 706

<210> SEQ ID NO: 21

<211> LENGTH: 325

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 21

agatcccggt gcatttaaag gccggcgtga tctgcaccac gtacctatct cggattctca 60

gtttcacttc gctggtgtct gccaccatct ttaccacatc ccggtagcta catttgtcta 120

ccgcttgagc caccagcgtc tgaaacctgg accggatttt gcgcgccgag aggtagccgg 180

aggcggtaat gaattccacc cagagggaca tgctcctctt gcgcccgtcg ctcaacttca 240

gcaccgcgca gccgggcagt gagccatcgt ccacgaagtt gaacaccccc atttggttga 300

gataaagcac cacttcaaat tcggt 325

<210> SEQ ID NO: 22

<211> LENGTH: 663

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 22

actatgcctt gagggtcaaa acgtctggat ttcctgatcg atgctgtcgt cgctgtccac 60

ggagctactg tcgccgtcag agcgggaagg cacgttcagg gagtagaagc gtgggcttgc 120

agaaagggac ctgttgctgc cttacatggg ggccggcagg gtagtcttgg aaatgcccaa 180

gattgcttcc gcgcgcgtca gttcagcgga cgtgtctgcc tggcacgagg accgttctac 240

aaactcgttc ctggaagccg ggctcgctgg aggcggagct ttggtttcct tcgggagctt 300

gtggggaatg gtcagcgtct aggcaccccg ggcaagggtc tgtggccttg gtggccactg 360

gcttcctcta gctgggtgtt ttcctgtggg tctcgcgcaa ggcacttttt tgtggcgctg 420

cttgtgctgt gtgcggggtc aggcgtcctc tctcctcccg gcgctgggcc ctctggggca 480

ggtccccgtt ggcctccttg cgtgtttgcc gcagctagta cacctggatg gcctcctcag 540

tgccgtcgtt gctgctggag tctgacgcct cgggcgcctg cgccgcactt gtgacttgct 600

ttccccttct cagggcgcca gcgctcctct tgaccccgct tttattctgt ggtgcttctg 660

aag 663

<210> SEQ ID NO: 23

<211> LENGTH: 1985

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 23

gcaagtcggg tagctaccgg gtgctggaga actccgcacc gcacctgctg gacgtggacg 60

cagacagcgg gctcctctac accaagcagc gcatcgaccg cgagtccctg tgccgccaca 120

atgccaagtg ccagctgtcc ctcgaggtgt tcgccaacga caaggagatc tgcatgatca 180

aggtagagat ccaggacatc aacgacaacg cgccctcctt ctcctcggac cagatcgaaa 240

tggacatctc ggagaacgct gctccgggca cccgcttccc cctcaccagc gcacatgacc 300

ccgacgccgg cgagaatggg ctccgcacct acctgctcac gcgcgacgat cacggcctct 360

ttggactgga cgttaagtcc cgcggcgacg gcaccaagtt cccagaactg gtcatccaga 420

aggctctgga ccgcgagcaa cagaatcacc atacgctcgt gctgactgcc ctggacggtg 480

gcgagcctcc acgttccgcc accgtacaga tcaacgtgaa ggtgattgac tccaacgaca 540

acagcccggt cttcgaggcg ccatcctact tggtggaact gcccgagaac gctccgctgg 600

gtacagtggt catcgatctg aacgccaccg acgccgatga aggtcccaat ggtgaagtgc 660

tctactcttt cagcagctac gtgcctgacc gcgtgcggga gctcttctcc atcgacccca 720

agaccggcct aatccgtgtg aagggcaatc tggactatga ggaaaacggg atgctggaga 780

ttgacgtgca ggcccgagac ctggggccta accctatccc agcccactgc aaagtcacgg 840

tcaagctcat cgaccgcaac gacaatgcgc cgtccatcgg tttcgtctcc gtgcgccagg 900

gggcgctgag cgaggccgcc cctcccggca ccgtcatcgc cctggtgcgg gtcactgacc 960

gggactctgg caagaacgga cagctgcagt gtcgggtcct aggcggagga gggacgggcg 1020

gcggcggggg cctgggcggg cccgggggtt ccgtcccctt caagcttgag gagaactacg 1080

acaacttcta cacggtggtg actgaccgcc cgctggaccg cgagacacaa gacgagtaca 1140

acgtgaccat cgtggcgcgg gacgggggct ctcctcccct caactccacc aagtcgttcg 1200

cgatcaagat tctagacgag aacgacaacc cgcctcggtt caccaaaggg ctctacgtgc 1260

ttcaggtgca cgagaacaac atcccgggag agtacctggg ctctgtgctc gcccaggatc 1320

ccgacctggg ccagaacggc accgtatcct actctatcct gccctcgcac atcggcgacg 1380

tgtctatcta cacctatgtg tctgtgaatc ccacgaacgg ggccatctac gccctgcgct 1440

cctttaactt cgagcagacc aaggcttttg agttcaaggt gcttgctaag gactcggggg 1500

cgcccgcgca cttggagagc aacgccacgg tgagggtgac agtgctagac gtgaatgaca 1560

acgcgccagt gatcgtgctc cccacgctgc agaacgacac cgcggagctg caggtgccgc 1620

gcaacgctgg cctgggctat ctggtgagca ctgtgcgcgc cctagacagc gacttcggcg 1680

agagcgggcg tctcacctac gagatcgtgg acggcaacga cgaccacctg tttgagatcg 1740

acccgtccag cggcgagatc cgcacgctgc accctttctg ggaggacgtg acgcccgtgg 1800

tggagctggt ggtgaaggtg accgaccacg gcaagcctac cctgtccgca gtggccaagc 1860

tcatcatccg ctcggtgagc ggatcccttc ccgagggggt accacgggtg aatggcgagc 1920

agcaccactg ggacatgtcg ctgccgctca tcgtgactct gagcactatc tccatcatcc 1980

tccta 1985

<210> SEQ ID NO: 24

<211> LENGTH: 213

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 24

atgcgccctc tgcaccccta gagccagaag acgctaggtg ggctgcgcgc tctgccaggc 60

gaaggctgga gcgcagacgg caaagccgcg cgtttcagcc gtggtcgggt ccgcaggacc 120

tgggcgtggg gacaccacca ggcaggagca gaggcaggac tgggacgcca aaagctgaga 180

atcctcgatg cccgcgcgag agccccgtgt tat 213

<210> SEQ ID NO: 25

<211> LENGTH: 1558

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 25

ttctggaaac cgggccccac ttgcaggccc ggccaccttg ggttctggtg gccgaagccg 60

gagctgtgtt tctcgcagac tcggggagct acattgtgcg taggcaattg tttagtttga 120

aaggaggcac atttcaccac gcagccagcg ccctgcatgc aggagaagcc cccagggccc 180

agggtcggct ggctttagag gccacttagg ttgttttaag cacatgtgaa agggcagaca 240

gcaggggagc aggatatggg taagatcttc gggtctcaga acaggggctg cccttgggct 300

gtcccggcgc cctgggctct gacactgaag ggtggaatgg aggaaggaat ggagaaagga 360

cggtggaact ttcgcttccc ctctgggccg ccttcccagg gtcatgcctg agctgctttg 420

atcccagtgt cgcgcatctt ggtccgctac ctcccaggcg atagctactg ggctcctcgc 480

tggcctcact gggggccatc ccgggcagtg gcctgccctc cgaggcccgc gggacccagc 540

ccagagctga ggttggagtt ctccgggcca cgttccgggt cgcttaggct cggagatttc 600

ccggagaccg tcgtcctccc tttctgcttg gcactgcgga gctccctcgg cctctctcct 660

cctctggtcc ctaaggcccg gagtggttgg cggtactggg gcccgtcgtc atctctgctt 720

ctaaggcatt cagactgggc tccagctggg accggcagag gaggttctca aggaaactgg 780

tgggaaatat agttttcttt cgtctggtcg tttaatttaa atgcaacttc ccttggggac 840

attttcctgg acgttaacca gaccaccttg agatgtcgtt gatgacctag agacccagat 900

gatgcgtccc aggaaagttc actgctgact attgtcactc ttggcgttat atctatagat 960

atagacctat gtacatatct ccaccctgat ctctccgtgg acatgaaacc cacctacctt 1020

gtgaaagccc tacgggtgac acatgactac tacgtctctg tcccaacagg ggctgggcct 1080

cccctgccta atagttgcca ggagtttcgc agcccaagtg aataatgtct tatggctgaa 1140

cgtggccaag gactcctgtg atttaggtcc caggaggagc agagacgtcc ccgccccgcc 1200

tgggccctgc cgcattcaaa gctggaagaa ggcgctgatc agagaagggg cttccaggtc 1260

ctgggttaga acaacaacaa acaaacgaaa ctccacaaca gacacgcctg cccatgaccc 1320

cacgcaagga cataggaagt tctgtcgcct tcctgctccg cggatagccg cctgccgtct 1380

gctgccacca gaacgcacgg acgctcgggg tggaggtagt caatgggcag caggggaccc 1440

ccagccccca caagcgcggc tccgaggacc tggaagcggg tgcctgtcgc tctccgcagg 1500

ctccgctctg cctccaggag caagatcccc aaaagggtct ggaagctgtg gagaaaac 1558

<210> SEQ ID NO: 26

<211> LENGTH: 1264

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 26

ttttttaaac acttcttttc cttctcttcc tcgttttgat tgcaccgttt ccatctgggg 60

gctagaggag caaggcagca gccttcccag ccagcccttg ttggcttgcc atcgtccatc 120

tggcttataa aagtttgctg agcgcagtcc agagggctgc gctgctcgtc ccctcggctg 180

gcagaagggg gtgacgctgg gcagcggcga ggagcgcgcc gctgcctctg gcgggctttc 240

ggcttgaggg gcaaggtgaa gagcgcaccg gccgtggggt ttaccgagct ggatttgtat 300

gttgcaccat gccttcttgg atcggggctg tgattcttcc cctcttgggg ctgctgctct 360

ccctccccgc cggggcggat gtgaaggctc ggagctgcgg agaggtccgc caggcgtacg 420

gtgccaaggg attcagcctg gcggacatcc cctaccagga gatcgcaggt aagcgcgggc 480

gcgctgcagg ggcaggctgc agccctcggc tgccgcacgt cccactggcc gcccggcgtc 540

cccttccttc cccctgttgc tgagttggtg ctcactttct gccaccgcta tgggactccg 600

cgtctccgtg ttgggcggcg gatgctcctg cggcttcttc ggcgggggaa ggtgtgcgtc 660

tccgccgcct cattgtgtgc acacgcggga gcaccctggc tcccgcctcc cgctgctctc 720

gcgcccttct accccttagt tgatggctca ggcccggctg gccagggagc ccgggtcact 780

ccggggcggc tgcaaggcgc agacggagag ccgagccggg cgctcactcc gcgttctggt 840

tcgggcaaac ttggaagaac tgcgaccgca gtttgcccag cgccacagtc tgagtggcgc 900

cttctccact cccgcccttg cgccggcagg ggcggtggag agacgcggag ggctccccca 960

gcccctctct cccctatccg tccttcgggc gacagagcgc ccggcgctcg ggccgggggc 1020

gggcaaggct gggagggacc ctcgccgggg acctggcctc tggacgccgg cgtttcaagg 1080

ctggtttggg gacttcacgg gctgcctgtt tcagatgtgg ggcgggcttt cccgttaggg 1140

ttcctcagtg cttccccagt tgctgttggc cactcagggc ccggggacac cctgccaccc 1200

ggtctggagc cggcctcgtc tgccagcgaa cagccaactt tagcgggtgg ctcagctggg 1260

gatt 1264

<210> SEQ ID NO: 27

<211> LENGTH: 761

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 27

cactcagtgt gtgcatatga gagcggagag acagcgacct ggaggccatg ggtgggggcg 60

ggtggtgaag ctgccgaagc ctacacatac acttagcttt gacacttctc gtaggttcca 120

aagacgaaga cacggtggct tcagggagac aagtcgcaag ggcgactttt ccaagcggga 180

gatggtgaag tctttggacg tgtagtgggt aggtgatgat ccccgcagcc gcctgtaggc 240

ccgcagactt cagaaaacaa gggccttctg tgagcgctgt gtcctccccg gaatccgcgg 300

cttaacacat tctttccagc tgcggggcca ggatctccac cccgcgcatc cgtggacaca 360

cttagggtcg cctttgtttt gcgcagtgat tcaagttggg taacccttgc tcaacacttg 420

ggaaatgggg agaatctccc ccacccgcaa cctcccgcac cccaggttcc caaaatctga 480

atctgtatcc tagagtggag gcagcgtcta gaaagcaaag aaacggtgtc caaagacccc 540

ggagagttga gtgagcgcag atccgtgacg cctgcggtac gctagggcat ccaggctagg 600

gtgtgtgtgt gcgggtcggg gggcgcacag agaccgcgct ggtttaggtg gacccgcagt 660

cccgcccgca tctggaacga gctgcttcgc agttccggct cccggcgccc cagagaagtt 720

cggggagcgg tgagcctagc cgccgcgcgc tcatgtttat t 761

<210> SEQ ID NO: 28

<211> LENGTH: 1198

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 28

agtcactcca ggatcagagg ccgcgtcggt tctgcttggg gcatgggcag agggaggctg 60

ctggggccaa gccccggctg gacgcgaggg aagaaactcg tcccaggacc cgcacgccca 120

tacctggctg tcccagagct cttccctagg ccggcacctt cgctcttcct cttccccacc 180

ccctagccct tttgtctctt tttcagacgg atgttttcag tctcaagtgg ttttattttc 240

cgcacaaaac cctgagatca agggcagatc acagactgta ccggaggctc gggtttccct 300

ggactctgtg ctgttctgcg tcccagggtt ggctaggaag gaaggcctgg gccggcgagg 360

tgacgggtct cccgcccagg tcggcaggac ggggggaggt gtgtcccggt aggtccctgg 420

tgagctcacc cgtggcatcg gggacccgcg ggaacccacc gggcgcccac tagagactcg 480

ggtcctaccc tcccccacac tactccaccg aaatgatcgg aagggcgcgc taggcctgct 540

tccaagggct cagtgataaa ggcctcaaaa tcacactcca tcaagacttg gttgaagctt 600

tgggtaggtt tgttgttgtt gttgttgttg tttgtttgtt tgttttagca gacacgtcct 660

ggaaagaggt cctcagaacc caaaggttca ataatgattt gtggatggat tgattatagt 720

ctgatatcgc tctggttcca cagaaacccg gagctccttg gcccactgtt accccagcag 780

acctaaatgg acggtttctg tttttcactg gcagctcaga actggaccgg aagaagttcc 840

cctccacttc ccccctcccg acaccagatc attgctgggt ttttattttc gggggaaaaa 900

caacaacaac aacaacaaaa aaaacactag gtccttccag actggatcag gtgatcgggc 960

aaaaaccctc aggctagtcc ggctgggtgc ccgagcatga aaaggcctcc gtggccgttt 1020

gaacagggtg ttgcaaatga gaacttttgt aagccataac cagggcatcc tgagggtctg 1080

agttcacggt caaggctgtg ggctactagg tccagcgagt ccaggcctcg ccccgccccc 1140

gagctgccac agccaagatc ttcggcaggg aattcgagac cagggtcctc ccactcct 1198

<210> SEQ ID NO: 29

<211> LENGTH: 377

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 29

tttcgtgccg ctgttttcaa tgcgctaacg aggcacgtta ttcttagccg cgtccgggag 60

gggatcacat tcctgcgcag ttgcgctgct ggcggaagtg acttgttttc taacgaccct 120

cgtgacagcc agagaatgtc cgtttctcgg agcgcagcac agcctgtccc atcgagaagc 180

ctcgggtgag gggcccggtg ggcgcccgga ggccgctgga gggctgtggg agggacggtg 240

gctccccact cccgtggcga agggcaggca aaccagaagc ctcttttgag agccgtttgg 300

gattgagacg agtaagccac agcgagtggt tagaagtagg ttaggaagaa ggggaggtaa 360

gaaagccgag tagggtt 377

<210> SEQ ID NO: 30

<211> LENGTH: 256

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 30

gttcggtgga caagggggca gcgcccacag caagccggaa agagggaggc gcggggccgc 60

gcttggggcc tgccgctgca cgccagcctg ggcaaagagc tgccaccttc tgcgggcgaa 120

gcgggtcggg acgcaggacg gcagcggggc tggaggcagc tacgtgggtc cacaccccca 180

tgccctgcaa ggctccttgg ccctgcttct cctctgtctc ggcgggagag gagcagcctc 240

ggttttacag aatttc 256

<210> SEQ ID NO: 31

<211> LENGTH: 189

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 31

tgtgccattt agtgagaggt gttttgggca aagaatcaat ttaactgtga ctgaccgacg 60

ggcttgactg tattaattct gctaccgaaa aaaaaaaaaa aaaaaaagca atgagccgca 120

agccttggac tcgcagagct gccggtgccc gtccgagagc cccaccagcg cggctcacgc 180

ctcagtctc 189

<210> SEQ ID NO: 32

<211> LENGTH: 707

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 32

agagtcccag ttctgcaggc cgctccaggg ctaggggtag agatggtggc aggtggtgcg 60

tcaactctct agggaagagg aacttgcatt acaaagactt gtctttctga gctgaagtca 120

aaacgggggc gtcaagcgcg ctccgtttgg cggcggtgga ggggccgcgc gcccgcgctg 180

tcccagccgg agctgccctg gctggtgatt ggaggtttaa cgtccggaat tcaggcgctt 240

ctgcagctca gatttgccgg ccaaggggcc tcagttgcaa cttttcaaaa tggtgtttct 300

ggaaaataac aaattcagac tcaactggtg acagcttttg gctatagaga atgaaactgc 360

ttccctttgg cggtggaact cttaaacttc gaagagtgaa agaatacaat gaaataaaat 420

gccataagat cactggattt ttcagaaaaa ggaagacccc aaattactcc caaaatgagg 480

ctttgtaaat tcttgttaaa aatctttaaa tctcgaattt ccccctacaa catctgatga 540

gtgctttaag agcaaacgag caaatcccac ctcgagaatc aacaaaccca agctctggcc 600

aaggctctcc ccgcgttttc ttctcgtgac ctggggaatg tcccgcccca tcgctcacct 660

ggctcttgtc atctcgctca tcttgaagtg acccgtggac aatgctg 707

<210> SEQ ID NO: 33

<211> LENGTH: 182

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 33

agctgccctc tgtggccatg agcgggtgtc cagccccttc caaggctgca ccggggagac 60

gctggttttc tgctcgctgt gaccgaacaa agcccctaag agtcagtgcg cggaacagaa 120

gagccggacc ccgacgggcc gagtcccaac gtgaggcacc cggcagagaa aacacgttca 180

cg 182

<210> SEQ ID NO: 34

<211> LENGTH: 179

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 34

cctcggcagc accggcatgg ctggaggcca gtacggccag gtgtggcggg agggagcgcc 60

gtctggcttg ggtcgtccat cctgacagga cgctgcaagg gcaggagccc cgcgccccgt 120

gtcctgcgcc cccgctcgag gacaagcccc agccgccggt ctccgctggg ttccgacag 179

<210> SEQ ID NO: 35

<211> LENGTH: 369

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 35

ctttaagagg ctgtgcaggc agacagacct ccaggcccgc taggggatcc gcgccatgga 60

ggccgcccgg gactatgcag gagccctcat caggcgagtg ccccgcgtcc ccctgattgc 120

cgtgcgcttc caatcgcctt gcgttcggtg gcctcatatt cccctgtgcg cctctagtac 180

cgtaccccgc tcccttcagc cccctgctcc ccgcattctc ttgcgctccg cgaccccgcg 240

cacacaccca tccgccccac tggtgcccaa gccgtccagc cgcgcccgcg ggcagagccc 300

aatcccgtcc cgcgcctcct caccctcttg cagctgggca caggtaccag gtgtggctct 360

tgcgaggtg 369

<210> SEQ ID NO: 36

<211> LENGTH: 176

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 36

agacttgcag aactcgggcc ccctggagga gacctaaccg ccacggtctt ggggaggttc 60

cggagggcct cggttgtctg cactcccaac accaagaaac ccctgagacg cgaagctgcc 120

agcgtgctgc cctcagagca gggcgacgca aagccagcgg accccggggt ggcggg 176

<210> SEQ ID NO: 37

<211> LENGTH: 167

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 37

tgctcggctg gggggctcgc tccgcacttt cggtgccaga aaatgcccag aggagcgggg 60

cggccccaga gcctcctttc ggggcgcgag gcccggcgcg tgtgtacgga gtccagtccc 120

cccagggagt ggggtgcccg caccttcccc tccgcgctcg gagccac 167

<210> SEQ ID NO: 38

<211> LENGTH: 1205

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 38

tcttgcacac ctgcttgtag ttctgcaccg agatctggtc gttgaggaac tgcacgcaga 60

gcttggtgac ctgggggatg tgcaggatct tgctgaccga cagcacctcc tccaccgtgt 120

ccagggacag ggtcacgttg gccgtgtaga ggtactcgag caccaggcgc agcccgatgg 180

acgagcagcc ctgcagcacc aggttgttga tggcccgggg gctggtcagc agcttgtcgt 240

cgggggagga agaaggagtc ccgggctcct cctgcggcgg cggctgctgc tgctgtgacg 300

gctgctgctg cggcggctgc tgctggtcct tgggggcccc caggccgtcc tggccgccga 360

cccctccccc gagagggggg tggctggaga agagcgatcg gaagtactgc gagcaggagg 420

ccagcacggc cttgtggcaa tggaactgct ggccctgggc cgtcagggtc acgtcgcaaa 480

acagctgctt cctccacagc aggttgaggc cgtgcagcag gttgtcgctg tggctggggt 540

cgaaggtgga ggtcctgtcc ccggatctgg acatggcgag ctgactcggt gcacctggct 600

ttaaaccctc ctccaacctg gcagacaggg gtgggggatg ggagggaggg gagcagggtg 660

gtggagcggg tggggtgtgg tcggggtggg gaagggtgtg gaggggaggg gagggcgaag 720

aacaagaatc aaggctcagc ttgactccct cctggcgcgc tccggacccc gaccctagga 780

ggaaagtccg aagacgctgg atccgtgagc gccaccagaa gggccctgtc tggggtcccg 840

gcgccggttc tgcgccctgc ggctcctctc gccacctccc acacacttcg tccctcactt 900

tcctaaaacc aaccacctca gctcggctgt tggcagcaac agcagtggca gcagcgacgg 960

caaagtggcg gctgaggccg aggcacctcg tgggctcgtg tccatgccgg gccagatgaa 1020

gggaaaggcc gggaagtggg gagccggggg tgccctgaaa gctcagaggc gaccgacggc 1080

gaaggttcca ggtcaacttg tgcccgaagc tttgcttttc gcagttggcc cagtttgggg 1140

gagggggtag gaacaggggc ccgaccagcg tgcggggtgt gcgaatctta gctctccaaa 1200

agctg 1205

<210> SEQ ID NO: 39

<211> LENGTH: 44

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 39

cctctgtgtt agtgccctcg ggaatttggt tgatggggtg tttg 44

<210> SEQ ID NO: 40

<211> LENGTH: 5002

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 40

tgatgtcgca cctgaacggc ctgcaccacc cgggccacac tcagtctcac gggccggtgc 60

tggcacccag tcgcgagcgg ccaccctcgt cctcatcggg ctcgcaggtg gccacgtcgg 120

gccagctgga agaaatcaac accaaagagg tggcccagcg catcacagcg gagctgaagc 180

gctacagtat cccccaggcg atctttgcgc agagggtgct gtgccggtct caggggactc 240

tctccgacct gctccggaat ccaaaaccgt ggagtaaact caaatctggc agggagacct 300

tccgcaggat gtggaagtgg cttcaggagc ccgagttcca gcgcatgtcc gccttacgcc 360

tggcaggtaa ggccggggct agccaggggc caggctgctg ggaagagggc tccgggtccg 420

gtgcttgtgg cccaagtctg cgcgccgagt cacttctctt gattctttcc ttctctttcc 480

tatacacgtc ctctttcttc tcgtttttat ttcttcttcc attttctctt tctcttccgc 540

tcttccccta ctttcccttc tcccttttct ttttctttct tactctctcc ttgtccctga 600

gctttcattg accgaccccc ccccatttca ttcgccctcc cctcaatgtg ccaacctttg 660

ccctatttcc gatcttccca ggtactggga ggcgggatgg gggtgtgcgt tttcctctag 720

gagccctgtc tttccaagac ccacagaaac caggacctgc ccttattcaa aaccccatgc 780

acttcaagtc tcttttagac aacacatttc aattttccgg gctgactagt ctccctgtgc 840

agaggcagtt gagaggcttt gctctgcaga gggaaaagag ctctctactc tcccacccac 900

catataggca aacttatttg gtcattggct gaaggcacag ccttgccccc gcggggaacc 960

ggcggccagg atacaacagc gctcctggag cccatctctg gccttggcgt tggcgcaggg 1020

actttctgac cgggcttgag gggctcgggc cagctccaat gtcactacct acagcgaggg 1080

cagggtgtaa ggttgagaag gtcacattca ccgctttggg aggacgtggg agaagagact 1140

gaggtggaaa gcgctttgcc ttgctcaccg gccgtccttg ccccggtccc agcgtttgct 1200

gggatttgcc aggatttgcc ggggctccgg gagaccctga gcactcgcag gaagaggtgc 1260

tgagaaatta aaaattcagg ttagttaatg catccctgcc gccggctgca ggctccgcct 1320

ttgcattaag cgggcgctga ttgtgcgcgc ctggcgaccg cggggaggac tggcggcccg 1380

cgggagggga cgggtagagg cgcgggttac attgttctgg agccggctcg gctctttgtg 1440

cctcctctag cggccaagct gcgaggtaca gccctctatt gttctaggag cacagaaacc 1500

tcctgtgtgg gcggcgggtg cgcgagctag agggaaagat gcagtagtta ctgcgactgg 1560

cacgcagttg cgcgcttttg tgcgcacgga ccccgcgcgg tgtgcgtggc gactgcgctg 1620

cccctaggag caagccacgg gcccagaggg gcaaaatgtc caggtccccc gctgggaagg 1680

acacactata ccctatggca agccagggtg ggcgacttcc catggatcgg gtggaggggg 1740

gtatctttca ggatcggcgg gcggtctagg ggaacaattc gtggtggcga tgatttgcat 1800

agcgcgggtc ttgggatgcg cgcggttccg agccagcctc gcacagctcg cttccggagc 1860

tgcgagctca ggtttccacc cccgatcccc cgggctttcc tcgcaccgct gagcccagct 1920

tgtggggtgc actcgaccaa cgcccgacag ggctggggaa tgtgacaggc agcaggttca 1980

cccgggcttg gggaggggga gtttccgctt tgacagcatt ttcctttgcc gtctgctggt 2040

ggattcctat tcccagtcgg taatcgcccc gcagtgttga tctaagaagg taaagaaaac 2100

taggtttccc tgcaaagagc ctcccccaaa tcggcggact ccggatactt tgagtggatt 2160

tagaaattta tgtaatcttt ctcctttagt ttatttttca tcctctccta cagttttctc 2220

tgatttgctg ttggttcggg gcaagataaa gcagccagta gagagcgata ataatagcgg 2280

cgggaaatga actggagact ggctgacagt tcttaacatt ttgtcataga tccccccgaa 2340

tgtcccaggc tgtctctggt gggttttagt acccgccggc ttcttgggca ccggggacca 2400

gaaggaactt ggcagctggt cttaggggta cagttaaagg caggatgaca gctattctcc 2460

tgctcatctc agagcgctgc cgccccctca tgccggtcgc gcaaagaaca cagcttttaa 2520

aaaacacgtg ccttctgccc atataggtct gaaagtgatg aggaaagtaa tgcttcgcct 2580

attagcgagt ttcagctttt aaaatgatcc caagcgttgc tgagatgaga aagcgtggca 2640

tcccgggggt cctcagcccc acccgcgccc atggtgcaag tctgcaggga caggcccggg 2700

acagcactgc ccacgctgct agattttccg cagaggatcg ctgaagctgc cttcgtggga 2760

gacagaatgc ctcctccagc gagtggaaaa ggcctgctga ggaccccgct ttgctcgagc 2820

attcaaatgt gtgtctgttt tattaccctg ggttgaaaag ggacaagagc tttagccttt 2880

ttatctggcc attttatcag caactacaag tgtgttgagt ggttattatt acataggagg 2940

cttttcagtt tggggtcagt agatcagtct cttcagacac tgatgcagaa gctgggactg 3000

gtaagtaggt attatgtgct cggagcgcta ggggacagga gcaaatggag aagaaaagcg 3060

gaggctttct ccgcccggag tatcgatcgg aatccccgcc ggtacgccgc agagggccct 3120

cgccgttggg ccccgggggt ttaacaagcc cagccgctcc gcaggcggct cggccggact 3180

ctcagaccgg tgcctggaag acaccgtccc tgcccccctc ccgccaaacc tgcctcttct 3240

ctttctctca taggttatag gttccctttc tctctcattt tggccccgcc cccgggtcct 3300

gccaaacagc caagcaggcc ggggtttagg gggctcagaa tgaagaggtc tgatttggcc 3360

agcgccggca aagctcaccc ttaggcgagg tcacaacaga ggcaggtcct tcctgcccag 3420

cctgccggtg tagtcacagc caagggtggc acttgaaagg aaaagggaga aaacttcgga 3480

gaaatttaga ttgccccaac gttagatttc agagaaattg actccaaatg cacggattcg 3540

ttcggaaagg gcggctaagt ggcaggtggt tgcaaccccg cccggtcggg ccttcgcaga 3600

ggttccccaa gaccagccct tgcagggcgg ttttcagcaa cctgacaaga ggcggccaag 3660

acaaatttct gcgggttcga gcacacactc tcgggcgttg ggccccagag acctctaaac 3720

caagcacaaa caagaaggga gtgagagaac ccaggctaga acttgcacgg gcatcccact 3780

gaggaaaagc gaggcctcgg tggcaggcat gttttcttcc gacgcccgaa aatcgagccg 3840

agcgcccgac tacatttact gcagaggttt ccgcctccag tgagcccgga tcccccagcg 3900

gcctgcccgg agctggtctc cagtccccgc cgtagtccga cgcacggccc tctcctggca 3960

gcaagctccc agcggccagt ctgaagccaa ttctgttcag gcggccgagg gcccttagcc 4020

aacccaccat gatgtcgcct gggccacctg atgcccgcag cggcgggaca cggcccgggc 4080

agtgcgcagt ggctcctgct aggggcaccg cgtgcgtgct tgtctcccgc tgcgccgggg 4140

acgtccttgg gtgacacggg ccgctgggca cctcccaagc cgaggaaacg gacccccttc 4200

gcagagtctc gcgcccaccc cccaacctcc cacctcgttt ctcgctgcta gggctcccga 4260

ctcagcccac ctctcctggc ggtttagtta gggatcagag ctggagaggc tgaacgcaac 4320

ccgtgccagt acggaacaga cgatatgttt gcctgctagc tgcttggatg aataattgaa 4380

aagttcgctg cagtctgtgc ttcgtcaagt cccgggtgcc gggagaacac cttcccaaca 4440

cgcatcaggg tgggcgggag cgggcagagg aggcgggacc cgagggagga gagtgaaccc 4500

gagcaggaga agcagcccag gcagccaggc gccctcgatg cgagaggctg ggcatttatt 4560

tttattccag gctttccact gtgtggttat gtcactttct caaacaaatg tgtatatgga 4620

gggagatcga tgctgataat gtttagaaga ttaaaagagc attaatgctg gcaacaataa 4680

cgtaaacgtg tggacccaga tttcattgat ctggaacttg atccggcgcg tttccagtaa 4740

gcccgacggc gcgctcttcc cagcagagcg ctcaccagcg ccacggcccc gcggttttcc 4800

agcggtgccg cttcgccagc tctgcgcggg ttctcccgtc tgaccgcagc tcctcccccg 4860

cgaggcccca gcccgcctta cttccccgag gttttctcct cctctcgcgg ggctctctgc 4920

cctctgcacc ccctcccccg acctctgcac cacccgcccc tgtgcgcaca caccgctact 4980

tgcgcttccg gcgatccgcc tg 5002

<210> SEQ ID NO: 41

<211> LENGTH: 150

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 41

aaccggagat ctgcttggtg aactgagagg agtccttagg agagcgggga cgccaggggc 60

cgggggacac ttcgctctcg ccctagggaa ggtggtcttg acgctttcta ttgaagtcaa 120

acttgaaaat atcagctgcc gctggactat 150

<210> SEQ ID NO: 42

<211> LENGTH: 339

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 42

cgtgagcaga acgcccgccc tggagcagtt aggaccgaag gtctccggag agtcgccggc 60

ggtgccaggt aacgcagagg gctcgggtcg ggccccgctt ctggggcttg ggactccggg 120

cgcgcggagc cagccctctg gggcgaaatc cccgggcggc gtgcgcggtc cctctccgcg 180

ctgtgctctc ccagcaactc cctgccacct cgacgagcct accggccgct ccgagttcga 240

cttcctcgga cttagtggga gaaggggttg gaaatgggct gccgggactg ggggagctgc 300

tctctggaag cagggaagct ggggcgcacc ggggcaggt 339

<210> SEQ ID NO: 43

<211> LENGTH: 1961

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 43

tagaagagga agactcctct ggccccacta ggtatcatcc gcgctctccc gctttccacc 60

tgcgccctcg cttgggccaa tctctgccgc acgtgtccat ccctgaactg cacgctatcc 120

tccacccccg gggggttcct gcgcactgaa agaccgttct ccggcaggtt ttgggatccg 180

gcgacggctg accgcgcgcc gcccccacgc ccggttccac gatgctgcaa tacagaaagt 240

ttacgtcggc cccgacccgc gcgggactgc agggtccgcc ggagcgcggc gcagaggctt 300

ttcctgcgcg ttcggccccg ggaaaggggc gggagggctg gctccgggag cgcacgggcg 360

cggcggggag ggtactcact gtgaagcacg ctgcgcccat ggatcatgtc tgtgcgttac 420

accagaggct ccgggctcca ctaattccat ttagagacgg gaagacttcc agtggcgggg 480

ggaggacagg gtcgagaggt gttaaagacg caaagcaaga aggaaataaa ggggggccga 540

gagggagacc gagaggaagg gggagctccg agcccacgct gcagccagat ccggatgagt 600

ccgtcctccg ccccgggcgg gctctcgctc tcgctggccc tcagcgccgc gcagccagca 660

gcatccccac cgtgacgctc gcatcacacc cgggcgccgg ccgccaccat ccgcgccgcc 720

gccgtcagga ccctcctccc gggcatcgtc gccgccgcgg ggtcgggagg acgcggcgcg 780

cgggaggcgg cggtcgcagg gcgagccccg ggacgccccg agccggggcc ggggccgggg 840

agagggcgca gcgaggtggg ggccagtcca gaccgacggc agcgacggag cgggcggcgg 900

cggcggcgcc ggcggcggcg gggtggctca gtccccagtc tcagacgcgc cgcgcagcag 960

gtcggagcag cctccccggg aggatgtcca gcggcagcgc tcctcgctcc agcccttggg 1020

gatcttccgc tgaggcattg aaggcaggaa gaaggggtcc gtcatcggct cgccgggctg 1080

cgcgccacct ctgctatctt gcggaaagag gagcgggtgg gtgggcgtct gggaggcggg 1140

ctggagggcg gtgcagggga gcggggcggc cggggggggg gccggggggc ggggaaggga 1200

gggaggagaa aggagccgga agagggcaga gttaccaaat gggctcctta gtcatggctt 1260

ggggctccac gaccctcctg gaagcccgga gcctgggtgg gatagcgagg ctgcgcgcgg 1320

ccggcgcccc ggggctggtg cgcggcagaa tggggccgcg gcggcggcag caaggacatc 1380

ccagccgcgc ggatctgggg gaggggcggg gagggggtga ggacccggct gggatccgcg 1440

gctcggcccg ccagggcgca gagagaggat gcagccgcaa atcccgagcc ggatcctcgt 1500

gccggacgga aggcgtggaa gcgggagggg ccttcgtgtg aaaatccctt gtggggtttg 1560

gtgtttcact ttttaaaggt tagaccttgc gggctctctg cctcccaccc cttcttttcc 1620

atccgcgtaa aggaactggg cgccccctct ccctccctcc ctggggcgca ggtttcgccg 1680

cggactccgc gctcagcttg ggagacacgg caggggcgcg ccccagggaa aggcggccgt 1740

aaaagtttcg cggttgagca ctgggcctga tgtccagtcc ccccaccaaa ttactcctgc 1800

aaagacgcgg gcttcttgca attgagcccc ccacctcgag gtatttaaaa ccaccccaag 1860

gcacacacgg acccccgttc ccccgcgcca cttcctccta caggctcgcg cggcgcgtta 1920

aagtctggga gacacgagtt gcggggaaac agcaccggaa g 1961

<210> SEQ ID NO: 44

<211> LENGTH: 314

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 44

aagaaacagc tcatttcgga gctgaggaca aggcgtggga agaagacgcg tttggtttca 60

cccaggcggg tggcggcaaa gctgtgggat gcgcgctgca cactccttcc gtcatcccgt 120

tcccaccttc cacacacacc tgcgggaggt cggacatgtc ctgattgcgt gttcatcacg 180

atggcaaacc gaacatgagg agaacgccac tgacgctggg tgcgccggct ttcccagccc 240

tcgtgcataa cggggaggga gatgcagaag ttttttccaa catcggtgca aaggggaagc 300

tgaggttttc ctat 314

<210> SEQ ID NO: 45

<211> LENGTH: 584

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 45

tctgtcagct gctgccatgg ggcagcggga aggccctgga gggtgcctgg gctgtgtctg 60

gtcccggcca cgcgtccctg cagcgtctga gaccttgtgg aacacacttg acccggcgct 120

gggacggggt cggcccacac gcaccgccag cccgcaggag tgaggtgcag gctgccgctg 180

gctccttagg cctcgacagc tctcttgagg tcggccctcc tcccctcccg agagctcagc 240

agccgcagac ccaggcagag agagcaaagg aggctgtggt ggcccccgac gggaacctgg 300

gtggccgggg gacacaccga ggaactttcc gccccccgac gggctctccc accgaggctc 360

aggtgctcgt gggcagcaag gggaagcccc atggccatgc cgcttccctt tcaccctcag 420

cgacgcgccc tcctgtgccc gcggggaaca agacggctct cggcggccat gcaggcggcc 480

tgtcccacga acacgatgga gacctcagac gccgtcccca ccctgtcact gtcaccatca 540

cccatcctgt cccctcacgc ctccccacat cccatcatta ctac 584

<210> SEQ ID NO: 46

<211> LENGTH: 349

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 46

gaagtagaat cacagtaaat gaggagttag ggaatttagg gtagagatta aagtaatgaa 60

cagaggagga ggcctgagac agctgcagag agaccctgtg ttccctgtga ggtgaagcgt 120

ctgctgtcaa agccggttgg cgctgagaag aggtaccggg ggcagcaccc gcctcctggg 180

agagggatgg gcctgcgggc acctggggga accgcacgga cacagacgac actataaacg 240

cgggcgagac atcagggacc gggaaacaga aggacgcgcg tttcgagcag ctgcccagtg 300

ggccacaagc cccgccacgc cacagcctct tcccctcagc acgcagaga 349

<210> SEQ ID NO: 47

<211> LENGTH: 3510

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 47

tactccggcg acgggaggat gttgagggaa gcctgccagg tgaagaaggg gccagcagca 60

gcacagagct tccgactttg ccttccaggc tctagactcg cgccatgcca agacgggccc 120

ctcgactttc acccctgact cccaactcca gccactggac cgagcgcgca aagaacctga 180

gaccgcttgc tctcaccgcc gcaagtcggt cgcaggacag acaccagtgg gcagcaacaa 240

aaaaagaaac cgggttccgg gacacgtgcc ggcggctgga ctaacctcag cggctgcaac 300

caaggagcgc gcacgttgcg cctgctggtg tttattagct acactggcag gcgcacaact 360

ccgcgccccg actggtggcc ccacagcgcg caccacacat ggcctcgctg ctgttggcgg 420

ggtaggcccg aaggaggcat ctacaaatgc ccgagccctt tctgatcccc acccccccgc 480

tccctgcgtc gtccgagtga cagattctac taattgaacg gttatgggtc atccttgtaa 540

ccgttggacg acataacacc acgcttcagt tcttcatgtt ttaaatacat atttaacgga 600

tggctgcaga gccagctggg aaacacgcgg attgaaaaat aatgctccag aaggcacgag 660

actggggcga aggcgagagc gggctgggct tctagcggag accgcagagg gagacatatc 720

tcagaactag gggcaataac gtgggtttct ctttgtattt gtttattttg taactttgct 780

acttgaagac caattattta ctatgctaat ttgtttgctt gtttttaaaa ccgtacttgc 840

acagtaaaag ttccccaaca acggaagtaa cccgacgttc ctcacactcc ctaggagact 900

gtgtgcgtgt gtgcccgcgc gtgcgctcac agtgtcaagt gctagcatcc gagatctgca 960

gaaacaaatg tctgaattcg aaatgtatgg gtgtgagaaa ttcagctcgg ggaagagatt 1020

agggactggg ggagacaggt ggctgcctgt actataagga accgccaacg ccagcatctg 1080

tagtccaagc agggctgctc tgtaaaggct tagcaatttt ttctgtaggc ttgctgcaca 1140

cggtctctgg cttttcccat ctgtaaaatg ggtgaatgca tccgtacctc agctacctcc 1200

gtgaggtgct tctccagttc gggcttaatt cctcatcgtc aagagttttc aggtttcaga 1260

gccagcctgc aatcggtaaa acatgtccca acgcggtcgc gagtggttcc atctcgctgt 1320

ctggcccaca gcgtggagaa gccttgccca ggcctgaaac ttctctttgc agttccagaa 1380

agcaggcgac tgggacggaa ggctctttgc taacctttta cagcggagcc ctgcttggac 1440

tacagatgcc agcgttgccc ctgccccaag gcgtgtggtg atcacaaaga cgacactgaa 1500

aatacttact atcatccggc tcccctgcta ataaatggag gggtgtttaa ctacaggcac 1560

gaccctgccc ttgtgctagc gcggttaccg tgcggaaata actcgtccct gtacccacac 1620

catcctcaac ctaaaggaga gttgtgaatt ctttcaaaac actcttctgg agtccgtccc 1680

ctccctcctt gcccgccctc tacccctcaa gtccctgccc ccagctgggg gcgctaccgg 1740

ctgccgtcgg agctgcagcc acggccatct cctagacgcg cgagtagagc accaagatag 1800

tggggacttt gtgcctgggc atcgtttaca tttggggcgc caaatgccca cgtgttgatg 1860

aaaccagtga gatgggaaca ggcggcggga aaccagacag aggaagagct agggaggaga 1920

ccccagcccc ggatcctggg tcgccagggt tttccgcgcg catcccaaaa ggtgcggctg 1980

cgtggggcat caggttagtt tgttagactc tgcagagtct ccaaaccatc ccatccccca 2040

acctgactct gtggtggccg tattttttac agaaatttga ccacgttccc tttctccctt 2100

ggtcccaagc gcgctcagcc ctccctccat cccccttgag ccgcccttct cctccccctc 2160

gcctcctcgg gtccctcctc cagtccctcc ccaagaatct cccggccacg ggcgcccatt 2220

ggttgtgcgc agggaggagg cgtgtgcccg gcctggcgag tttcattgag cggaattagc 2280

ccggatgaca tcagcttccc agccccccgg cgggcccagc tcattggcga ggcagcccct 2340

ccaggacacg cacattgttc cccgcccccg cccccgccac cgctgccgcc gtcgccgctg 2400

ccaccgggct ataaaaaccg gccgagcccc taaaggtgcg gatgcttatt atagatcgac 2460

gcgacaccag cgcccggtgc caggttctcc cctgaggctt ttcggagcga gctcctcaaa 2520

tcgcatccag agtaagtgtc cccgccccac agcagccgca gcctagatcc cagggacaga 2580

ctctcctcaa ctcggctgtg acccagaatg ctccgataca gggggtctgg atccctactc 2640

tgcgggccat ttctccagag cgactttgct cttctgtcct ccccacactc accgctgcat 2700

ctccctcacc aaaagcgaga agtcggagcg acaacagctc tttctgccca agccccagtc 2760

agctggtgag ctccccgtgg tctccagatg cagcacatgg actctgggcc ccgcgccggc 2820

tctgggtgca tgtgcgtgtg cgtgtgtttg ctgcgtggtg tcgatggaga taaggtggat 2880

ccgtttgagg aaccaaatca ttagttctct atctagatct ccattctccc caaagaaagg 2940

ccctcacttc ccactcgttt attccagccc gggggctcag ttttcccaca cctaactgaa 3000

agcccgaagc ctctagaatg ccacccgcac cccgagggtc accaacgctc cctgaaataa 3060

cctgttgcat gagagcagag gggagataga gagagcttaa ttataggtac ccgcgtgcag 3120

ctaaaaggag ggccagagat agtagcgagg gggacgagga gccacgggcc acctgtgccg 3180

ggaccccgcg ctgtggtact gcggtgcagg cgggagcagc ttttctgtct ctcactgact 3240

cactctctct ctctctccct ctctctctct ctcattctct ctcttttctc ctcctctcct 3300

ggaagttttc gggtccgagg gaaggaggac cctgcgaaag ctgcgacgac tatcttcccc 3360

tggggccatg gactcggacg ccagcctggt gtccagccgc ccgtcgtcgc cagagcccga 3420

tgaccttttt ctgccggccc ggagtaaggg cagcagcggc agcgccttca ctgggggcac 3480

cgtgtcctcg tccaccccga gtgactgccc 3510

<210> SEQ ID NO: 48

<211> LENGTH: 333

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 48

ttaattcgaa aatggcagac agagctgagc gctgccgttc ttttcaggat tgaaaatgtg 60

ccagtgggcc aggggcgctg ggacccgcgg tgcggaagac tcggaacagg aagaaatagt 120

ggcgcgctgg gtgggctgcc ccgccgccca cgccggttgc cgctggtgac agtggctgcc 180

cggccaggca cctccgagca gcaggtctga gcgtttttgg cgtcccaagc gttccgggcc 240

gcgtcttcca gagcctctgc tcccagcggg gtcgctgcgg cctggcccga aggatttgac 300

tctttgctgg gaggcgcgct gctcagggtt ctg 333

<210> SEQ ID NO: 49

<211> LENGTH: 385

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 49

ccggtcccca gtttggaaaa aggcgcaaga agcgggcttt tcagggaccc cggggagaac 60

acgagggctc cgacgcggga gaaggattga agcgtgcaga ggcgccccaa attgcgacaa 120

tttactggga tccttttgtg gggaaaggag gcttagaggc tcaagctata ggctgtccta 180

gagcaactag gcgagaacct ggccccaaac tccctcctta cgccctggca caggttcccg 240

gcgactggtg ttcccaaggg agccccctga gcctaccgcc cttgcagggg gtcgtgctgc 300

ggcttctggg tcataaacgc cgaggtcggg ggtggcggag ctgtagaggc tgcccgcgca 360

gaaagctcca ggatcccaat atgtg 385

<210> SEQ ID NO: 50

<211> LENGTH: 105

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 50

gcgcaggtcc ccccagtccc cgagggagtg cgcccgacgg aaacgcccct agcccgcggg 60

cctcgctttc ctctcccggg ttcctgggtc acttcccgct gtctc 105

<210> SEQ ID NO: 51

<211> LENGTH: 147

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 51

ttccctcgcg gctttggaaa gggggtgcaa atgcaccctt ctgcgggccc gctacccgct 60

gcaacacctg tgtttccttt ctgggcacct tctaggtttc tagatattgc tgtgaatacg 120

gtcctccgct gtacagttga aaacaaa 147

<210> SEQ ID NO: 52

<211> LENGTH: 365

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 52

tgggaattta ggtcgggcac tgccgatatg tcgccttcca caaggcgggc ccgggcctct 60

gctgaccgtg caccggtcct ggggctgggt aattctgcag cagcagcgca gcccatgccg 120

gggaatttgc gggcagagga gacagtgagg cccgcgttct gtgcgggaac tcccgagctc 180

acagagccca agaccacacg gctgcatctg cttggctgac tgggccaggc ccacgcgtag 240

taacccggac gtctctctct cacagtcccc ttgcgtctgg ccagggagct gccaggctgc 300

accccgcggt ggggatcggg agaggggcag tgtcgcccat ccccggaagg ctgagcctgg 360

tgcag 365

<210> SEQ ID NO: 53

<211> LENGTH: 418

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 53

cggttttctc ctggaggact gtgttcagac agatactggt ttccttatcc gcaggtgtgc 60

gcggcgctcg caagtggtca gcataacgcc gggcgaattc ggaaagcccg tgcgtccgtg 120

gacgacccac ttggaaggag ttgggagaag tccttgttcc cacgcgcgga cgcttccctc 180

cgtgtgtcct tcgagccaca aaaagcccag accctaaccc gctcctttct cccgccgcgt 240

ccatgcagaa ctccgccgtt cctgggaggg gaagcccgcg aggcgtcggg agaggcacgt 300

cctccgtgag caaagagctc ctccgagcgc gcggcgggga cgctgggccg acaggggacc 360

gcgggggcag ggcggagagg acccgccctc gagtcggccc agccctaaca ctcaggac 418

<210> SEQ ID NO: 54

<211> LENGTH: 906

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 54

agggaatcgg gctgaccagt cctaaggtcc cacgctcccc tgacctcagg gcccagagcc 60

tcgcattacc ccgagcagtg cgttggttac tctccctgga aagccgcccc cgccggggca 120

agtgggagtt gctgcactgc ggtctttgga ggcctaggtc gcccagagta ggcggagccc 180

tgtatccctc ctggagccgg cctgcggtga ggtcggtacc cagtacttag ggagggagga 240

cgcgcttggt gctcagggta ggctgggccg ctgctagctc ttgatttagt ctcatgtccg 300

cctttgtgcc ggcctctccg atttgtgggt ccttccaaga aagagtcctc tagggcagct 360

agggtcgtct cttgggtctg gcgaggcggc aggccttctt cggacctatc cccagaggtg 420

taacggagac tttctccact gcagggcggc ctggggcggg catctgccag gcgagggagc 480

tgccctgccg ccgagattgt ggggaaacgg cgtggaagac accccatcgg agggcaccca 540

atctgcctct gcactcgatt ccatcctgca acccaggaga aaccatttcc gagttccagc 600

cgcagaggca cccgcggagt tgccaaaaga gactcccgcg aggtcgctcg gaaccttgac 660

cctgacacct ggacgcgagg tctttcagga ccagtctcgg ctcggtagcc tggtccccga 720

ccaccgcgac caggagttcc ttcttccctt cctgctcacc agccggccgc cggcagcggc 780

tccaggaagg agcaccaacc cgcgctgggg gcggaggttc aggcggcagg aatggagagg 840

ctgatcctcc tctagccccg gcgcattcac ttaggtgcgg gagccctgag gttcagcctg 900

actttc 906

<210> SEQ ID NO: 55

<211> LENGTH: 860

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 55

cactacggat ctgcctggac tggttcagat gcgtcgttta aagggggggg ctggcactcc 60

agagaggagg gggcgctgca ggttaattga tagccacgga agcacctagg cgccccatgc 120

gcggagccgg agccgccagc tcagtctgac ccctgtcttt tctctcctct tccctctccc 180

acccctcact ccgggaaagc gagggccgag gtaggggcag atagatcacc agacaggcgg 240

agaaggacag gagtacagat ggagggacca ggacacagaa tgcaaaagac tggcaggtga 300

gaagaaggga gaaacagagg gagagagaaa gggagaaaca gagcagaggc ggccgccggc 360

ccggccgccc tgagtccgat ttccctcctt ccctgaccct tcagtttcac tgcaaatcca 420

cagaagcagg tttgcgagct cgaatacctt tgctccactg ccacacgcag caccgggact 480

gggcgtctgg agcttaagtc tgggggtctg agcctgggac cggcaaatcc gcgcagcgca 540

tcgcgcccag tctcggagac tgcaaccacc gccaaggagt acgcgcggca ggaaacttct 600

gcggcccaat ttcttcccca gctttggcat ctccgaaggc acgtacccgc cctcggcaca 660

agctctctcg tcttccactt cgacctcgag gtggagaaag aggctggcaa gggctgtgcg 720

cgtcgctggt gtggggaggg cagcaggctg cccctccccg cttctgcagc gagttttccc 780

agccaggaaa agggagggag ctgtttcagg aatttcagtg ccttcaccta gcgactgaca 840

caagtcgtgt gtataggaag 860

<210> SEQ ID NO: 56

<211> LENGTH: 452

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 56

ggagcctgaa gtcagaaaag atggggcctc gttactcact ttctagccca gcccctggcc 60

ctgggtcccg cagagccgtc atcgcaggct cctgcccagc ctctggggtc gggtgagcaa 120

ggtgttctct tcggaagcgg gaagggctgc gggtcgggga cgtcccttgg ctgccacccc 180

tgattctgca tccttttcgc tcgaatccct gcgctaggca tcctccccga tcccccaaaa 240

gcccaagcac tgggtctggg ttgaggaagg gaacgggtgc ccaggccgga cagaggctga 300

aaggaggcct caaggttcct ctttgctaca aagtggagaa gttgctctac tctggagggc 360

agtggccttt tccaaacttt tccacttagg tccgtaagaa aagcaattca tacacgatca 420

gcgctttcgg tgcgaggatg gaaagaaact tc 452

<210> SEQ ID NO: 57

<211> LENGTH: 1992

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 57

ttttcctgtt acagagctga gcccactcat gtggtgccaa gtagcgacta tctctcggcc 60

acctccaccc agagcaatgt gggcgccccc agcgggtggg agcgattgcc gagcggcgca 120

agggcgttta acgcctaacc ccctcctcct gggttgccaa gccgctaggt cgccgtttcc 180

aacgtggctg cgcgggactg aagtccgacg actcctcgtc ctcagtagga gacacacctc 240

ccactgcccc cagccacgcg agctatgggc agaatcgggg caacggtaat atctggatgg 300

ggcaggctcc cctgaggctg tgcttaagaa aaaaggaatc tggagtagcc tgaggggccc 360

cacgaggggg cctcctttgc gatcgtctcc cagccttagg ccaaggctac ggaggcaggc 420

ggccgagtgt tggcgcccag cccggccgag gactggatgg aggacgagaa gcagcctgcc 480

tctgggcgac agctgcggac gcagcctcgc cgcctcgccg cctcagcctc ggtcccagcg 540

tctctaaagc cgcgcccatt ttacagatgc agggcaggga gacaagaggc atctccgggg 600

gccgagtaga atgatggcgc gggttctccc ggcgccctga tttcgaggct gcgcccgggg 660

ccctacatgc aggcggggag gcctgggccg aaggcgtctg caaggagggg cgagtctgcc 720

cggtccgggc agggagtgag gccacagtca gttctcccta ggaggccgcg cagcgggtag 780

ggtatgggac tgggggacgc aacggggacc tggccgaatc agagccctca gcagagaacg 840

ccgaaaactc tggggccggc cgctcgcttc ccgctagtgg gaatggtttc cggtcatccg 900

ttcccagtcc agccccgggt agggagctct gatttgcaat gcacagcact tgcgaggttc 960

gaatgccccc gcaatttgca gatggaaata ctaagcctag gccgggcgtg gtggctcaag 1020

cctatcatct cagccctttg ggaggccaag ccgggaggat tgtttgagcc caagaattca 1080

aaaccagcct gagcaacata gcgaccccgt ctctacaaaa taaaataaaa taaattatcc 1140

gggcgtggtg gcacgcgcct gtggttccag ctactccgga ggctgaggtg ggaggatcgc 1200

ttgagtccgg gaggtcgagg ctacagtgag ccgtgatcgc accactgcac tccagcctgg 1260

gcgacagagt gagaccttgt ctcaaaaaag gaaaaaaaga aaaagaaagt aagcttcaaa 1320

gaagctctga taatagttct gggtcgtgca gcggtggcgg ccccgcgctc tcgcccctaa 1380

agcaagcgct ctttgtactg ggtggaggag ctttgagtag tgagggtgga gatgcagctt 1440

cggggtggcg cagccaccct gacactaggc ccggggtcgc agtgggacag aagagtctgc 1500

cgctctgact tgggctctga gttccaaggg cgcccggcac ttctagcctc ccaggcttgc 1560

gcgctggcgc ctttgccatc cgtgccgaag tggggagacc tagccgcgac caccacgagc 1620

gcagcggtga cacccagagg tcccaccggg cccctgggca gggtaacctt agcctgtccg 1680

cttcggcagc tttgcgaaga gtggcgcgca gctagggctg aggctcttgc ggacctgcgg 1740

tcgaagcagg cggctgagcc agttcgatcg ccaaggcctg ggctgccgac agtggtgcgc 1800

gctctgttcc gccgcggccg ggccaggcgc tctggaatag cgatgggggg acacggcctc 1860

caactttctg cagagaccat cgggcagctc cgggcctaag cagcgacctc accgaaggtt 1920

cctgggaacc tttgccaaaa tcccagcctc tgcctcggtc cagctaaacc gtgtgtaaac 1980

aagtgcacca ag 1992

<210> SEQ ID NO: 58

<211> LENGTH: 448

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 58

ataaaggacc gggtaatttc gcggaatgcg gattttgaga caggcccaga cggcggcgga 60

ttccctgtgt cccccaactg gggcgatctc gtgaacacac ctgcgtccca ccccgatcct 120

aggttggggg gaaagggtat gggaaccctg agcccagagc gcgccccgct ctttcctttg 180

ctccccggct tccctggcca gccccctccc ggctggtttc ctcgctcact cggcgcctgg 240

cgtttcgggc gtctggagat caccgcgtgt ctggcacccc aacgtctagt ctccccgcag 300

gttgaccgcg gcgcctggag ccgggaatag gggtggggag tccggagaac caaacccgag 360

cctgaagttg ccattcgggt gactcccgag aaagcccggg agcattttgg ccaatgcggg 420

tttttacctg aacttcagca tcttcacc 448

<210> SEQ ID NO: 59

<211> LENGTH: 395

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 59

aattggaaaa ccctggtatt gtgcctgttt gggggaagaa aacgtcaata aaaattaatt 60

gatgagttgg cagggcgggc ggtgcgggtt cgcggcgagg cgcagggtgt catggcaaat 120

gttacggctc agattaagcg attgttaatt aaaaagcgac ggtaattaat actcgctacg 180

ccatatgggc ccgtgaaaag gcacaaaagg tttctccgca tgtggggttc cccttctctt 240

ttctccttcc acaaaagcac cccagcccgt gggtcccccc tttggcccca aggtaggtgg 300

aactcgtcac ttccggccag ggaggggatg gggcggtctc cggcgagttc caagggcgtc 360

cctcgttgcg cactcgcccg cccaggttct ttgaa 395

<210> SEQ ID NO: 60

<211> LENGTH: 491

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 60

gggaagcgat cgtctcctct gtcaactcgc gcctgggcac ttagcccctc ccgtttcagg 60

gcgccgcctc cccggatggc aaacactata aagtggcggc gaataaggtt cctcctgctg 120

ctctcggttt agtccaagat cagcgatatc acgcgtcccc cggagcatcg cgtgcaggag 180

ccatggcgcg ggagctatac cacgaagagt tcgcccgggc gggcaagcag gcggggctgc 240

aggtctggag gattgagaag ctggagctgg tgcccgtgcc ccagagcgct cacggcgact 300

tctacgtcgg ggatgcctac ctggtgctgc acacggccaa gacgagccga ggcttcacct 360

accacctgca cttctggctc ggtaagggac ggcgggcggc gggaccccga cgcaccaagg 420

ccggcgaggg gagggcgtag gggtctgaga tttgcaggcg tgggagtaaa ggggaccgca 480

aactgagcta g 491

<210> SEQ ID NO: 61

<211> LENGTH: 1284

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 61

ctcaggggcg ggaagtggcg ggtgggagtc acccaagcgt gactgcccga ggcccctcct 60

gccgcggcga ggaagctcca taaaagccct gtcgcgaccc gctctctgca ccccatccgc 120

tggctctcac ccctcggaga cgctcgcccg acagcatagt acttgccgcc cagccacgcc 180

cgcgcgccag ccaccgtgag tgctacgacc cgtctgtcta ggggtgggag cgaacggggc 240

gcccgcgaac ttgctagaga cgcagcctcc cgctctgtgg agccctgggg ccctgggatg 300

atcgcgctcc actccccagc ggactatgcc ggctccgcgc cccgacgcgg accagccctc 360

ttggcggcta aattccactt gttcctctgc tcccctctga ttgtccacgg cccttctccc 420

gggcccttcc cgctgggcgg ttcttctgag ttacctttta gcagatatgg agggagaacc 480

cgggaccgct atcccaaggc agctggcggt ctccctgcgg gtcgccgcct tgaggcccag 540

gaagcggtgc gcggtaggaa ggtttccccg gcagcgccat cgagtgagga atccctggag 600

ctctagagcc ccgcgccctg ccacctccct ggattcttgg gctccaaatc tctttggagc 660

aattctggcc cagggagcaa ttctctttcc ccttccccac cgcagtcgtc accccgaggt 720

gatctctgct gtcagcgttg atcccctgaa gctaggcaga ccagaagtaa cagagaagaa 780

acttttcttc ccagacaaga gtttgggcaa gaagggagaa aagtgaccca gcaggaagaa 840

cttccaattc ggttttgaat gctaaactgg cggggccccc accttgcact ctcgccgcgc 900

gcttcttggt ccctgagact tcgaacgaag ttgcgcgaag ttttcaggtg gagcagaggg 960

gcaggtcccg accggacggc gcccggagcc cgcaaggtgg tgctagccac tcctgggttc 1020

tctctgcggg actgggacga gagcggattg ggggtcgcgt gtggtagcag gaggaggagc 1080

gcggggggca gaggagggag gtgctgcgcg tgggtgctct gaatccccaa gcccgtccgt 1140

tgagccttct gtgcctgcag atgctaggta acaagcgact ggggctgtcc ggactgaccc 1200

tcgccctgtc cctgctcgtg tgcctgggtg cgctggccga ggcgtacccc tccaagccgg 1260

acaacccggg cgaggacgca ccag 1284

<210> SEQ ID NO: 62

<211> LENGTH: 554

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 62

tggagaacct tgggctctgt ggcctcaaag gtaggggtga tttcgagggg ccggcacctc 60

acagggcagg ttccaccgcg gaaacgcagt catcgcccag cgaccctgct cctggccctc 120

agcctccccc caggtttctt tttctcttga atcaagccga ggtgcgccaa tggccttcct 180

tgggtcggat ccggggggcc agggccagct tacctgcttt caccgagcag tggatatgtg 240

ccttggactc gtagtacacc cagtcgaagc cggcctccac cgccaggcgg gccagcatgc 300

cgtacttgct gcggtcgcgg tcagacgtgg tgatgtccac tgcgcggccc tcgtagtgca 360

gagactcctc tgagtggtgg ccatcttcgt cccagccctc ggtcacccgc agtttcactc 420

ctggccactg gttcatcacc gagatggcca aagcgttcaa cttgtcctta cacctctgcg 480

aagacaaggg gacccccacc gacggacacg ttagcctggg caaccgccac ccctcccggc 540

ccctccatca gcct 554

<210> SEQ ID NO: 63

<211> LENGTH: 772

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 63

tctcacgacc catccgttaa cccaccgttc ccaggagctc cgaggcgcag cggcgacaga 60

ggttcgcccc ggcctgctag cattggcatt gcggttgact gagcttcgcc taacaggctt 120

ggggagggtg ggctgggctg ggctgggctg ggctgggtgc tgcccggctg tccgcctttc 180

gttttcctgg gaccgaggag tcttccgctc cgtatctgcc tagagtctga atccgacttt 240

ctttcctttg ggcacgcgct cgccagtgga gcacttcttg ttctggcccc gggctgatct 300

gcacgcggac ttgagcaggt gccaaggtgc cacgcagtcc cctcacggct ttcggggggt 360

cttggagtcg ggtggggagg gagacttagg tgtggtaacc tgcgcaggtg ccaaagggca 420

gaaggagcag ccttggatta tagtcacggt ctctccctct cttccctgcc atttttaggg 480

ctttctctac gtgctgttgt ctcactgggt ttttgtcgga gccccacgcc ctccggcctc 540

tgattcctgg aagaaagggt tggtcccctc agcaccccca gcatcccgga aaatggggag 600

caaggctctg ccagcgccca tcccgctcca cccgtcgctg cagctcacca attactcctt 660

cctgcaggcc gtgaacacct tcccggccac ggtggaccac ctgcagggcc tgtacggtct 720

cagcgcggta cagaccatgc acatgaacca ctggacgctg gggtatccca at 772

<210> SEQ ID NO: 64

<211> LENGTH: 1362

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 64

tggtttcctt tcgcttctcg cctcccaaac acctccagca agtcggaggg cgcgaacgcg 60

gagccagaaa cccttcccca aagtttctcc cgccaggtac ctaattgaat catccatagg 120

atgacaaatc agccagggcc aagatttcca gacacttgag tgacttcccg gtccccgagg 180

tgacttgtca gctccagtga gtaacttgga actgtcgctc ggggcaaggt gtgtgtctag 240

gagagagccg gcggctcact cacgctttcc agagagcgac ccgggccgac ttcaaaatac 300

acacagggtc atttataggg actggagccg cgcgcaggac aacgtctccg agactgagac 360

attttccaaa cagtgctgac attttgtcgg gccccataaa aaatgtaaac gcgaggtgac 420

gaacccggcg gggagggttc gtgtctggct gtgtctgcgt cctggcggcg tgggaggtta 480

tagttccaga cctggcggct gcggatcgcc gggccggtac ccgcgaggag tgtaggtacc 540

ctcagcccga ccacctcccg caatcatggg gacaccggct tggatgagac acaggcgtgg 600

aaaacagcct tcgtgaaact ccacaaacac gtggaacttg aaaagacaac tacagccccg 660

cgtgtgcgcg agagacctca cgtcacccca tcagttccca cttcgccaaa gtttcccttc 720

agtggggact ccagagtggt gcgccccatg cccgtgcgtc ctgtaacgtg ccctgattgt 780

gtacccctct gcccgctcta cttgaaatga aaacacaaaa actgttccga attagcgcaa 840

ctttaaagcc ccgttatctg tcttctacac tgggcgctct taggccactg acagaaacat 900

ggtttgaacc ctaattgttg ctatcagtct cagtcagcgc aggtctctca gtgacctgtg 960

acgccgggag ttgaggtgcg cgtatcctta aacccgcgcg aacgccaccg gctcagcgta 1020

gaaaactatt tgtaatccct agtttgcgtc tctgagcttt aactccccca cactctcaag 1080

cgcccggttt ctcctcgtct ctcgcctgcg agcaaagttc ctatggcatc cacttaccag 1140

gtaaccggga tttccacaac aaagcccggc gtgcgggtcc cttcccccgg ccggccagcg 1200

cgagtgacag cgggcggccg gcgctggcga ggagtaactt ggggctccag cccttcagag 1260

cgctccgcgg gctgtgcctc cttcggaaat gaaaaccccc atccaaacgg ggggacggag 1320

cgcggaaacc cggcccaagt gccgtgtgtg cgcgcgcgtc tg 1362

<210> SEQ ID NO: 65

<211> LENGTH: 476

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 65

gaaagccatc cttaccattc ccctcaccct ccgccctctg atcgcccacc cgccgaaagg 60

gtttctaaaa atagcccagg gcttcaaggc cgcgcttctg tgaagtgtgg agcgagcggg 120

cacgtagcgg tctctgccag gtggctggag ccctggaagc gagaaggcgc ttcctccctg 180

catttccacc tcaccccacc cccggctcat ttttctaaga aaaagttttt gcggttccct 240

ttgcctccta cccccgctgc cgcgcggggt ctgggtgcag acccctgcca ggttccgcag 300

tgtgcagcgg cggctgctgc gctctcccag cctcggcgag ggttaaaggc gtccggagca 360

ggcagagcgc cgcgcgccag tctattttta cttgcttccc ccgccgctcc gcgctccccc 420

ttctcagcag ttgcacatgc cagctctgct gaaggcatca atgaaaacag cagtag 476

<210> SEQ ID NO: 66

<211> LENGTH: 300

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 66

atcgaaaatg tcgacatctt gctaatggtc tgcaaacttc cgccaattat gactgacctc 60

ccagactcgg ccccaggagg ctcgtattag gcagggaggc cgccgtaatt ctgggatcaa 120

aagcgggaag gtgcgaactc ctctttgtct ctgcgtgccc ggcgcgcccc cctcccggtg 180

ggtgataaac ccactctggc gccggccatg cgctgggtga ttaatttgcg aacaaacaaa 240

agcggcctgg tggccactgc attcgggtta aacattggcc agcgtgttcc gaaggcttgt 300

<210> SEQ ID NO: 67

<211> LENGTH: 1246

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 67

atcaacatcg tggctttggt cttttccatc atggtgagtg aatcacggcc agaggcagcc 60

tgggaggaga gacccgggcg gctttgagcc cctgcagggg agtccgcgcg ctctctgcgg 120

ctcccttcct cacggcccgg cccgcgctag gtgttctttg tcctcgcacc tcctcctcac 180

ctttctcggg ctctcagagc tctccccgca atcatcagca cctcctctgc actcctcgtg 240

gtactcagag ccctgatcaa gcttccccca ggctagcttt cctcttcttt ccagctccca 300

gggtgcgttt cctctccaac ccggggaagt tcttccgtgg actttgctga ctcctctgac 360

cttcctaggc acttgcccgg ggcttctcaa ccctcttttc tagagcccca gtgcgcgcca 420

ccctagcgag cgcagtaagc tcataccccg agcatgcagg ctctacgttc ctttccctgc 480

cgctccgggg gctcctgctc tccagcgccc aggactgtct ctatctcagc ctgtgctccc 540

ttctctcttt gctgcgccca agggcaccgc ttccgccact ctccgggggg tccccaggcg 600

attcctgatg ccccctcctt gatcccgttt ccgcgctttg gcacggcacg ctctgtccag 660

gcaacagttt cctctcgctt cttcctacac ccaacttcct ctccttgcct ccctccggcg 720

cccccttttt aacgcgcccg aggctggctc acacccacta cctctttagg cctttcttag 780

gctccccgtg tgcccccctc accagcaaag tgggtgcgcc tctcttactc tttctaccca 840

gcgcgtcgta gttcctcccc gtttgctgcg cactggccct aacctctctt ctcttggtgt 900

cccccagagc tcccaggcgc ccctccaccg ctctgtcctg cgcccggggc tctcccggga 960

atgaactagg ggattccacg caacgtgcgg ctccgcccgc cctctgcgct cagacctccc 1020

gagctgcccg cctctctagg agtggccgct ggggcctcta gtccgccctt ccggagctca 1080

gctccctagc cctcttcaac cctggtagga acacccgagc gaaccccacc aggagggcga 1140

cgagcgcctg ctaggccctc gccttattga ctgcagcagc tggcccgggg gtggcggcgg 1200

ggtgaggttc gtaccggcac tgtcccggga caacccttgc agttgc 1246

<210> SEQ ID NO: 68

<211> LENGTH: 984

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 68

acaaataaaa caccctctag cttcccctag actttgttta actggccggg tctccagaag 60

gaacgctggg gatgggatgg gtggagagag ggagcggctc aaggacttta gtgaggagca 120

ggcgagaagg agcacgttca ggcgtcaaga ccgatttctc cccctgcttc gggagacttt 180

tgaacgctcg gagaggcccg gcatctcacc actttacttg gccgtagggg cctccggcac 240

ggcaggaatg agggaggggg tccgattgga cagtgacggt ttggggccgt tcggctatgt 300

tcagggacca tatggtttgg ggacagcccc agtagttagt aggggacggg tgcgttcgcc 360

cagtccccgg atgcgtaggg aggcccagtg gcaggcagct gtcccaagca gcgggtgcgc 420

gtccctgcgc gctgtgtgtt cattttgcag agccagcctt cggggaggtg aaccagctgg 480

gaggagtgtt cgtgaacggg aggccgctgc ccaacgccat ccggcttcgc atcgtggaac 540

tggcccaact gggcatccga ccgtgtgaca tcagccgcca gctacgggtc tcgcacggct 600

gcgtcagcaa gatcctggcg cgatacaacg agacgggctc gatcttgcca ggagccatcg 660

ggggcagcaa gccccgggtc actaccccca ccgtggtgaa acacatccgg acctacaagc 720

agagagaccc cggcatcttc gcctgggaga tccgggaccg cctgctggcg gacggcgtgt 780

gcgacaagta caatgtgccc tccgtgagct ccatcagccg cattctgcgc aacaagatcg 840

gcaacttggc ccagcagggt cattacgact catacaagca gcaccagccg acgccgcagc 900

cagcgctgcc ctacaaccac atctactcgt accccagccc tatcacggcg gcggccgcca 960

aggtgcccac gccacccggg gtgc 984

<210> SEQ ID NO: 69

<211> LENGTH: 545

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 69

aggaggcgca acgcgctgcc agggcggctt tatcctgccg ccacagggcg gggaccagcc 60

cggcagccgg gtgtccagcg ccgctcacgt gcctcgcctg gagcttagct ctcagactcc 120

gaagagggcg actgagactt gggcctggga gttggcttcg gggtacccaa ggcgacgaca 180

gctgagttgt accacgaagc tcaggccgag gcctcctccc ttgtctggcc ttcgaatcca 240

tactggcagc ctctcctctc aggcactccg cgggccgggc cactaggccc cctgctcctg 300

gagctgcgct atgatccggg tcttgagatg cgcgcgattc tctctgaacc ggtggagagg 360

aggctctgcc ccgcgcggag cgaggacagc ggcgcccgag cttcccgcgc ctctccaggg 420

cccaatggca agaacagcct ccgaagtgcg cggatgacag gaaaagatct tcagttcttc 480

tgccgctaga gaagtgcggg atacaagcct ctattggatc cacaacctgg agtcctgcct 540

tcgga 545

<210> SEQ ID NO: 70

<211> LENGTH: 1533

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 70

atctgcgtgc ccttttctgg gcgagccctg ggagatccag ggagaactgg gcgctccaga 60

tggtgtatgt ctgtaccttc acagcaaggc ttcccttgga tttgaggctt cctattttgt 120

ctgggatcgg ggtttctcct tgtcccagtg gcagccccgc gttgcgggtt ccgggcgctg 180

cgcggagccc aaggctgcat ggcagtgtgc agcgcccgcc agtcgggctg gtgggttgtg 240

cactccgtcg gcagctgcag aaaggtggga gtgcaggtct tgcctttcct caccgggcgg 300

ttggcttcca gcaccgaggc tgacctatcg tggcaagttt gcggcccccg cagatcccca 360

gtggagaaag agggctcttc cgatgcgatc gagtgtgcgc ctccccgcaa agcaatgcag 420

accctaaatc actcaaggcc tggagctcca gtctcaaagg tggcagaaaa ggccagacct 480

aactcgagca cctactgcct tctgcttgcc ccgcagagcc ttcagggact gactgggacg 540

cccctggtgg cgggcagtcc catccgccat gagaacgccg tgcagggcag cgcagtggag 600

gtgcagacgt accagccgcc gtggaaggcg ctcagcgagt ttgccctcca gagcgacctg 660

gaccaacccg ccttccaaca gctggtgagg ccctgcccta cccgccccga cctcgggact 720

ctgcgggttg gggatttagc cacttagcct ggcagagagg ggagggggtg gccttgggct 780

gaggggctgg gtacagccct aggcggtggg ggagggggaa cagtggcggg ctctgaaacc 840

tcacctcggc ccattacgcg ccctaaacca ggtctccctg gattaaagtg ctcacaagag 900

aggtcgcagg attaaccaac ccgctccccc gccctaatcc ccccctcgtg cgcctgggga 960

cctggcctcc ttctccgcag ggcttgctct cagctggcgg ccggtcccca agggacactt 1020

tccgactcgg agcacgcggc cctggagcac cagctcgcgt gcctcttcac ctgcctcttc 1080

ccggtgtttc cgccgcccca ggtctccttc tccgagtccg gctccctagg caactcctcc 1140

ggcagcgacg tgacctccct gtcctcgcag ctcccggaca cccccaacag tatggtgccg 1200

agtcccgtgg agacgtgagg gggacccctc cctgccagcc cgcggacctc gcatgctccc 1260

tgcatgagac tcacccatgc tcaggccatt ccagttccga aagctctctc gccttcgtaa 1320

ttattctatt gttatttatg agagagtacc gagagacacg gtctggacag cccaaggcgc 1380

caggatgcaa cctgctttca ccagactgca gacccctgct ccgaggactc ttagtttttc 1440

aaaaccagaa tctgggactt accagggtta gctctgccct ctcctctcct ctctacgtgg 1500

ccgccgctct gtctctccac gccccacctg tgt 1533

<210> SEQ ID NO: 71

<211> LENGTH: 702

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 71

aggtctcttc agactgccca ttctccgggc ctcgctgaat gcgggggctc tatccacagc 60

gcgcggggcc gagctcaggc aggctggggc gaagatctga ttctttcctt cccgccgcca 120

aaccgaatta atcagtttct tcaacctgag ttactaagaa agaaaggtcc ttccaaataa 180

aactgaaaat cactgcgaat gacaatacta tactacaagt tcgttttggg gccggtgggt 240

gggatggagg agaaagggca cggataatcc cggagggccg cggagtgagg aggactatgg 300

tcgcggtgga atctctgttc cgctggcaca tccgcgcagg tgcggctctg agtgctggct 360

cggggttaca gacctcggca tccggctgca ggggcagaca gagacctcct ctgctagggc 420

gtgcggtagg catcgtatgg agcccagaga ctgccgagag cactgcgcac tcaccaagtg 480

ttaggggtgc ccgtgataga ccgccaggga aggggctggt tcggagggaa ttcccgctac 540

cgggaaggtc ggaactcggg gtgatcaaac aaggaatgca tctcacctcc gtgggtgctt 600

gtgctgcgca aggaattatt accggagcgg ttgcgatggc ctttgcccgg cgacccaaga 660

agagtaagca aactaccgtc cacccagcgg atcaggtcca at 702

<210> SEQ ID NO: 72

<211> LENGTH: 3180

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 72

gatgtcctgt ttctagcagc ctccagagcc aagctaggcg agaggcgtag gaggcagaga 60

gagcgggcgc gggaggccag ggtccgcctg ggggcctgag gggacttcgt ggggtcccgg 120

gagtggccta gaaacaggga gctgggaggg ccgggaagag cttgaggctg agcgggggac 180

gaacgggcag cgcaaagggg agatgaacgg aatggccgag gagccacgca ttcgccttgt 240

gtccgcggac ccttgttccc gacaggcgac caagccaagg ccctccggac tgacgcggcc 300

tgagcagcag cgagtgtgaa gtttggcacc tccggcggcg agacggcgcg ttctggcgcg 360

cggctcctgc gtccggctgg tggagctgct gcgccctatg cggcctgccg agggcgccgc 420

cgagggcccg cgagctccgt ggggtcgggg tggggggacc cgggagcgga cagcgcggcc 480

cgaggggcag gggcaggggc gcgcctggcc tggggtgtgt ctgggccccg gctccgggct 540

cttgaaggac cgcgagcagg aggcttgcgc aatcccttgg ctgagcgtcc acggagaaag 600

aaaaagagca aaagcagagc gagagtggag cgagggatgg gggcgggcaa agagccatcc 660

gggtctccac caccgccctg acacgcgacc cggctgtctg ttggggaccg cacgggggct 720

cgggcgagca ggggagggag gagcctgcgc ggggctcgtg ttcgcccagg aatcccggag 780

aagctcgaag acggtctggt gttgaacgca cacgtggact ccatttcatt accaccttgc 840

agctcttgcg ccacggaggc tgctgctgcc cggcggctgc tacccaccga gacccacgtg 900

gcccctcccc aggggtgtag gggtgacggt tgtcttctgg tgacagcaga ggtgttgggt 960

ttgcgactga tctctaacga gcttgaggcg caaacctagg attccctgag tgttggggtg 1020

cggcgggggg gcaagcaagg tgggacgacg cctgcctggt ttccctgact agttgcgggg 1080

ggtgggggcc ggctctcagg ggccaccaga agctgggtgg gtgtacagga aaatattttt 1140

ctcctgccgt gtttggcttt ttcctggcat ttttgcccag ggcgaagaac tgtcgcgcgg 1200

ggcagctcca ccgcggaggg agaggggtcg cgaggctggc gcgggaagcg ctgtaggtgg 1260

cagtcatccg tccacgccgc acaggccgtc tgcgccgtcg gaccatcggg aggtctgcag 1320

caactttgtc ccggccagtc cccttgtccg ggaaggggct gagcttcccg acactctacc 1380

ctccccctct tgaaaatccc ctggaaaatc tgtttgcaat gggtgtttcc gcggcgtcca 1440

ggtctgggct gccgggggag gccgagcggc tgctgcagcc tccctgctgc caggggcgtc 1500

ggactccgct tcgctcacta cgcccaggcc cctcaggggc ccacgctcag gacttcgggg 1560

ccacacagca ggacccggtg ccccgacgac gagtttgcgc aggacccggg ctgggccagc 1620

cgcggagctg gggaggaagg ggcgggggtc ggtgcagcgg atcttttctg ttgctgcctg 1680

tgcggcggca ggaagcgtct tgaggctccc caagactacc tgaggggccg cccaagcact 1740

tcagaagccc aaggagcccc cggccacccc cgctcctggc ctttttgcca acgactttga 1800

aagtgaaatg cacaagcacc agcaattgac ttcccttccg tggttattta ttttgtcttt 1860

gtggatggtg ggcagatggg gagagaggcc cctacctaac ctcggtggct ggtccctaga 1920

ccacccctgc cagccggtgt ggggaggagc tcaggtccgc gggagagcga atgggcgcca 1980

ggaggtggga cagaatcctg ggaaggtaca gcggacgccc tggaagctcc cctgatgccc 2040

cagagggccc ttcctgggaa acctcccggg ggggtgcccc ataccatccc acccggctgt 2100

cttggcccct cccagggagc cgcaggagaa actagcccta cacctgggat tcccagagcc 2160

ttctgctggg gctcctgccc ccgacttcgg ataaccagct ccgcacaggt ccccgagaag 2220

ggccgctggc ctgcttattt gatactgccc cctcccagac aggggctggt cgagcccctg 2280

gttctgctgc cagactgaag ccttccagac gccacctcgg tttgggcccc cagggccctc 2340

aggggcccca ggagaggaga gctgctatct agctcagcca caggctcgct cctggtgggg 2400

gccaggctga aggagtggac cctggagagg tcgggaacct tttaacagcc gtgggctgga 2460

gggtggctac taagtgttcg gtctgggaag aggcatgacc cgcaccatcc cggggaaata 2520

aacgacttct taagggaatc ttctcgctga gcgggtgctc tgggccagga gattgccacc 2580

gccagcccac ggaacccaga tttgggctct gccttgagcg ggccgcctgt ggcttcccgg 2640

gtcgctcccc cgactcagaa agctctcaag ttggtatcgt tttcccggcc ctcggaggtg 2700

gattgcagat caccgagagg ggatttacca gtaaccacta cagaatctac ccgggcttta 2760

acaagcgctc atttctctcc cttgtcctta gaaaaacttc gcgctggcgt tgatcatatc 2820

gtacttgtag cggcagctta ggggcagcgg aactggtggg gttgtgcgtg cagggggagg 2880

ctgtgaggga gccctgcact ccgcccctcc acccttctgg aggagtggct ttgtttctaa 2940

gggtgccccc ccaacccccg ggtccccact tcaatgtttc tgctctttgt cccaccgccc 3000

gtgaaagctc ggctttcatt tggtcggcga agcctccgac gcccccgagt cccaccctag 3060

cgggccgcgc ggcactgcag ccgggggttc ctgcggactg gcccgacagg gtgcgcggac 3120

ggggacgcgg gccccgagca ccgcgacgcc agggtccttt ggcagggccc aagcacccct 3180

<210> SEQ ID NO: 73

<211> LENGTH: 1038

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 73

tggcggccgg cgggcacagc cggctcattg ttctgcacta caaccactcg ggccggctgg 60

ccgggcgcgg ggggccggag gatggcggcc tgggggccct gcgggggctg tcggtggccg 120

ccagctgcct ggtggtgctg gagaacttgc tggtgctggc ggccatcacc agccacatgc 180

ggtcgcgacg ctgggtctac tattgcctgg tgaacatcac gctgagtgac ctgctcacgg 240

gcgcggccta cctggccaac gtgctgctgt cgggggcccg caccttccgt ctggcgcccg 300

cccagtggtt cctacgggag ggcctgctct tcaccgccct ggccgcctcc accttcagcc 360

tgctcttcac tgcaggggag cgctttgcca ccatggtgcg gccggtggcc gagagcgggg 420

ccaccaagac cagccgcgtc tacggcttca tcggcctctg ctggctgctg gccgcgctgc 480

tggggatgct gcctttgctg ggctggaact gcctgtgcgc ctttgaccgc tgctccagcc 540

ttctgcccct ctactccaag cgctacatcc tcttctgcct ggtgatcttc gccggcgtcc 600

tggccaccat catgggcctc tatggggcca tcttccgcct ggtgcaggcc agcgggcaga 660

aggccccacg cccagcggcc cgccgcaagg cccgccgcct gctgaagacg gtgctgatga 720

tcctgctggc cttcctggtg tgctggggcc cactcttcgg gctgctgctg gccgacgtct 780

ttggctccaa cctctgggcc caggagtacc tgcggggcat ggactggatc ctggccctgg 840

ccgtcctcaa ctcggcggtc aaccccatca tctactcctt ccgcagcagg gaggtgtgca 900

gagccgtgct cagcttcctc tgctgcgggt gtctccggct gggcatgcga gggcccgggg 960

actgcctggc ccgggccgtc gaggctcact ccggagcttc caccaccgac agctctctga 1020

ggccaaggga cagctttc 1038

<210> SEQ ID NO: 74

<211> LENGTH: 1200

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 74

gtcctaacat cccaggtggc ggcgcgctgg ctccctggag cggggcggga cgcggccgcg 60

cggactcacg tgcacaaccg cgcgggacgg ggccacgcgg actcacgtgc acaaccgcgg 120

gaccccagcg ccagcgggac cccagcgcca gcgggacccc agcgccagcg ggaccccagc 180

gccagcggga ccccagcgcc agcgggaccc cagcgccagc gggaccccag cgccagcggg 240

tctgtggccc agtggagcga gtggagcgct ggcgacctga gcggagactg cgccctggac 300

gccccagcct agacgtcaag ttacagcccg cgcagcagca gcaaagggga aggggcagga 360

gccgggcaca gttggatccg gaggtcgtga cccaggggaa agcgtgggcg gtcgacccag 420

ggcagctgcg gcggcgaggc aggtgggctc cttgctccct ggagccgccc ctccccacac 480

ctgccctcgg cgcccccagc agttttcacc ttggccctcc gcggtcactg cgggattcgg 540

cgttgccgcc agcccagtgg ggagtgaatt agcgccctcc ttcgtcctcg gcccttccga 600

cggcacgagg aactcctgtc ctgccccaca gaccttcggc ctccgccgag tgcggtactg 660

gagcctgccc cgccagggcc ctggaatcag agaaagtcgc tctttggcca cctgaagcgt 720

cggatcccta cagtgcctcc cagcctgggc gggagcggcg gctgcgtcgc tgaaggttgg 780

ggtccttggt gcgaaaggga ggcagctgca gcctcagccc caccccagaa gcggccttcg 840

catcgctgcg gtgggcgttc tcgggcttcg acttcgccag cgccgcgggg cagaggcacc 900

tggagctcgc agggcccaga cctgggttgg aaaagcttcg ctgactgcag gcaagcgtcc 960

gggaggggcg gccaggcgaa gccccggcgc tttaccacac acttccgggt cccatgccag 1020

ttgcatccgc ggtattgggc aggaaatggc agggctgagg ccgaccctag gagtataagg 1080

gagccctcca tttcctgccc acatttgtca cctccagttt tgcaacctat cccagacaca 1140

cagaaagcaa gcaggactgg tggggagacg gagcttaaca ggaatatttt ccagcagtga 1200

<210> SEQ ID NO: 75

<211> LENGTH: 900

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 75

caccttcccc gaggtaatta ttttctgggg ggtaggggtg ggggttggga gggtgaagaa 60

aggaagaaaa agaaggccga tcacactggg caccggcgga ggaagcgtgg agtccattga 120

tctaggtact tgtggggagg ggagaacccg agcagcagct gcaaacggaa gggctgtgag 180

cgagcgggcg ggcgggtggc tggcagcgag gccaccagca gggggggccc gggccgaggc 240

cgcgccacct cggcaccacg cgggcagccg gtgcggcggg gtcgccacgg ccaggggagc 300

gctgggtgcc caccatggca gttatgcaag cggtgacccc ctggtcttgc ctccccgccg 360

ccctgcactc cttcctcccc gctgccgaca cttggatctc tctagctctt tctctcccct 420

gtgttttcaa acaggaagtg cacggctgtc tataacgtgc tgccgggtct caggatggag 480

gagtgaagtc tcctgtcgcc gtggttccag cctccggagc tcgcccaagc cgcgtcccca 540

gagagcgccc tgagagaaca gggtggccgc ttggtccagg tgcgcggggt cgggtctggg 600

tccagggagc gggtcgggaa gtctgcggca cggagcactg ctagtgtcgg atctgcatct 660

ccagctctgt gctgcagctt cacttgcccg ccccccacca ctggcttctc acccggggtc 720

tctgccaaac tctggctgct gccgccctgg gttcgggccg gcggaaggcc ctgggcgtgc 780

gctgcggagc cgcctgcgag gactccacta gggcgctttc caggctggac tgccccgggc 840

tgcgctggag ctgccagtgc tcggggagtc ttcctggagt ccccagctgc cctctccacc 900

<210> SEQ ID NO: 76

<211> LENGTH: 200

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 76

ctcttcccaa gttacgccac cggtcgagga cggcaggaga cccccgagtg cagagaaagc 60

tcaaaccggc agcgaagtcg gtcctagcca agctgaaaaa acgtctcgga tttcgcggac 120

agcggcctag acacagcccg atcttccagt cctagtgccc tggtcgagac ggttctatcc 180

ttttgcaaag aagccggaaa 200

<210> SEQ ID NO: 77

<211> LENGTH: 400

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 77

tctcggttgc aatccccacc ctcctcaccc agcagggcag gaggcaccca acttggagga 60

gaaaggggtg ggggaggtga aacagagacc ggagagtcac gagggctggg ccgccgagag 120

caggagaata taccgtgtca cacacctcca ttctctcaca cacgttgcag acacaaatca 180

ctgacggttt ccacgtgctg cgctcgtgag cggaggtgtt caaagagggg gcagatgagt 240

tacttcccga gacggaaccg ggggtcccac gtccgccgcc ttcagtagca caaccaatct 300

ctgaacactc aaaccgcgca tctctggcgc atcaccatcc tatttaaggc cacgggctcc 360

gcccttttcc tcccctccct tcttttccac tctttttcca 400

<210> SEQ ID NO: 78

<211> LENGTH: 700

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 78

ctgccagaga tgtgtctgtc ttgcgccccg catgcactgc ctgcggggct gcgctgcact 60

ccccggcggc gccacgggtc tggcccccgc gcttctacgt gttgggggga tgcatggacc 120

ttggagatcc gtagttggcc ctaaccttct cggaatctcc tctgcacgcg ctgcctgttc 180

ctcctctgca cgctctgtcc gttcctttgc aacttctgtg ggaattgtcc tggcgtggga 240

aacgcccccg cgctctttgg cacttagggt gtgagtgttg cgccccttgc cgcagcgctc 300

agggcagcat cccgctcgag gatgcagggt tctcaccaag cagtgagggg gactcacgcg 360

ccgccgggga gcggagccag gctccgagaa gggagcaggc tcgagccgct gggttttcgc 420

aagccttggg gcctctggcc gcccttccat gcctccgggc gcgggcggct cagcaggtcc 480

ccggcttcgg gaagttttgt gcgcggatcg ctggtgggga gggcgcgcgg gccagtggct 540

gagcttgcag cgaagtttcc gtgaaggaaa ctgcatgtgc ctttggaggc gactcgggac 600

tgctgtaggg tggactgggt gtctatggag ttgcgggtca gagcgagtag ggtgggtcct 660

ttcctgggac aggactggga attggggctc gaagtagggg 700

<210> SEQ ID NO: 79

<211> LENGTH: 200

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 79

aggggtgtcc tccaacatct ctgaaccgcc ttcccttcct cctcactggc gccctcttgc 60

ctcagtcgtc ggagatggag aggcggctga agattggcag gcggcggcca gggtcgaggc 120

tgggagactc agagccgctg aggctgccgg agctcaggga gccgcttagg tagctgtcgc 180

ggtccgacag cgagtccggg 200

<210> SEQ ID NO: 80

<211> LENGTH: 5000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 80

tctgactctc gggctggagc agccgagaca gcgctcccca gcgggactac agaatcccgg 60

gtgtcggcct gggggccctg gattggcagt ggtggagtct tctgagccta acagctacta 120

ggaatgacag agttgcagat ggctttgtcg cccgcggggc ggctcaagcg tcctgggtcc 180

caggcctctg tcctacggcc aggccgccgg ctcaacgggc cgaagggaat cgggctgacc 240

agtcctaagg tcccacgctc ccctgacctc agggcccaga gcctcgcatt accccgagca 300

gtgcgttggt tactctccct ggaaagccgc ccccgccggg gcaagtggga gttgctgcac 360

tgcggtcttt ggaggcctag gtcgcccaga gtaggcggag ccctgtatcc ctcctggagc 420

cggcctgcgg tgaggtcggt acccagtact tagggaggga ggacgcgctt ggtgctcagg 480

gtaggctggg ccgctgctag ctcttgattt agtctcatgt ccgcctttgt gccggcctct 540

ccgatttgtg ggtccttcca agaaagagtc ctctagggca gctagggtcg tctcttgggt 600

ctggcgaggc ggcaggcctt cttcggacct atccccagag gtgtaacgga gactttctcc 660

actgcagggc ggcctggggc gggcatctgc caggcgaggg agctgccctg ccgccgagat 720

tgtggggaaa cggcgtggaa gacaccccat cggagggcac ccaatctgcc tctgcactcg 780

attccatcct gcaacccagg agaaaccatt tccgagttcc agccgcagag gcacccgcgg 840

agttgccaaa agagactccc gcgaggtcgc tcggaacctt gaccctgaca cctggacgcg 900

aggtctttca ggaccagtct cggctcggta gcctggtccc cgaccaccgc gaccaggagt 960

tccttcttcc cttcctgctc accagccggc cgccggcagc ggctccagga aggagcacca 1020

acccgcgctg ggggcggagg ttcaggcggc aggaatggag aggctgatcc tcctctagcc 1080

ccggcgcatt cacttaggtg cgggagccct gaggttcagc ctgactttcc cgactccgcc 1140

gggcgcttgg tgggctcctg ggcttctggg ctcaccctta cacctgtgta ctaaagggct 1200

gctaccctcc cgaggtgtac gtccgccgcc tcggcgctca tcggggtgtt ttttcaccct 1260

ctcgcggtgc acgctttttc tctcacgtca gctcacatct ttcagtacac agccactggg 1320

tctccctgcc cctccagcct ttcctaggca gctttgaggg cccagacgac tgaagtctta 1380

ctgctaggat gggaacacga tgaaaaagga aggggcccag tcaaaagtcc tctcctcttc 1440

ggtttttctt caactgtcct tcacaaaaac atttatttct gtcccagcgc cctggcggat 1500

ttcggcagat gggccctagg gggttgtgga ggccaaattc ccaggatgct ggtcctgcct 1560

ttttcattgg ccaaaactgt atttcctaca acgactaaag ataaccaaga actgagtaga 1620

ccctgttctc tcaccagatc tccctggctc tgtttaactt ttcctggtgc aatgcgatgg 1680

caccaccagc tccccaggca ggcaccactc cctcaagata ccatttgggg tagggatttg 1740

agtcctggag agggtcagcg gggcgccggg gtgggggtgg gaaggagact gacagggaca 1800

caccgcgagc tccgcatact ctcctctgcc ccctgtagcc cggggcttta atgaccccaa 1860

gcagatttcc tgtctctggt ctagccagct gcccctaggg ctggatttta tttcttcatg 1920

gggtttcacc ctaaagggcc ccctggtcat gggacctggt tgggaacaaa tgaaagatgt 1980

cttgtagcaa atgctttcag gggagcagaa aagaagattg ggcacttcca gtcacttggt 2040

cactttaggt ggctggaaca aaactggtga ctttcacgac tgctacaggg tgagggggtg 2100

aagggtggca gagaggtgac aagccactgg gaatcctatt cagtggggat gccgacaggg 2160

agtggctgta atcaactgag caacatctgt gtgaatgtta ttcacaggtc aggacagcag 2220

cttggtcttc ccaggtgagg aactgaggac tggcctgcat agatttgtgc agtaggtgag 2280

tagcttccaa atttattttc agaacttcca tgtagtacct gcctctccat ttaaatattt 2340

tttaaaattt tatttattta aatattttct tggttagctt tccaagaggg aggaaaagag 2400

gggagttgca acaagtagtg cccctatgct gggattcatt ttccagagta aagcctggga 2460

ctggcaccct gacccctacc ggcaggtgaa aactccaggc aaactgctga gatcccacct 2520

gggctggctg agatagtgcc tggggtgcat ccctcagcag ctgccacctg ggccctgggg 2580

ccatctcttt ctctggcatc aagcagccag gtgtcaaggc cttcccagca atccatgctg 2640

catggctggg tcttgttcta gcaggtcgat gggcagggac tggtagctta gccagggcac 2700

cagtgcgtgg ctgtgggttt gtgtgcttct gtggagaagc atgatgtgta tgtgtgtgtg 2760

tgggcacagg catgaggaag ggttcatttg tgcaggtatc tcccatgtat atcagtgtgg 2820

gagagtgcct gaggatgtgt ttgtgtgtct gaaaatgggc ggagggtctg ttgtgctaat 2880

gtgtgcaggg gtgaacatgt gtgtgacagt ctgtgtgttt ccctgagtgg tggctgcgtg 2940

agagggtgag gggatttggt gttgtctacc atgcccggca catagcaggc tcttaataat 3000

cttgaattta attaatgtta aatgtgtatg ttcccatcct tgtggaagtt ggtatagagc 3060

ctgttttcct gtgattgtga gactggaaaa tgggggacgg gcaggggcga gacaggatac 3120

agaggctact gttttcttcc tccctagaag taagtacata gaagagtggg ctctggcacc 3180

tcacgggaca tcaccaagtc ctgtgtggct ggctaggctg tcccaaggtg gcttcaggca 3240

tcacttgaat cttttgagac cttcaggcag tagcctgcca ttcaccctgt cagtcagcag 3300

aagttgggcc cacacaggcc atagaaacac agagcagttc ccgggaggac ctgagctgtc 3360

cctgagagca gagcttccag gagaggccgc aggaactgcc ttgaccggaa ttcctcttgg 3420

ggtgcaaagg tggagggaca catggtgcga ccccaggcag aggactgcag ccactccgtg 3480

cagtcccagc ctctggggta gccccttgac ctccaggcct gcacagatcc aaggccgagg 3540

tccaggctcc agcgccaaat tagctggcct agcagcctgc agccgctcta atctcaacta 3600

ggaaggaatc cttgcgctta gaaagtccaa gcgaaagggt attctgattt tatcccggtt 3660

ttaccagaaa atgctgaaag gaaaagcccc gagaggacac agtgctctag gaactcgggg 3720

cgccacgagc gcctcatccc ctcccttccg cccggccgcg gtgccctggt cgctgaggga 3780

cgcggtcagt acctaccgcc actgcgaccc gagaagggaa agcctcaact tcttcctctc 3840

ggagtcctgc ccactacgga tctgcctgga ctggttcaga tgcgtcgttt aaaggggggg 3900

gctggcactc cagagaggag ggggcgctgc aggttaattg atagccacgg aagcacctag 3960

gcgccccatg cgcggagccg gagccgccag ctcagtctga cccctgtctt ttctctcctc 4020

ttccctctcc cacccctcac tccgggaaag cgagggccga ggtaggggca gatagatcac 4080

cagacaggcg gagaaggaca ggagtacaga tggagggacc aggacacaga atgcaaaaga 4140

ctggcaggtg agaagaaggg agaaacagag ggagagagaa agggagaaac agagcagagg 4200

cggccgccgg cccggccgcc ctgagtccga tttccctcct tccctgaccc ttcagtttca 4260

ctgcaaatcc acagaagcag gtttgcgagc tcgaatacct ttgctccact gccacacgca 4320

gcaccgggac tgggcgtctg gagcttaagt ctgggggtct gagcctggga ccggcaaatc 4380

cgcgcagcgc atcgcgccca gtctcggaga ctgcaaccac cgccaaggag tacgcgcggc 4440

aggaaacttc tgcggcccaa tttcttcccc agctttggca tctccgaagg cacgtacccg 4500

ccctcggcac aagctctctc gtcttccact tcgacctcga ggtggagaaa gaggctggca 4560

agggctgtgc gcgtcgctgg tgtggggagg gcagcaggct gcccctcccc gcttctgcag 4620

cgagttttcc cagccaggaa aagggaggga gctgtttcag gaatttcagt gccttcacct 4680

agcgactgac acaagtcgtg tgtataggaa ggcgtctggc tgtttcggga ctcaccagag 4740

agcatcgcca accagaacgg cccacccggg gtgtcgagtc ttggtaggga aatcagacac 4800

agctgcactc ccggcccgcg ggccttgtgg catataacca tttatatatt tatgatttct 4860

aattttatta taaaataaaa gcagaaatat ttcccgaaga acattcacat gagggcatta 4920

cggggagacg gcaagtcggc ggctcggggg gcgcgctcag ccgggagcgc tgtagtcaca 4980

gtcccgggag gaagagcgcg 5000

<210> SEQ ID NO: 81

<211> LENGTH: 1500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 81

tggaacaagt gtcagagagt aagcaaacga ctttctgagc tgtgactctg ctcctcgact 60

gcccacgtgc tctccgctgt ctgcactcct gcctcacctg ggctgactcg gactctccac 120

ctcctttgct gcttccggca tgagctaccc aggagcctaa ggcgctcctt cccgcaactc 180

cggtccccgc gccccgggac tgcaaatcct ttaaacagag gccccagagc taggggtttt 240

cccaggctct ggtgggcgtg ggctgacagt cgctgggagc cccgcaacag gggggatgtc 300

caggcaggta tgcacccagc tcccggcgtt tcccggagtc accacaatgt ttccctttct 360

ctctccccca cgtatgctgc taggggtact ccccagatag gattttcttt gtcttttctc 420

ctagtaacac cgaagccctc tcgtgcccgg ggactgcaga ggaacgccag accatccgga 480

ccttgcggga tggctcggtg tgtgtgtttt actgtgtgtc ggagtgtcgc gcatgtgtgc 540

gtgttggggc gcgttatcaa caggggccta gggcaccccc actctttctt gctctcttcc 600

cccatcactt catggacctc cgaggcgcaa agcgctcgac cctctcctgg gctcagtggc 660

ttgggtactc cgggctgagc tcagctgggg agtcccctta cccagcccgc accggcaccc 720

cgaagcttca aagttgcggc aaacagttgc ggggagcaga ggaactgagg tccaggccag 780

cgcgcccgcg gtcgctcgcc ttggggagca ggctgagccg agggtcgtgc gggtgcgcgg 840

cagaggcggt aggaggcgga ggagaggggg gagaaagagg gggcggtggg gaacagctgc 900

cggggtaggc gaggcgcaag gtggctcccc gcggccccgc gccccgcggc tctcggacgc 960

accaggcagc caatggctgc gcagaggtgt acagcagatg gcgtctgact gcgccgttcc 1020

ttcctcctcc tcctcctcct ccttctcttc ctcctcctcc ttctcttcct cctcctcctc 1080

cttcagtgct gaggagccag agtcgccgcc gggttgccag acgctggaat gggtggtctt 1140

ccgacacaca ccaccatctt tcttgcgctc gggaagctcg gggctcagcg gctcccagag 1200

gttacggcgg cggctctggc gagacgggtg agtgcaagca cgcggagccc cgagtcgggg 1260

atgccgggcc ccctggccgg ccgactgggg cgcggggtgg cagcgccggg gaagggggcg 1320

cgctgccggc gcagactttg ctctttcctc gccggacagc catcgtcgcc ccttctccca 1380

gccagacgcg ggaacttgga agcggatctt ctcggacgcc tctggcttgg ggctgcggga 1440

agcgtgggct gcccggggcg cagtgtgcgg agaccctcta ggcgggcggg gacgccccac 1500

<210> SEQ ID NO: 82

<211> LENGTH: 800

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 82

gttattatcc acggggtcct aattaaagct tgattaaaat gcccttcttt ctctaaaaaa 60

ttacgaacta ggcaacttca tacattttga atggcgcagt gtttcctctt ccaactgttt 120

agtttgtagt atactatgta agcaacatca attatcaacc cttgcaagat gacaacatga 180

gcctgtgggg gaagcacttg aggggaggga ggagaaactt ctctttttta ataatcagcc 240

ggaaacaatg tttaacaaga atctgatgag gtcactgcag taaatatttt tcctcttaca 300

gagccaatca tcacggaggg atcccctgaa tttaaagtcc tggaggatgc atggactgtg 360

gtctccctag acaatcaaag gtgtttgctt tctgctctgt tgcttttaaa ttgtatggga 420

aaggaagatt ggtccgacgg cgcgcttgtg gcccggccgg agcttgcgtg cgcgttctga 480

cggctgggtg ctgtgttaca ggtcggcgca gttcgagcac acggttctga tcacgtcgag 540

gggcgcgcag atcctgacca aactacccca tgaggcctga ggagccgccc gaaggtcgcg 600

gtgacctggt gcctttttaa ataaattgct gaaatttggc tggagaactt ttagaagaaa 660

cagggaaatg accggtggtg cggtaacctg cgtggctcct gatagcgttt ggaagaacgc 720

gggggagact gaagagcaac tgggaactcg gatctgaagc cctgctgggg tcgcgcggct 780

ttggaaaaac aaatcctggc 800

<210> SEQ ID NO: 83

<211> LENGTH: 40

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 83

tccctgctgt gggacccgag gagaggagaa ctggttcgct 40

<210> SEQ ID NO: 84

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 84

tctctctctc tctcttgctt ggtttctgta atgaggaagt tctccgcagc tcagtttcct 60

ttccctcact gagcgcctga aacaggaagt cagtcagtta agctggtggc agcagccgag 120

gccaccaaga ggcaacgggc ggcaggttgc agtggagggg cctccgctcc cctcggtggt 180

gtgtgggtcc tgggggtgcc tgccggcccg gccgaggagg cccacgccca ccatggtccc 240

ctgctggaac catggcaaca tcacccgctc caaggcggag gagctgcttt ccaggacagg 300

caaggacggg agcttcctcg tgcgtgccag cgagtccatc tcccgggcat acgcgctctg 360

cgtgctgtga gtacaacctg ctccctcccc gggcacagat atgacagagg ggcttagagg 420

gggcccagct ttgagatggg ttgttcttat gtcacaggac agagtgatct gacatgcaca 480

cttccccgcc accctgtcat 500

<210> SEQ ID NO: 85

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 85

tgtcctcgaa gaagggcctg agcagcagca gaggacccca ggcgaccgtg cctgagccgg 60

gcgccgacga cgactgagca cctgatatgt ccccggcact cgcagccccg cggccggagt 120

cgctgtgggt gagcggtcgt cgagcttcac agaggccggg ctctgtgcca gggccccgac 180

agggcaggaa gcagatagag tcccacaagc acaagcccag tgcgcagaaa gggttactta 240

aaaaataagt tctgtgataa aatcaaacag ggtgaagggc tggaaacagg tcatgagggc 300

gcaaacaggt cgtgagggcg caaacaggtc gtgagggcgc aaacaggtcg tgagggcgca 360

aacaggtcgt gagggcgcaa acaggtcgtg agggcgcaaa cagatcgtga gggcgcaaac 420

aggtcgtgag ggcgcaaaca ggtcgtgagg gtgcaaacag gtcgtgaggg cgcaaacagg 480

tcgtgagggt gcaaacaggt 500

<210> SEQ ID NO: 86

<211> LENGTH: 300

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 86

aaatgagacc tctggggaga ctgtcaaccc caggggtaaa acaaaaattc tgatcagaaa 60

ctgagtttcc caaagaaggg gctaaatgtt ttccaacact ttcggggctc agggaagatg 120

actctgtaag gacactgaga atcttcctcg cgtgccacgg ggaggaggac tgggggcgtt 180

tgaggggctc agcgcaccag aggagtgagg tggaggaggg cgttcccgcg tcctcctctt 240

caatccagag cagctcaacg acgtggctcc ctttctatgt atccctcaaa gccttcgcgt 300

<210> SEQ ID NO: 87

<211> LENGTH: 600

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 87

taggctctag tggacctagc agtgggagag ctacttgggc tggtttcttt cctgacgctg 60

cagggatggg catcggcctg gaaccagaag cgcaggagct gggccacggc agagtaatta 120

agaaaataat gaaattgatg gcggatgggg gcgctagaaa tcctggggcg tctacttaaa 180

accagagatt cgcggtcggc cccacggaat cccggctctg tgtgcgccca ggttccgggg 240

cttgggcgtt gccggttctc acactaggaa ggagcctgaa gtcagaaaag atggggcctc 300

gttactcact ttctagccca gcccctggcc ctgggtcccg cagagccgtc atcgcaggct 360

cctgcccagc ctctggggtc gggtgagcaa ggtgttctct tcggaagcgg gaagggctgc 420

gggtcgggga cgtcccttgg ctgccacccc tgattctgca tccttttcgc tcgaatccct 480

gcgctaggca tcctccccga tcccccaaaa gcccaagcac tgggtctggg ttgaggaagg 540

gaacgggtgc ccaggccgga cagaggctga aaggaggcct caaggttcct ctttgctaca 600

<210> SEQ ID NO: 88

<211> LENGTH: 800

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 88

gaggttgctg actcaggagc caggagctga gaaactccta ggctagcagc cgttgagcct 60

aattttattt tctggctttc tccgaaatgt ctcgtttccc tcatctttct ggtccttttc 120

gtctctctta ttttccccaa aacgtctacc tcacttcgtc ttcctttctc ctcccctccc 180

cctctctttc ctctatactc tcttcccatt tagccttgca ggcccctcct ccccggtgtt 240

ggagagctca aagacgcgcg aaactcaagg atctggccct gaccagggac gggattaggc 300

gggaagtggt gacggcctga aaaggctggg ctcgaacccg tgccttcctg aaaggactct 360

ccccgccaca agtcacaccc acccgcaggc ctgctggcca aagaaacaaa ggagtcgggc 420

gtggatccag gagaaacagg ttttcgctct cggatctccc tgggcaaatc agggatcctg 480

agcgctatac cccgcagtcg tacggagcct ctgggaaagg ggatttaagg gtgacttcca 540

ctttcagctt cggctacttg ttgcctgcgg tccaagcctt ctctgcttcc tcctacctcg 600

tcttaggcct ctgtagaaag tgcacgccgc gtttcccctt ccaggctctg agagggcctg 660

caggcccgtg gccgcctccg acaagatgcc ttccagtgct aggggggcca ctttggcggg 720

atgggggtcg gttggttaaa aaaaacttaa gttctggctc agtcgagtgt ggcaaaagcc 780

gagggtcggg ggttgggggg 800

<210> SEQ ID NO: 89

<211> LENGTH: 2000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 89

tactgacctg gtctccgcct caccggcctc ttgcggccgc tgcagaagcg cactttgctg 60

aacaccccga ggacgtgcct ctcgcacagg gagcgcccgt ctttgctggg gctggagcgg 120

cgcttggagg ccgacactcg gtcgctgttg gactccctcg cctgccgctt ctgccggatc 180

aaggagctgg ctatcgccgc agccatagct gctcagcgag ggcctcaggc cccagcctct 240

actgcgccct ccggcttgcg ctccgccggg gcgagggcag gacctgggcg gccagggaaa 300

gggcagtcgc ggggaggcag tgctaaaatt tgaggaggct gcagtatcga aaacccggcg 360

ctcacaaggt tagtcaaagt ctgggcagtg gcgacaaaat gtgtgaaaat ccagatgtaa 420

acttccccaa cctctggcgg ccggggggcg gggcggggcg gtcccaggcc ctcttgcgaa 480

gtagacgttt gcaccccaaa cttgcacccc aaggcgatcg gcgtccaagg ggcagtgggg 540

agtttagtca cactgcgttc ggggtaccaa gtggaagggg aagaacgatg cccaaaataa 600

caagacgtgc ctctgttgga gaggcgcaag cgttgtaagg tgtccaaagt atacctacac 660

atacatacat agaaaacccg tttacaaagc agagtctgga cccaggcggg tagcgcgccc 720

ccggtagaaa atactaaaaa gtgaataaaa cgttccttta gaaaacaagc caccaaccgc 780

acgagagaag gagaggaagg cagcaattta actccctgcg gcccgcggtt ctgaagatta 840

ggaggtccgt cccagcaggg tgaggtctac agaatgcatc gcgccggctg cggctttcca 900

ggggccggcc acccgagttc tggaattccg agaggcgcga agtgggagcg gttacccgga 960

gtctgggtag gggcgcgggg cgggggcagc tgtttccagc tgcggtgaga gcaactcccg 1020

gccagcagca ctgcaaagag agcgggaggc gagggagggg ggagggcgcg agggagggag 1080

ggagatcctc gagggccaag cacccctcgg ggagaaacca gcgagaggcg atctgcgggg 1140

tcccaagagt gggcgctctt tctctttccg cttgctttcc ggcacgagac gggcacagtt 1200

ggtgattatt tagggaatcc taaatctgga atgactcagt agtttaaata agccccctca 1260

aaaggcagcg atgccgaagg tgtcctctcc agctcggcgc ccacacgcct ttaactggag 1320

ctccccgcca tggtccaccc ggggccgccg caccgagctg gtctccgcac aggctcagag 1380

ggagcgaggg aagggaggga aggaaggggc gccctggcgg gctcgggatc aggtcatcgc 1440

cgcgctgctg cccgtgcccc ctaggctcgc gcgccccggc agtcagcagc tcacaggcag 1500

cagatcagat ggggattacc cgccggacgc aaggccgatc actcagtccc gcgccgccca 1560

tcccggccga ggaaggaagt gacccgcgcg ctgcgaatac ccgcgcgtcc gctcgggtgg 1620

ggcgggggct ggctgcaggc gatgttggct cgcggcggct gaggctcctg gccggagctg 1680

cccaccatgg tctggcgcca ggggcgcagg cggggcccct aggcctcctg gggctacctc 1740

gcgaggcagc cgagggcgca acccgggcgc ttggggccgg aggcggaatc aggggccggg 1800

gccaggaggc aggtgcaggc ggctgccaac tcgcccaact tgctgcgcgg gtggccgctc 1860

agagccgcgg gcttgcgggg cgccccccgc cgccgcgccg ccgcctcccc aggcccggga 1920

gggggcgctc agggtggagt cccattcatg ggctgaggct ctgggcgcgc ggagccgccg 1980

ccgcccctcc ggctggctca 2000

<210> SEQ ID NO: 90

<211> LENGTH: 800

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 90

gggggacaca gagaggaggg gttgcgggcc tgtgagaatg aagagcacag agcggagagg 60

gggaggagga gggaaaggaa ggcgtggcag tgagagagaa gaggaagaag agaggaggag 120

tggggagggg agggagagca agacagcagc gggtctggat tcccctccga gccacatctg 180

gtcaggttct aagtaattag aagattttcc cattggttta cccaagggct ctctctctga 240

ttaattttcg aaagagttgg ccaattttaa tcatagcaaa cacgatgatc acggtgatca 300

tggcctgaac agctaaaagc agaaaataaa acccccagaa cggactatga tcttgacctt 360

tgcccgtggt caccggctgg gcccacaccc agggttctga gctgttggga gccaaggctg 420

ggtggacagg ggcttccgag gagctgtccg cagcggggcg gggaggcggg ccccgggggc 480

ccgggcactc cgcgtcaccc cccggcaggg cccagagcgg caggccggcg tgcgccccag 540

ggcctgcgca ccgtgggggc tcttccccgc ccacgaggcc taggtgctgc cgcagccacc 600

ccaggaaggg ccccaggcca cagtcgcagc gccaggagtt gtgccccaac aggacctccg 660

tcagccgggg cagagcccca aacacgtcgc caggcagggt ctccagctgg ttgtggtcga 720

gctggacgct ctccaggctg ctgagattgc ggaagagggc acggggcagg gcgcgcagcc 780

tgttgcggcg cagggacacc 800

<210> SEQ ID NO: 91

<211> LENGTH: 550

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 91

gccccggtgc accgcgcgtc cagccggccc aactcgagct agaagcccca accactgccc 60

agtgcctgag ttgcagtctt gggtccttta gaaacctgga gatgtgcgta aaattcagat 120

gccggtattc ccgaacttcc ccaggcctca gcatatctcg gcggcctgtg gacagatggg 180

aggctaccaa tcgctccggc gtccgcagcc cgacccctgc cgccagaccc cggacgtctt 240

ccggataata aagttcccgc tctaattcat tttccctaat ctggacgccc ctaatctaca 300

gcttttattg cgcccagtta aaagtcgagg gaattcgctg tccctccgcg ctcggataat 360

tacccctaaa tggccacggc agccccttgt gtttcctgga gattagaacc ccgcagtcat 420

caatggcagg gccgagtgag ccgccaatca cctccgctca ctccctgaga gccgctggcc 480

tgggccgcag gaggagaggc cataaagcga caggcgcaga aaatggccaa gccccgaccc 540

cgcttcaggc 550

<210> SEQ ID NO: 92

<211> LENGTH: 2000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 92

agggtgcctc tgttcaaatt agaaaaaggc gccccctcag ggcagactca gcccagctgc 60

caggggacaa gtcctggcta acgggagctg gagctgggtt tcacctccag gtgcctcctt 120

ggcggggcgc cccgtgcagg ctacagccta cagctgtcag cgccggtccg gagccggagc 180

gcgggaatca ctcgctgcct cagcccaagc gggttcactg ggtgcctgcg gcagctgcgc 240

aggtggagag cgcccagcct gggaggcagt agtacgggta atagtaggag ggctgcagtg 300

gcagaagcga gggtggccgc agcacttcgc cgggcaggta ttgtctctgg tcgtcgcgca 360

ccagcacctt tacggccacc ttcttggcgg cgggcgccga ggccagcagg tcggctgcca 420

tctgccggcg ctttgtcttg tagcgacggt tctggaacca gattttcacc tgcgtctcgg 480

tgagcttcag cgacgcggcc aggtctgcgc gctcgggccc ggacaggtag cgctggtggt 540

taaagcggcg ctccagctcg aagacctgcg cgtgggagaa agcggcccgc gagcgcttct 600

tgcgtggctt gggcgccgcc ggctcctcct cctcctccgc gacgcctgcc ggcccgctgc 660

cgcccccgcc gccggccccg ctgcacagcg cggacacgtg tgcacctctg gggccaacac 720

cgtcgtcctc ggtccttggg ctgcggtcgc ctgcggaccc cggtgggaac agaaacaaga 780

gactgtcagc gccacagacg aggtgaggcc gggcctcaac tgcaggggtc acgggagtgg 840

ggcggaaata cactttgatc ccactcaagc ggagcggagg tctgggaggc cctgggcccg 900

ggagaccagt cttagactct tgccccactg ggtatcccat ctaggcctct tctggggagg 960

gcggcagact cagccgctgt gtcaacgctg tgttgtcgag accagctccc caccctctct 1020

gggccccagg ctcccctcag taacttgggg cactcgaccc gagcatccgc gaaagccctc 1080

ccggctctca gcgttgagca ttgggattct agactgcatt tccgtctctc tgcttgggtt 1140

cacgcgcctc tccacactta gttcacacgc acacacgcgc gcgtcctcgc agcacacact 1200

tgtctggtgc aggtaaggga aggtggaggc ggatcctggg gccaaaggta tttagaatct 1260

ttcaccctca gccgcctggg attgctgtga gagacatgga aacaggctga gccgaggcct 1320

tagatgagag gatggactgg agagtaaaga gggagggttg cccctgcatc gagtttttgg 1380

accctgatcc cacaccagct tctcggtctc gtacccgccc ttccgaagaa ctccagcaga 1440

aaggtccagc ggtcccctgt gcttgaggcc tacagaagct tgtacccaac tagggcaggc 1500

acccgggtct tccagaccac aggacaggac aggccacggc tgaggaggcc tctctcctgc 1560

ctccaggatg aactaaagac ccaatccggg atcttcggcc tagggctgct ctcccagacc 1620

tggggtctga gaaagccaaa ccagcccttt ccccaaagct ctagttctgc agattctcag 1680

ctctggccca ctcggaggtg ttcttcacca cctatccacc tactgtgggg cccggccctg 1740

ggaccttgaa ctggcaggtc tctggtccag agctaggtca ctggctacct gaggtctctg 1800

aacccctcac ttttccgctt ccctgatttt ggggatttgg ggacagacac ggcagaaagc 1860

actggcgacg aactcaaaaa ctcccgaacg caaggggcag cggttctccc aacccagtct 1920

aatgcacatt ggcccaggat gtctcaggcc tcaccccagg acgtagggct ctgaggagct 1980

actccggtct ctcgcgggct 2000

<210> SEQ ID NO: 93

<211> LENGTH: 1000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 93

gagaagggat gtggcggggg gctcctccgg ccctggactc cctgggtgga ctagaaaagg 60

gcaaagaagt ggtcacatct gtgggccaga ctggtgcgcg atctttggag gcgcagcagc 120

aaggccgcgc cagggctgag cccagaccgc ccacgaggag gcccgccagg cccggagcag 180

cggcgcgtgc gggggcgtgc cgagcgcagg ctctagggcc cctgcttcgc cccagctgga 240

ccccgcgggc ggtcggtgca gctcgagcgt gtgggctgcg atgccctgcc tgagacttcg 300

ggctagggat gcgggcggga agtgggggtg cggcggcagc tgcagattag attccttttt 360

tttttggccg gagggacgtg caaacttcta gtgcccgggc caagagggcg accccggagg 420

tgcgtaggtg gccctccggg ttcccgcttc tcctagtgcc tctgaaaata ccgtcagggt 480

aaagggagac aggcagtaag tcttaccacc accgcccttt ccccatgtca ttggccaaaa 540

actgaacatt aagataaagc agctgtttca gtcaatggaa agcggtaggg cgaggttgta 600

cccaaaaccc ggtttagacg gccaatgaag tcctaggaaa agccgccccg ggggcacgtt 660

caggtggagc ggctgcacct cgggtcgttc taagggatgg gctgcgtggt acccacggaa 720

ttcatgggtc caaaaggtcc tggtcacctg tccaaacatc catcccctgg cgcatggcgg 780

ttgacaagat ggcccggcca cccagaggaa ggaggatccg ggacggggaa cttcgcgccg 840

ggaagctgta gcccagagct gcagctcagc attcgcaaga gattcatctt ttttttctct 900

cgtgttcgga gaaacagata aacaagacac cgcctcatca gataagaacg tctccttcga 960

tgtcacggat ttcaagaggt agctggagaa actgacgtca 1000

<210> SEQ ID NO: 94

<211> LENGTH: 1300

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 94

caggtcaggc agaacttctg cccttcccgc tactggcacc ccaagcaggg atgcactggg 60

atgcgtggca ggggcgggat ctcctgggag cgtctcagcc cagcagggag tggggaagca 120

agagggaagg cttaccttcc tcggtggctg gcaggaggtg gtcgctgcta gcgaggggga 180

tgcaaaggtc gttgtcctgg gggaaacggt cgcactcaag catgtcgggc caggggaagc 240

cgaaggcgga catgaccggg gcgcagcggt ccttcacctg cacgcagagc gagtggcatg 300

gctggatggt ctcgtctagg tcatcgaggc agacgggggc gaagagcgag cacaggaact 360

tcttggtgtc cgggtggcac tgcttcatga ccagcgggat ccaagcgccg gcctgctcca 420

gcacctcctt catggtctcg tggcccagca ggttgggcag ccgcatgttc tggtattcga 480

tgccgtggca cagctgcagg ttggcaggga tgggcttgca attgctgcgc ttgtaggaga 540

agtcgggctg gccaaagagg aagagcccgc gcgccgagcc caggcagcag tgcgaggcga 600

ggaagagcag cagcagcgag ccagggccct gcagcatcgt gggcgcgcga ccccgagggg 660

gcagagggag cggagccggg gaagggcgag gcggccggag ttcgagcttg tcccgggccc 720

gctctcttcg ctgggtgcga ctcggggccc cgaaaagctg gcagccggcg gctggggcgc 780

ggagaagcgg gacaccggga ggacagcgcg ggcgaggcgc tgcaagcccg cgcgcagctc 840

cggggggctc cgacccgggg gagcagaatg agccgttgct ggggcacagc cagagttttc 900

ttggcctttt ttatgcaaat ctggagggtg gggggagcaa gggaggagcc aatgaagggt 960

aatccgagga gggctggtca ctactttctg ggtctggttt tgcgttgaga atgcccctca 1020

cgcgcttgct ggaagggaat tctggctgcg ccccctcccc tagatgccgc cgctcgcccg 1080

ccctaggatt tctttaaaca acaaacagag aagcctggcc gctgcgcccc cacagtgagc 1140

gagcagggcg cgggctgcgg gagtgggggg cacgcagggc accccgcgag cggcctcgcg 1200

accaggtact ggcgggaacg cgcctagccc cgcgtgccgc cggggcccgg gcttgttttg 1260

ccccagtccg aagtttctgc tgggttgcca ggcatgagtg 1300

<210> SEQ ID NO: 95

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 95

tgcgatcatt aaaatcagtt ccttccctcc tgtcctgagg gtaggggcgg gcagatttta 60

ttacttctct tttcctgata gcagaactga ggcggggttg tggaggagcg acggaggacc 120

acctctaact tcccttcact tcctggattt gaagcctcag ggccaccggc ctcagtcctg 180

ttacggtggc ggactcgcga ggttttccag cagctcattc cgggacggcg gtgtctagtc 240

cagtccaggg taactgggct ctctgagagt ccgacctcca tcggtctggg agcgagtggt 300

tcgagttcag atgctgggaa ccgtcgcttc tccccggccg ggctcgctgt tttctcctcc 360

gctcgccgtc atcaagcccg gctatgagca gggctttaaa tcctccctcc ctcacccgca 420

ggtttaccga gcagccccgg agctctcaga catgctgcgc tgcggcggcc agaggagggg 480

tgggggcatt gccctctgca 500

<210> SEQ ID NO: 96

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 96

gggcttgggc cgcaggcttc cctggacttc cgcagtcccc cttctcccca ttccagaacc 60

tgccgagccc ctgctgcatc tgggacccgc cttcaccgtt tcccaatccc agcggttagc 120

ccctgcgccc cctttttggt ctccactttg ccgttcgaaa atgcctaggt tggtggatcg 180

accctccgcg gagcaaagac ggatggctgg caggagcagg ttcaggagct gggccaaggt 240

attctctgct tccgcctttg tgtccgcccc cccgccccct gctccccgct tcccgccagc 300

atctctcctt ttctgctcag gagtgtttgg cccggcggtc caccccggct tcccgagata 360

cgctagagtt gcccccacgt cctgtccgcc gcgcccctac ccaccgggtt gccttcgggg 420

cccttcggtg ctgtgtagtc ggcgtggcgc tgtgagctag gcgaacagga acccccaggc 480

ccgccacgtc tacgctatta 500

<210> SEQ ID NO: 97

<211> LENGTH: 600

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 97

ttctggggcc tggatgggtg cgagcgggac ccgggggagt gggagtcgcc aggctctgag 60

caagcaaggg ctgcacctgc acctctgccg ggcatgaaga aaggtaagga aggaaggagc 120

tcacccgggt gggagacaga gccggggcgc gcgagcttgg tgtgggggcg ccactccggg 180

gcggagggga ggggctacca gtgacttctc cgagtcggga gctagaaaga ggcttccggc 240

caggttccct tggaacaggt gtcggagttg ttgggagagg gggctgcaag aaagaggggt 300

gcagaaactg gttcattaga tggaggctct gggcggaacc gcgaggacac cctggcagcg 360

cgctgtgcct gcgttaggcc gggaggggag aggcctccgg acggcgaagt gtccctaggg 420

acccagacgc ctcgggagcg atccgggccg ctgcgaagcc ctgcccacca ggagtggatc 480

cccaggattc acctcccggc tgcctgctct gagctgagaa ggggatctgg ttcttcacaa 540

taccgtggat ggcggggaag gggagggagc ctggggtaaa atcccatctt ggtttcctcg 600

<210> SEQ ID NO: 98

<211> LENGTH: 1300

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 98

tgtcacagaa accccagcag cgcagccacc ggactgggtt ctggaggccg agccgcagtc 60

cgtgcggcgg cgctgggaag agaaggcgcc ccggcagctc ccctgccacc ggccccgagg 120

agcggctggc tcccccagcc cagcgccgcc gccgcccggt aactccaggc gcaactgggc 180

gcaactgggg cagctgcgac accgaatccc tcacatctgc aacctgggtg ctgcggccac 240

tgagaaaatg gaggcgcaga ccaacgagcg gtgccgcgac cgagagacct cggctggcga 300

aatggtggtg ccgggagcct gcgagtgacg ccagccggcg gggttgtcaa ggacaacatt 360

cgttttgacg cagccaatgg cgccgtcacc aagaaaccat cgactctgag aaaaaagaga 420

ggttcggcca ccgagaaact ccgtacgaca agtgctgtgg cagaaaaacc gcctactccg 480

cgccacaggc aaaacagcca atggaaaccc caggtgctgc gaccgtgaca ccggcactag 540

agggtctcgg atggagaaag cggcgcacgg agaccaggaa actatgtgta gcacaactag 600

cagaaaaccg tctggtcggc catccgggag aaagcgcgga tcagaaacaa gcgacttcga 660

tgcagggaac cgcgcagcca ctgaagaaag tgacccacgt ggcagtggtg ccagcgaaac 720

actgcagttt ggacggcagc tgtggggatg ccacagagaa acatgcactg ccactgaagt 780

acatccagct ccgcggagct agtgttcata tgatcaagaa accgccagtt gggctctgct 840

agaaactttt agtcctccct taacggctat cctacccaca acagacaatg cctttaccca 900

gcacctagcg gtgctgagac ccgcctgggc cagcacagag cgcagagcag tacgggtacg 960

gagaaacgcc ggactcagtg aaaccagcct tgcctccagc ggattccccg gcttcgccgg 1020

acgccacagg cagagtgccg cggggaaacc tctggctccc taaaccgatt agattgtggg 1080

agtggggggg acactcacaa gttgtgtgga agggaaccag cggcaatggg acccggcgag 1140

cacttgcccg cagcaaatgc ctgcgctgct gcaaaaaaaa caacttttgg cgcaaagaat 1200

gttgcggcca gagagcatcc gctgtcgctg acaaaggagt agcaatggca atgagaaacc 1260

gccggcgcca cggccgaccg cggcggctca cgcctatgat 1300

<210> SEQ ID NO: 99

<211> LENGTH: 2100

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 99

caaacgctga gagacaaaaa gacaccaaca cccaccagga ctgcgtcctg ccagctcttc 60

actccgctga cctgaccttc cacgccccta gtcctcgagc ggacttgacc tgtgggggag 120

taccgaaccg tccccatgag gccctccaag cggccaggtg gcctccgcca ctctctccac 180

ccccacctcc tccacccccc agcccatcgg tccatcttcg atctgcaaaa cacgccgggt 240

cagcgacgca tcggtcccag gcttgtgacc acctctttct ctgttacttg gggagccagg 300

cccaccgctc aggatcacag tgaggagaaa aaagacacaa acgccaggac agggcggctg 360

gggaaggaaa ctgctaggga ccgctcattg tcagcctggc gtgtcccacg gatcgcagga 420

cccgtcgagg ctttgctctc tgcgacccga atactcctgg gcctctcgac ctcctcctcg 480

gactcaggcg tccgcgtctc cggtcatcac gggagaccaa ttggtttaca aatagtgatg 540

ataaacctgg gaccgacctt ggggctgtgt aaaagtctac tgacagatgt aatggagggt 600

tgttagcagt cacaaagcct gtcggacccg tagcattagt tcaagagact attttcgtgt 660

cgcaccaaaa ttactgcgcg tgtaaaccaa tttccccgac ggaagaataa acagagattc 720

gtttgaagcg cgagatgaaa acagatgggg tatcgcaaac agttccccaa aatacaacag 780

acttctgggc caattacacg tggttagctc tgaatggcag aggaaatagt tttctttgct 840

gctaaatgtc acaaaagtca cctaaaggca cagaggaggc cgctctgttt ttgcgaaact 900

tgctaaaatt aatctgcgct gggccacttg cagaaagcag aaccacctcc cgcccccacc 960

tcgcctccag ccgccggggt tcaggcgttt gtgaaagaca gaacctttgg gctagggacc 1020

cgggcactgg tgcttcgaag tccgaatccg ccggccgaga aaacgacaag agaaagaaaa 1080

tccagcgggc gctctctcca gcgccaggcc ggtgtaggag ggcgctgggg ctcggcctgc 1140

cacccctacc cgacattggg aagcagcccc tgcgctcccg cggcgcctca gcctccggtc 1200

cccgccccga ggtgcgcgtt cctcctcccg catgcccgtc tcgggcccca cggagcaaga 1260

agatagacga tgacgaggcg cgcccatcca tccgggccga cgaggtcagg cccgcgccac 1320

aggcaaaaat tgcgcaagcc cggccgcagg gatttcgcgg gcgcctgggt cccaggtgcg 1380

cggccgaaat cctcagggaa aatcccgagg ggccaacggt ctaggccaca gggctgctgg 1440

gcccgggcct ggctcagagc gcattcgggc ggggaggccg cacgccgcac ccgggcctct 1500

cctccgagcc cgaggcaggc actgagctcc gggccagcca ggtgcctccc ggctggtgcg 1560

agaccccggg cctgctggga ggcgtgggca gggcagggca gggctgaacc ccagcgactg 1620

aatctcgaag gcaggaggcc tcggaggtca tcggcccagc tcgcctgaaa ctgtccctgc 1680

tcgtgccagg gcgcgggcag aggagaaagg acagggcgga gcaagcccac tgcagaactg 1740

cggtcggtgg ctgcgaaggg tccgggtcac cgcgctcccg gacgccggaa gccgcgctgg 1800

cggggccgcg gggagggagg ctgggtaccg gggccgtccg gccggaggaa gcggctccgg 1860

ccgcgctgtc cgcgcttggg agccgcgtgc agggttcagc cgtgtttcag ttgccctctg 1920

acctgacccc gggcgcacaa aggcctcccg ggtgcgccgc catggcccag tcttccagtc 1980

gctgccaaat taatgagccc acgtcaggtt gggtttacag ctcggccggg aagcagccga 2040

gtggaaaatg agctcggggc cgctccagag gctcccgcac aactgcagag gctgcccgcg 2100

<210> SEQ ID NO: 100

<211> LENGTH: 250

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 100

tttccaagac agaaggaggg aactaggcgc cttttttcca ctccgctgac cccaacgtct 60

gggctgtgcg ttgtaacgca gttggcgggg ccttcagctt gggatgaggg cgaaggggct 120

cgggatgggt gggaaagcaa ggaccgggca acaggtgggg aggtggcgga cttttgtctc 180

ggggaaggaa atcggctgtg ctgaaagggc ggaaagcagt agcgcacaga actagtgtct 240

gcggggtccc 250

<210> SEQ ID NO: 101

<211> LENGTH: 250

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 101

ccctcctgtg gctgcttggg cagacgcctg tggcctgtcg gatgcggccc acatcgagag 60

cctgcaggag aagtcgcagt gcgcactgga ggagtacgtg aggagccagt accccaacca 120

gcccagccgt tttggcaaac tgctgctgcg actgccctcg ctgcgcaccg tgtcctcctc 180

cgtcatcgag cagctcttct tcgtccgttt ggtaggtaaa acccccatcg aaactctcat 240

ccgcgatatg 250

<210> SEQ ID NO: 102

<211> LENGTH: 2000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 102

tcctcctttg tgtatgtcaa cccagaggat ggacggatct ttgcccagcg tacctttgac 60

tatgaattgc tgcagatgct gcagattgtg gtgggggttc gagactccgg ctctccccca 120

ttgcatgcca acacatctct gcatgtgttt gtcctagacg agaatgataa tgccccagct 180

gtgctgcacc cacggccaga ctgggaacac tcagcccccc agcgtctccc tcgctctgct 240

cctcctggct ccttggtcac caaggtgaca gccgtggatg ctgatgcagg ccacaatgcg 300

tggctctcct actcactgtt gccacagtcc acagccccag gactgttcct cgtgtctaca 360

cacactggtg aggtgcgcac agcccgggcc ttactggagg atgactctga cacccagcag 420

gtggtggtcc tggtgaggga caatggtgac ccttcactct cctccacagc cacagtgctg 480

ctggttctgg aggatgagga ccctgaggaa atgcccaaat ccagtgactt cctcatacac 540

cctcctgagc gttcagacct taccctttac ctcattgtgg ctctagcgac cgtcagtctc 600

ttatccctag tcaccttcac ctttctgtca gcgaagtgcc ttcagggaaa cgcagacggg 660

gacgggggtg gagggcagtg ctgcaggcgc caggactcac cctccccgga cttctataag 720

cagtccagcc ccaacctgca ggtgagctcg gacggcacgc tcaagtacat ggaggtgacg 780

ctgcggccca cagactcgca gagccactgc tacaggacgt gcttttcacc ggcctcggac 840

ggcagtgact tcacttttct aagacccctc agcgttcagc agcccacagc tctggcgctg 900

gagcctgacg ccatccggtc ccgctctaat acgctgcggg agcggagcca ggtgaggggc 960

tcggcgccgc cccgggcgac ccctgggggc ggcactggag aagccgcccg tcctcataag 1020

ggattgaact tgcatccact cctctccggc cggcttggtc gctggctgcg ctccacccga 1080

ttctcgggat cattggaccg tttgcgcgaa accagagtgg ccgattaagg gatggggctc 1140

cgagcaccgg gggtggtggc gactgtgggc gaggggaggt gggaccgacc cccaccccta 1200

cactcaaaaa aggccggggc ctccttcgag cttccggtga atttcgggcg atttccgcgg 1260

gtgtcggggg tcccgggagg aggcagtcac agatccaccc ctgcagccag cctcctaggc 1320

gccggctccg gcacgcttcg ccggtctgta gatttcctct tcgatttctc cccagctccc 1380

agcatctgtg acttcactgt taccctccct atccccgcat cacccaaccg cacctgtctg 1440

cgggacttag gtgtgcgcgc ggggctcatg cgtgtcctcc ctgctggcca cccccacggc 1500

ccacacaagt tgcacgggct cgccacgccc cgccaacacg tgcgcggacg cacgcacgca 1560

ctcctcgcac gtgggcttac gcgaatacca gctttcactg ccactcgctc gcggccagat 1620

tcacaggcct gttccggtcc actcgcagct cccctctgcc gctccctccg ccgggctcag 1680

gagtactcgt agctgattgt gcgcgcctga gggtcccaga tcgcggccgc ccaggaccag 1740

gcgaggactc cggagcctcc tctcacctct cccacctgcg ccccgggctg ggccgggtcg 1800

cctggggggc ggcctgagcg aggcgcgggg ccaggagcgc tggagcgact gccgctctaa 1860

gtgccgggcg ggcaggactc tacgatcctt gggccagagg tccggatggt cccgggactc 1920

cgtctcaagg gtcggcgacc cctcaaccca gaagcctcga gcaggcggac aggcagagct 1980

gcccagtggc cgaggcgcgg 2000

<210> SEQ ID NO: 103

<211> LENGTH: 1100

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 103

atttgtcgtt gtgccattgc tgccactgtt gttcttgtcc agggaaacac cggtggccaa 60

cccagatcgg atacaatggt gcggctctgg actgagcctc caaccacatt agccatgggc 120

agcattgttg ctgccgctgc tgttatttta attatgattg tacgttaacc accaccttcc 180

ttcctctgcc tcccttcagc tgcaatgatg tatgttactt tttggtaact ggatttcatt 240

aacatttatg aactctcata aagtagtaga aaaagcaatt tgtgtggaag aattttccac 300

ctcattaaac agtgttcttt tgggggtcaa gctgatattt tttttgttgt tagatttttt 360

ttataggtcc tttgtccttc cctaagccct gggggatgaa aggagagccg tccacccagc 420

gaggggcttg tgtgccctag agggcgctgg gccccgcgcg ctttcctggc tgtccccgcc 480

ggctttccac cctccccaaa gcccaggtgc ccaccgtggg tcgctgcggc ctttcccctt 540

cttggccaaa tccgattact tcgcagcctg cagatggcat cgccggctaa gggcagcctg 600

cggcaggtcc ccgagcctga gcactcctcc tatctggggc ctgagaggac gctctgggct 660

ttttcccagg cccagggtgc gcggcctgct agcgcctttc gaggcacagt cccaagatag 720

gctcttgtcc ttcgacgccc ccttggcaca agcgcactgg cgccctccgc tcaacccacc 780

ttgcctttgg ggcgggcttc aaccctggga agacaggcct gggggaagcg agaggagagg 840

cccgaataga ggttccggct caatctttcc cagacggagg cctggtgttt ccagctcagt 900

tgcatcttcc agccgcgggc tcctggccca aacagaatgt gtttgctttc acaccgggac 960

ggcaagcgga gtccgcctca gtgagcagcg agctgcgcag tccggacggg tgtcgccccc 1020

agagactcgc cagccgcccc cagacactcg ccagccgtcc ccatctctaa tccaccgtcc 1080

aggcccgggc cctgggaaga 1100

<210> SEQ ID NO: 104

<211> LENGTH: 800

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 104

ccgtgtctcc cttaagaact ggggcctcat ctccactcca gctgcgcgtg cacgtgtgct 60

cccggcagga cgcgcgccca ggagcgcgct gggggctgcc ccgcccctct ctccctcccc 120

cgcgggtaaa ctccgggcat ccatcagtct gttaattgca ctaattagag atcgcagagg 180

tgttaattgg aaaaccctgg tattgtgcct gtttggggga agaaaacgtc aataaaaatt 240

aattgatgag ttggcagggc gggcggtgcg ggttcgcggc gaggcgcagg gtgtcatggc 300

aaatgttacg gctcagatta agcgattgtt aattaaaaag cgacggtaat taatactcgc 360

tacgccatat gggcccgtga aaaggcacaa aaggtttctc cgcatgtggg gttccccttc 420

tcttttctcc ttccacaaaa gcaccccagc ccgtgggtcc cccctttggc cccaaggtag 480

gtggaactcg tcacttccgg ccagggaggg gatggggcgg tctccggcga gttccaaggg 540

cgtccctcgt tgcgcactcg cccgcccagg ttctttgaag agccaggagc ctccggggaa 600

gtgggagccc ccagcggccc gcagactgcc tcagagcgga agaggcagcc gcggctttga 660

cccagcttcc ttccgacggc atctgcagga gcctctaggc ctgacatagg ctccgaggtg 720

ccctggctcc cccacgggga atgctgaggg ttgggccact aggtcctgcc taagtgcagg 780

acctgagcct cagacaaatc 800

<210> SEQ ID NO: 105

<211> LENGTH: 300

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 105

gggattgccg gctttgagaa aatatgaaga aaccgatttc tccttccact ttgccagtgc 60

actttccttc cactttcact ggtgctgggg gcggcgcact ctttacgaca tataagcgga 120

aaattctgca aaagtggccc ccggggatcc ccgcccgacc cctgtctgtc gctaatgtgg 180

gcctgtctcc ggaaattcga ggttgggcct ttgcctgaat ctgttgctat tgctcccctt 240

gctaccgctg acacttggca ccgccgcctc ctagcagcgg ccagacgcgg ggctgggggc 300

<210> SEQ ID NO: 106

<211> LENGTH: 400

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 106

gttgcgagcg cggcacaggt tgctggtagc ttctggactc tggaggcttg gccttccttc 60

taagccgatg gcggggaaag aacctcgttt ccacagcttc cccgaccccc gccgcttgcc 120

atttggggac gggaagcgcg cccgggtcgc ttcacgtccc tctgggccgg agccctttcc 180

atggctggct cctctggggg cccttgggcc tgtgagcagc gtctccttcc ctcagagaag 240

aatcctttcc ttcccccatc gaagtgtccc tttctgtatc ctgaaataac ccctcctggg 300

tgaggccagt tcccctctgt cgccctcctc ccgcaggcgt ccgggagcct cgtgaggacc 360

ccgtgcagtt gagtccaggc gacaggtgcc tccccaggtg 400

<210> SEQ ID NO: 107

<211> LENGTH: 800

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 107

cagtgcgccc cttaccggag cacccatggc ctcccgcgtt accccaaatt ttgtaggcag 60

actgtcagag ttcgaagcca gctgtgtcct ctgcgggccg tgtgacccta ggctatctgg 120

gctgctcgga gccttagttt ccctagttgt gaagagggag ggtgtgacca tggcccggag 180

ctctccgaaa ggctgtgcgg attgctcggt ggcgggatgt ggagcgcgtc ttctatgatg 240

ccaggtgctg gccaagcgct cgatgcaggc tgctccagtt aggtcgatgc gatggcggga 300

agcactttcc tctgcaatgg agagacgccg acaccccgag cccgaaggct tgcaaggcgc 360

gctctcgcca ctggggtcgg ggatccgtgg gttctctatc ccgcttaccc actccatcct 420

tagcagctgt cgtcggtccc agacctctac cttggagaga ccaaggcggc ccagagccca 480

ggagactact gcgcggtacg ccaggatcca gaagtggatt ctgacttcta aagacccctc 540

ccaagccaac gctatcaggg tccctgcaag cggttgactg tggcggaggc agaaccaaaa 600

cctttgctct gcccgcggcg ctccagcctc tcacccagga cagtgctctg ggctccagcc 660

gctgcagtgg ggtcgggaca cagacgccga gttagaagcc ccgccgctgc aggtccctgc 720

ttggtcggcg cggtgacggt gtcgctggcg gcggcggggg ccttcctttg gctgcccggc 780

catttaatca gagctattat 800

<210> SEQ ID NO: 108

<211> LENGTH: 1000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 108

tttagtattt aaggagaaaa gcctcatttt ccagaatcga ataagcgaat taatcgcaca 60

attgtgtaga atggaactca gtctgtaaaa aatcaagacc aacgtacttt ttaatattct 120

aacatctcca agtagtagtt acaagtattg tacccatgaa gtccaggtaa ttaatttgtt 180

caatgtcaca ctgttaaaag tcaggtgggc tccaaagcac agtcctaacc agcatgctct 240

actgcctcct ctgaggcaac agccgaagtg cagaccactg ggaataaata gctgcccggt 300

cttccccact cctaaattct cccgacagac cccaaagcct ctctgagagc ctctctgacc 360

gccctgcggc ccaccccgag ttcccggcat cctctgggat ccctcttcct ggagccaaaa 420

cctacgcagg ctcctttcct ccgagctggt tgctaggtga tctccgaagg ctgtccgaag 480

tctcgcgagg gcggacccgt tgcctgatga cgagagttgg gagtgtggct ggggctgcgg 540

atctccagca gtggcgttac ttctagcggc tggataccgg gttctccgcg agatcgcgag 600

atcccgagat attctccccg cacggaagcg acgactggcc tggccagagg actcgcgtgg 660

gagcgaggtg ccggccccga caggacggtg aggtatgcag aagtaaggcg gggcgccccc 720

tgcgggaagc gagcgcgccc cggaaaatga gcgcctcccc acaccaaggt gtccaggagt 780

gagtgcggga aggaactcgg ccgcccggag ttgtggcctc atcgtgcttc ccgccaaaaa 840

cgccttggta ctgtcgggac gcggctaagc gtggacgcgc ccgcatctgc ccctcctccg 900

cagtggtgga agacacccgc ggagcgccgg tggataaggg ccgtttcctg agaccagagc 960

tgtatccgca gcaggtcagc acttcgtgcg ccctgtgtgc 1000

<210> SEQ ID NO: 109

<211> LENGTH: 300

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 109

agcggcgctg ttcccgggct gggtgcagct gctaaggaca aggcccctgc tccgaagaac 60

gcggtggctc ggggataccc tgaaagggac ggccatggcg cacatgggat gccctagggt 120

tcgtgggagg gcatgcaggc gcagcccccg caggggttgg cctgccagag aaggcagggg 180

agagcactcg gggctgcaca aatggtgtgg ccggagggaa ggtgcagcct tgtgtgtgtc 240

tggatgaggg ctgggcatag gagcttggta tttgatcctg aaagctctgc gtttccaaag 300

<210> SEQ ID NO: 110

<211> LENGTH: 600

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 110

gagtcatact tgtagtcaca tccttttcct ttctccaacc cactggttaa tcatgaaagg 60

ctcttctgat tggctgcctc ctggcagtag tgcctcagcg cgacggttcg ggagcaaata 120

aataattccc gctgggaagc tgtttctcag acaggagcag cgacacccct gccacgcctg 180

ccgcctggag ttgagtgggg taagcacgcc ggcctccagg aatcgacggt gccacgtggt 240

tcttcttgca cttctcttct tctccagttt caggggacac cgtggggtgt gcgagcccgg 300

gggagcgcag ggaagggcgg gttgggctgc aggtgggaat gtgcggtcct tctgcgccct 360

caacagagct tccttccttt ttgccaaggt ccccgtgccg ccttcagcgc gcctccttat 420

gcacctctac ctctgctgca gcgtacctct tccgcagccc tagcggcctc cccgaggggc 480

gccgcggcct cggctgtccc tcccctgcct ggcacgacca cctgaccccc agcgacccaa 540

gaagcaagtt gtgtttgcag acgcaaaggg gctgtcgttg gtatcggtgc actggtttga 600

<210> SEQ ID NO: 111

<211> LENGTH: 1700

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 111

acactttctg tgtgggaggg cacaagacat gggctatgac atggccagag accccacctt 60

ctttacacat gtaaaaacca accaaatcaa gatgcgtcaa cggtgattct tcctcccaca 120

ttgtttccct ttttaaactg ttattttttc aatccatgga gcagttgaga aacgggtatg 180

catctctcct cccctcccct tctatcaaag cctgtaagac acataaggaa atccaaagcc 240

acagtaatag agagagagag agagagagag agagagagag agagagagag agagaaaaca 300

gaacaaaaga aatcctcctt ggcttgtttt tccagggtgg ccaggcaagg tgtgaaaatc 360

catatttccc tctgggctgg caggtagaag ttactgggaa ggctgcgctc ccttctctcc 420

caccggctct cacatccagg ctgttccctc accctcagcc tcccccagcg ccagcttcct 480

cctccgcctc tctgcagcca ggcctcccct gcaaggcgga ccttggccca ccttggttcc 540

gggccaaggc ggcgggaaag gcaccgctac ctgcagccgc acgactccac caccatgtcc 600

tcgtactgct tgtagaccac attattgccc gcgtcgatgt atagaatgct gatgggagtc 660

aatttggtgg gcacgcagca gctgggcggg gtggagccgg ggtccatgga gttcatcagc 720

gtctggatga tggcgtggtt ggtgggctcc aggtgcgagc gcagcgggaa gtcgcataca 780

ccctcgcagt gataggcctc gtactccagg ggcgcgataa tccagtcgtc ccagcccagc 840

tccttgaagt tcacgtgcag gggcttcttg ctgcagcgta gcctggactt cttgccgtgc 900

cgcttgccat ggcgactggc gaaggccgtg cgccgccgcc ggcggccggg cgagggcagc 960

caaggcctgg catccggggc gcccgacggc ggcggccacg acccctcggc gcccgcgccc 1020

gggcccgcag cctcggccga gcccagctgc tcgcgcatct ctgcgaacag gttcttgcgc 1080

tgggatctgg tgaataccac cagcagggcc cgctcctggg gaggccgcac cctccggccg 1140

aagcccagac tccgcaggtc cgggggcggc ggttgctggg gtccccgcgc gcgcgcctcg 1200

gcctccccgg cgtccagctc gccccatgcg gcccgcagct ccaagcacag ctgcttccag 1260

ggctggtggc gcaggccctg ccacacgtcg aagacttccc agccggccgg cggcgccccc 1320

tgcgggtcca gggtccgcgc gtccagcagt aggggcgaaa ggcaagggaa gagctgcacg 1380

tggagcggcc cggctggtgg cccccagggc gctgagggcg cctggcgaaa gagccgcagc 1440

tccgcgccca ccagctcttc tttgtctgag agcatggaca catcaaacaa atacttctgt 1500

ctccggagag gagtgtgcga gagatcgtct gcgagataaa aaataattac agtcagtttc 1560

acttaagggg gagatcagcc cggtgctctt cggccgcccc gggaggaaaa gggcggggag 1620

tgggggcagg tcggccgggc agtccagctt gcccggccca gggcctgacc accccggctc 1680

cccatctggc tggtgcatgg 1700

<210> SEQ ID NO: 112

<211> LENGTH: 2000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 112

gcccgctgtg aatgtaggtg aggtgatccc gggaacctgg gtctgaaatc agacctgtgt 60

tgccattggg agcacggaga gaggggaagc gccctgctta ggcccaggcc gggcgtcctg 120

gtggtgggac cgcagccgca ctcacctcca ggccaacgga caaggttcct gcaagccagc 180

agggccactc tgtgcttggc ctactgcagc tcccctgcag ctcctttcct ctccctcccc 240

ggagcgctct cctctctcct ctcccctctc ttctctctcc tctctcgtct cctggggcat 300

cccgggtgga gggatgtagg ggtcgctcct cggtgccagg ccgggaagca gctcaggcct 360

cccaagagct tggcgctcag tctgggaaaa ggggttcctc tggcctcagg gacgttctcc 420

gcccccaccc caccccctgg gagcctgaac catctggaag ggatcttagt cgggggttgg 480

gaggagagcc cgtggatagg aggagggggc gattctaggc cgaatccagc ccctgaggtg 540

tcacttttct ttcctgcggc ccgtcaccgc tgatagatgg ggctgagggc agaggaagga 600

aaaagaaaac ctccgaggtc agtgcggggc gaggtgagcc cctcccaggg ccctctggcc 660

caggaggatg aagcgcgccg gcttcgctct tgcacgccgg cttgccatcc gggtaagcgc 720

gggaaaggcg gccacagggc gcggcggcag cgcagcgcgt gggatctcac gacccatccg 780

ttaacccacc gttcccagga gctccgaggc gcagcggcga cagaggttcg ccccggcctg 840

ctagcattgg cattgcggtt gactgagctt cgcctaacag gcttggggag ggtgggctgg 900

gctgggctgg gctgggctgg gtgctgcccg gctgtccgcc tttcgttttc ctgggaccga 960

ggagtcttcc gctccgtatc tgcctagagt ctgaatccga ctttctttcc tttgggcacg 1020

cgctcgccag tggagcactt cttgttctgg ccccgggctg atctgcacgc ggacttgagc 1080

aggtgccaag gtgccacgca gtcccctcac ggctttcggg gggtcttgga gtcgggtggg 1140

gagggagact taggtgtggt aacctgcgca ggtgccaaag ggcagaagga gcagccttgg 1200

attatagtca cggtctctcc ctctcttccc tgccattttt agggctttct ctacgtgctg 1260

ttgtctcact gggtttttgt cggagcccca cgccctccgg cctctgattc ctggaagaaa 1320

gggttggtcc cctcagcacc cccagcatcc cggaaaatgg ggagcaaggc tctgccagcg 1380

cccatcccgc tccacccgtc gctgcagctc accaattact ccttcctgca ggccgtgaac 1440

accttcccgg ccacggtgga ccacctgcag ggcctgtacg gtctcagcgc ggtacagacc 1500

atgcacatga accactggac gctggggtat cccaatgtgc acgagatcac ccgctccacc 1560

atcacggaga tggcggcggc gcagggcctc gtggacgcgc gcttcccctt cccggccctg 1620

ccttttacca cccacctatt ccaccccaag cagggggcca ttgcccacgt cctcccagcc 1680

ctgcacaagg accggccccg ttttgacttt gccaatttgg cggtggctgc cacgcaagag 1740

gatccgccta agatgggaga cctgagcaag ctgagcccag gactgggtag ccccatctcg 1800

ggcctcagta aattgactcc ggacagaaag ccctctcgag gaaggttgcc ctccaaaacg 1860

aaaaaagagt ttatctgcaa gttttgcggc agacacttta ccaaatccta caatttgctc 1920

atccatgaga ggacccacac ggacgagagg ccgtacacgt gtgacatctg ccacaaggcc 1980

ttccggaggc aagatcacct 2000

<210> SEQ ID NO: 113

<211> LENGTH: 2000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 113

cactcccccg ccgcctccgc ccctaaccct cggccccgtg cgcgagcgag cgagggagcg 60

aacgcagcgc aacaaaacaa actagtgccg gcttcctgtt gtgcaactcg ctcctgagtg 120

agtcgggggc cgaaagggtg ctgcggctgg gaagcccggg cgccggggac ctgcgcgcgc 180

tgcccggcct ggccggagcc tgtagcccgg gggcgccacg gccgggctcg cagtcccccc 240

acgccggccc cccggtcccc gccgagccag tgtcctcacc ctgtggtttc ctttcgcttc 300

tcgcctccca aacacctcca gcaagtcgga gggcgcgaac gcggagccag aaacccttcc 360

ccaaagtttc tcccgccagg tacctaattg aatcatccat aggatgacaa atcagccagg 420

gccaagattt ccagacactt gagtgacttc ccggtccccg aggtgacttg tcagctccag 480

tgagtaactt ggaactgtcg ctcggggcaa ggtgtgtgtc taggagagag ccggcggctc 540

actcacgctt tccagagagc gacccgggcc gacttcaaaa tacacacagg gtcatttata 600

gggactggag ccgcgcgcag gacaacgtct ccgagactga gacattttcc aaacagtgct 660

gacattttgt cgggccccat aaaaaatgta aacgcgaggt gacgaacccg gcggggaggg 720

ttcgtgtctg gctgtgtctg cgtcctggcg gcgtgggagg ttatagttcc agacctggcg 780

gctgcggatc gccgggccgg tacccgcgag gagtgtaggt accctcagcc cgaccacctc 840

ccgcaatcat ggggacaccg gcttggatga gacacaggcg tggaaaacag ccttcgtgaa 900

actccacaaa cacgtggaac ttgaaaagac aactacagcc ccgcgtgtgc gcgagagacc 960

tcacgtcacc ccatcagttc ccacttcgcc aaagtttccc ttcagtgggg actccagagt 1020

ggtgcgcccc atgcccgtgc gtcctgtaac gtgccctgat tgtgtacccc tctgcccgct 1080

ctacttgaaa tgaaaacaca aaaactgttc cgaattagcg caactttaaa gccccgttat 1140

ctgtcttcta cactgggcgc tcttaggcca ctgacagaaa catggtttga accctaattg 1200

ttgctatcag tctcagtcag cgcaggtctc tcagtgacct gtgacgccgg gagttgaggt 1260

gcgcgtatcc ttaaacccgc gcgaacgcca ccggctcagc gtagaaaact atttgtaatc 1320

cctagtttgc gtctctgagc tttaactccc ccacactctc aagcgcccgg tttctcctcg 1380

tctctcgcct gcgagcaaag ttcctatggc atccacttac caggtaaccg ggatttccac 1440

aacaaagccc ggcgtgcggg tcccttcccc cggccggcca gcgcgagtga cagcgggcgg 1500

ccggcgctgg cgaggagtaa cttggggctc cagcccttca gagcgctccg cgggctgtgc 1560

ctccttcgga aatgaaaacc cccatccaaa cggggggacg gagcgcggaa acccggccca 1620

agtgccgtgt gtgcgcgcgc gtctgcgagg gcagcggcgg cagggggagg aggaggcaga 1680

ggcggggtgg ctggaccctc ggcatcagct cattctcccc tgctacacac atacacacac 1740

aaataatgtt tctaaaaagt tcagttgcga ctttgtgcct cgcctgtcct gttcatcctc 1800

gtcctgggcc ggggaatgct tctgggggcc gaccccggga tgctggctaa ttgctgccgg 1860

cgggttccgt cgccggtgtg accctggacg gcgcggacgg cgtacagggg gtcccgggag 1920

gggcagtggc cgcggcactc gccgccggtg cccgtgcgcg ccgcgctctg ggctgcccgg 1980

gcggcgcagt gtggacgcgg 2000

<210> SEQ ID NO: 114

<211> LENGTH: 800

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 114

ctgaaaagcc gtcagggaaa ccacacatgt tcaacccctg gcggctcccc caaacctctc 60

atttccagta actgtgtgtt tccgctcgtc aacagctgaa accgagcgga acttgggggg 120

ccccaccacg cggccctgct gtgcggcacg gggctcatct gtcccccggc tgcggggagt 180

cagctctcac cgcccacctc cttcccagat agtctctgtg cccactcgac ggcccggcaa 240

gcccagcccc tgcctgccac ggccacagca gcctcagaga gctgccctct ctggccaggg 300

tcagggcctg agctgctgcc tcccgcaggg tcgagggcag gacacttgtc tgaggcttgg 360

gtggggcaat ggcacctcct cagggcctca gcccccgggc aggctcggtg accatgggcc 420

tacagcaggg aaaattctgg gccaaaagct ccagcctcct actagggcat ctgtctgcaa 480

atgcacctta acctgaccgc ttgggctgtg ggggagcctg tttcagggaa agtgagggac 540

gcgccagttt cctcctttgg acttgatgag gcacgaacgc atctctaata aagccaggtc 600

tccccgccgt ggctccctgg gcgggtgcct gtggctcggg ccatgagtca cgctgggtaa 660

ccccactacg gggaagaggg caggaagctg ggagccaccg cctctgtgcc cggttgtcat 720

ctcggcacga gggcgaccgt cggcttcgtc ctgccctcat ggctgagggc ttttgggatg 780

tggcgggaga cgggggagtc 800

<210> SEQ ID NO: 115

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 115

aaatcatcag aatggctaaa atgaaaaaga cagacaacag caagtgctga caagggtgtg 60

gggcggccaa atgctcctgc actgctggca ggggacctga gaactgcagg gcattccctg 120

gcttcctgcc cctcctggga ctggggaccc cccagggaca gcctaaggga actgcattta 180

tcttcacgtc tgccaaaaga taacacgaag atgttcaaag ctaagccccc aggctggtaa 240

gagctccaag gcaccagcag tgtgtgcaga actgggggga gtctgttctc ccagggatgc 300

tcccatcacc tgctgccagc agtggggcat gccggtcccc tggggtgtgg ccaaggggct 360

gtgtctcctg cccgggctgc cggcccctct caggttcact ttcccatctc taagcccacg 420

tctcgctgca gttcaagttt gccaggccac caacgggtga cacgcccggc gcagtggggg 480

actccgcact ttctgcgcac 500

<210> SEQ ID NO: 116

<211> LENGTH: 1200

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 116

accctttgtg cctgggtccc ataaacaatg tgctttttaa aggggagccc cctcccagct 60

ccggcctttt tctccagcgt gggcagccaa tcagctgcgc agagctgcat agctggaccg 120

ctttccattc tgagtagcaa caacgtacta atttgatgca cacatggatg cctcgcgcac 180

tctgcaaatt catcacccgc atcttgcatt agtcatctga cggactgcca agtgtttcat 240

tttctttcca tgtgacttta ttattaccac ctctctcctc tcttccaaaa acctcccaaa 300

aagggcggtg gggcgggggg cggggcaggg agagggagag aaatccagca gacatctagc 360

tctgcctttc tttcccagcc acagccaggg tagggctgat aaggcgctga tgcgttgatg 420

gcagccttgc agagctagac ctgcacttaa cttgcagctg cctcccgagc ctccaagatg 480

tccacgccct gggtgacagg cggcagggcg ctgccccgtg ctcccccggc tctgctcgac 540

agcagcacgc agtgagagcc tcgccgccgc cgaggagcaa ctcatggtgc ctccgctttg 600

ttttagttca tcaaatttct acgactcatt aggcactttg ccactgctct tcttcctcct 660

ccttccgcct ccccgctccc ccacccccac tattttttct tcctgtccct catcgtgccg 720

ccctaactct ggctcccggt tccgtttttg acagtaacgg cacagccaac aagatgaacg 780

gagctttgga tcactcagac caaccagacc cagatgccat taagatgttt gtcggacaga 840

tcccccggtc atggtcggaa aaggagctga aagaactttt tgagccttac ggagccgtct 900

accagatcaa cgtcctccgg gaccggagtc agaaccctcc gcagagtaaa ggtacagagc 960

gcggggcggg ggtcgccagg cgtccaggtg ggcgtcgcgg ggcactgggg ctgtccgagc 1020

ccccagcctg caggaggaag ggcgggtagg caggagggct ggaagcagcc ggtgctggcg 1080

gcccctgtgc tccaggggct gctcccgact cctccccgca cccccgcccg cctgcccgcc 1140

gggacaggtt ggaggcggga gagagggacc gaggcagggc gggagcgcag aggctcggtc 1200

<210> SEQ ID NO: 117

<211> LENGTH: 800

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 117

taacaaataa gccgcccgtg gtccgcgctg tgggtgaccc ttggcgcctt cgaggtctgg 60

agccctaggg taaataagga aacggggcgc ctctagagtt ttaaatgaac tctgttattg 120

gaagcttcag tagggaccct gaaaacaatt aacgtcttaa ttagcatttt aatgtctcca 180

ttattacggc gcgggctcta gctcagccct ttaccttacc ttctcaccgt taacagggga 240

gggggattgt atttttagtt catcttttta tgtttttgag ttgttatcct gtctgtctga 300

ttccagcctc gagggtttga tgatgcggcc cgagcctggc tgtggtcgcc tgtcggggct 360

ggagcgggac cctcagccgg gccgggcctg ggggctaacg ttttcacagt gcgccctgag 420

tttccttggg ttactgctgg gaccgcgcag gaggaagcaa agagtttttc gagctagacc 480

aacaggaaac acattgacgg aaatgttgcc atagcccatg gggtggcttt aactggccgc 540

ccccgcgggc tgggtgtgaa atcagaggag gccgcggctc ccccggccag gattggaggc 600

tcctcgcgca acctaatgcg ggtgtccggg cccgagcgct tcccgcgcag ccaggccttg 660

tcggtgcagc agccccgctc ctccccaaca cgcacacacc cggtgttcgc aagtgcggct 720

caccaaggga gatccaaggg ggcaaaaagt tatgtataaa tccgagagcc actggggaaa 780

gagggtcgtg gtattgtaag 800

<210> SEQ ID NO: 118

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 118

ctaccctgtg ctatcctgag ctgtagtctt ctgaaatgat cgtttggctt cccagccaag 60

gcagggctcc cccaaagttc attcccactc ttgcagtttc acctcgggat gcttccgcag 120

aatttcagcg cctaagcaga caaggtcaaa gtaaaccgct tcaccgctgc ttctggcgca 180

ggggcccaga gcgcgtgcag ctccccagca cagaccaaca gcaggagagg ggtccgggcg 240

ggagccctgg gctgtagata agcaaaacgc acccattttc tctcctattt actccagagg 300

cacctctcct cccccactcc tggcatctct ttatcactgg ctccctctcc ctgtggcata 360

tttttgggta gtagaatgct gaggtcacag ggagcggctc tttatccaag cagtggggac 420

atcagcctgg agccctgagc atgaaccagc aagatgcaga ctctcgctct tgactttggg 480

ctccaggagc tgccccgacc 500

<210> SEQ ID NO: 119

<211> LENGTH: 1100

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 119

cagtgctccg ctccgggaaa ttgcatcgtc acgacaaacg ggaccgtgat aaaacgaccc 60

tttccgtcct tatttgtaga tcactcagac gagattgaac tgcacttgtt tccccttcga 120

ggggagccgc gttttcaggg tagccgaagg cttggggctg agggggggcc ctcaccaagg 180

cgcgggtggg ggccggagcc tcaactcgat gagaagtgac aggcgtttgg gggatctggg 240

ctccggccgg gaccagcgca agcagggact ttgcggggac accgcttctc caacagagca 300

aggcctggcc cacgtttccg gtttctccta acttcctttt attgccttcc tttgcttcgc 360

aagttccatc tacccctcca gctacagagc cccacctcta ggcacaggaa gcttcccgga 420

aaaagaaagg ctgtcccaga aagagaccga gagagacttt ccaaacttcg ggcatagcca 480

cggcaattcc cagtctgcta atgccaaggc gggcgcgtaa ggccgcctaa atctagacct 540

ccctcctcac tcatttcaaa aaataacaac gtgccagcca cctccgcaga taccgccggc 600

tggtgcttgc ccaggagacg ccagggccag agcgccactc ccagcatcga aatggcagag 660

agaaagcgca gctccaaatt ccccttcaga ggttaagcct caatcattgt gtcccttccc 720

tagggactgc tggcgctctc gcccactggc gatgattatg cgcctagaac tcgaccgcga 780

agcaactaat aggaaaacat atggtgtcaa tttggatgct ccgcgcctcg cgcacacccg 840

ggaacgagcg gcacaaagcc ctgccggccg gcccgcgacc ccgcgcccct cggggcctgc 900

cagccgggcc gcagcgacaa acgctcaggg ctgcgcgccc tggctggggc ccgcccgaga 960

gacagcctgc ggctggggag tctgagctcc aaggggagag cccagccgcc gaaggcgagc 1020

ctaccggcca agccctgggg tccggcaggt tctgcacaac tactcccgca aagctcgcca 1080

cctttgtgcc ctttcctcag 1100

<210> SEQ ID NO: 120

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 120

gggccctcgc ggctcaagcg ccagcgctgg agagagagtc tgagggtacc acgggcgtgc 60

tggcctgggt gctcactccc gccctccttc atgagcggct ttcctctggg tgtgtccagg 120

gcatcacaga gctcttctgc ccaaacccgg aggcctacca gggcctgccc accttgcctc 180

cttccacact ctctgtagca gcagccgcag ccatggcggg gatgaagaca gcctccgggg 240

actacatcga ctcgtcatgg gagctgcggg tgtttgtggg agaggaggac ccagaggccg 300

agtcggtcac cctgcgggtc actggggagt cgcacatcgg cggggtgctc ctgaagattg 360

tggagcagat cagtgagtgt ccgctgcccg cttgctgaac tcggcaccat gggcggccgc 420

cacgggtgtc tctgggcact tccgggccat ccctgctgct cagctcccga taatggtgtc 480

acggtgactc aggcattagc 500

<210> SEQ ID NO: 121

<211> LENGTH: 600

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 121

tgtttacgga atcgggatcg aggggccgat aagtagttta cacgccggcc agagcagagg 60

gctggaggtc ggagttgggg gctggaggaa cgggtggcgt ttttaggatt cagtaacagg 120

atcacagctt tttcttgtgg tggaagctat tggaatttgg ggagggtagc acgaggggtc 180

ctgcagctcc gcgtgtgaaa aagcgtttag gtaggcgatg aaagtagttg atctgagcca 240

tggcaggcga gccccgaatt tttgctgctt ccccctgaaa gtgtttcttt aggaggagag 300

gacttgggcc acacaggacc cggtcctaag agagcgattc cgggaagcgg acagatcgaa 360

gagaccttct gggcgaagcg gcagggcagc ctcgcggggc tgggagtgga tctgaggtcc 420

cgacccaggc ggctcggagt gctccaggag ccacctgggt ctgcgggcgc agcgcggcgg 480

ggcgggagcg gtggcccgca ggggccgcgg cctgcgatga aggccggggg gcagcgctag 540

cagcgaggtg ccacagtggg ccgaggagtc tgggctgtgg cccagggtag gaccggctca 600

<210> SEQ ID NO: 122

<211> LENGTH: 150

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 122

acctaaacca agctctccct ccctgccgtc tccttccctg gcctgggtct gaaggagagg 60

aggtgcccag aagttcagag cggcataacc acagagatac tacctaatta acataccaga 120

agcataaaga actcatttgc attggagagt 150

<210> SEQ ID NO: 123

<211> LENGTH: 900

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 123

ataactacgg gggtgggggt ggggaaggaa gagatccaag gaggcagaag gctgcggtca 60

aaatattttg gggtggcaga gtcacgtagg atgtggctgt gggttctggc agcccagaga 120

ttcagctccc gcctcctccc tcagagcgag tccatagcta ccctcacgtc ccccgtggcg 180

gtcctcgcca cgctccggag cgggttaccc atgagggtgc tagacctggg cagcgggaac 240

ctcgaagagg tggagattgc aggctgggac tccagatttc gggcagggat gcggggaagg 300

gaagacgcct cgctggaggc ggaatggagg gcaaggcgaa ggaggatggt gcaggaaacg 360

gcgacaaggc gcccggccag gcccgcgagc taccgagacc cgggttccaa tcctcccccc 420

ttccgcaaac gcccgggttc gaggtacctg gcgggcaagg gccgcagcgg agcgaagcgg 480

gctggccatg gggaggctgc ggggacgcgg ggctgcagag agcggcagtg gcacggagcg 540

cgcggctgga agcgaaagca ggcggtgtgg ccaagccccg gcgcacggcc catagggcgc 600

tgggtaccac gacctggggc cgcgcgccag ggccaggcgc agggtacgac gcaacccctc 660

cagcatccct tggggaggag cctccaaccg tctcgtccca gtctgtctgc agtcgctaaa 720

accgaagcgg ttgtccctgt caccggggtc gcttgcggag gcccgagaat gcgcgccacg 780

aacgagcgcc tttccaagcg cagatatttc gcgagcatcc ttgtttatta aacaacctct 840

aggtgaatgg ccgggaagcg cccctcggtc aaggctaagg aaacctcgga gaaactacat 900

<210> SEQ ID NO: 124

<211> LENGTH: 600

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 124

cagtccagcc gcttgcctca cttcttcccg cttgccttat ctccccgcag acgtggttcc 60

cctgcagccc gaggtgagca gctaccggcg cgggcgcaag aaacgcgtgc cctacactaa 120

ggtgcagctg aaggagctag agaaggaata cgcggctagc aagttcatca ccaaagagaa 180

gcgccggcgc atctccgcca ccacgaacct ctctgagcgc caggtaacca tctggttcca 240

gaaccggcgg gtcaaagaga agaaggtggt cagcaaatcg aaagcgcctc atctccactc 300

cacctgacca cccacccgct gcttgcccca tctatttatg tctccgcttt gtaccataac 360

cgaacccacg gaaagacgct gcgcgggtgc agaagagtat ttaatgttaa ggaaagagaa 420

gaaccgcgcc gcccggaggc agagaggctc catggccgtg ctgctgggcc atccccaact 480

ccctatccca tccccagcct ccacccccat ccagatggga ctcacgtggc ttcaacagct 540

ttggaaatgg gtcccgagtg ggccgtgcga ggaaggctgt cgacctctac tcctccttgc 600

<210> SEQ ID NO: 125

<211> LENGTH: 1500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 125

caagatcgac tttcttagga agggggagag gagggaactc ttcacgaagg gaggtgggag 60

tccacctcag acctctattg gaaggaaatc gagttgttcc gggggactga ggtctcttgc 120

ataaggcatg ggatccttat tattattatt attattttta aatcccccgc ggaggagctc 180

tgggcaaatg aataccgagg cgccgctcta gctggttagg cttgggatgc gataactcag 240

tgccctcttg cagacttgca tagaaataat tactgggttg tcgtggaggg gacacgagac 300

agagggagtt ctccgtaatg tgccttgcgg agagaaaggt ccaagaatgc aattcgtccc 360

agagtggccc ggcaggggcg gggtgcgagt gggtggtgga gtaggggtgg gagtggagag 420

aggtggtttc tgtagagaat aattattgta ccagggcccg ccgaggcacg aggcactcta 480

ttttgttttg taatcacgac gactattatt tttagtctga tcaatgggca caatttctaa 540

gcagcgcagt ggtggatgct cgcaaacttt tgcgcaccgc tggaaaccca ctaggttgag 600

ttgcaaaacg taccgcgtag acgcccctgg tggcgccgag agaagagcta ggcctgccca 660

gcacagagcc ggagagcgtc gggccttccg gaagggtaag ttctccgcca aggggtcccg 720

agggagctgg acgtctgaat ctggacttgc ccccagcttc ggggttcgat tctgggtttt 780

gcgcgtcccc aacccccagg gctttccgaa gcatggcctg gctccaggcc cggtcctgta 840

aggactggaa cggcagcaaa atgtgcaggg aggcagtcgg ccggcagagc tgcggcggga 900

gccaaggtca ggcccgcggg gagagcgggc agcttccagc gccggccaca agctcccagg 960

ccagctgggc cgcagacccc tttgcttcca gagagcacaa cccgcgtcct ttctctcagc 1020

caggctgcag tggctgcccc gagcttcgct ttcgtttccc aagctgttaa taacgatatg 1080

tccccaaatc cgaggctcgt gtttgctccc agatgccaag aacgcaaccc gaaatccttc 1140

tcccaaaccc taggtcgacg agatgagttc ctacttgacc tctgagccga ggtgggccgg 1200

aaaccgaggc ctaggccccg ccggggctgc aaggaaaagg ggaaactccg agcgtagcgt 1260

cttttccttg tggttccttt ctccggcatc ccggactgcg ggccctgcag ccacctggac 1320

cggcattcaa aggattctgc aagtccagct tcacagactg gctttcccag acgctccgaa 1380

gcccgcacca cgaacagaat aaaggagaga cgagagatcg caactagatt tgagaatcct 1440

cgttcttttc cccaatcgtt cgggcagtaa actccggagc cggctacagc gcgcatcctc 1500

<210> SEQ ID NO: 126

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 126

actgtcctcc tccctcaatt gcctattttt tgcccatagc tctaacttaa ccctgtgatc 60

accccagatc gctacttctg acccccatct cctctcccac accaacctcc agcgcgcgaa 120

gcagagaacg agaggaaagt ttgcggggtt cgaatcgaaa atgtcgacat cttgctaatg 180

gtctgcaaac ttccgccaat tatgactgac ctcccagact cggccccagg aggctcgtat 240

taggcaggga ggccgccgta attctgggat caaaagcggg aaggtgcgaa ctcctctttg 300

tctctgcgtg cccggcgcgc ccccctcccg gtgggtgata aacccactct ggcgccggcc 360

atgcgctggg tgattaattt gcgaacaaac aaaagcggcc tggtggccac tgcattcggg 420

ttaaacattg gccagcgtgt tccgaaggct tgtgctgggc ctggcctcca ggagaaccca 480

cgaggccagc gctccccgga 500

<210> SEQ ID NO: 127

<211> LENGTH: 900

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 127

ctcagggaat cacatgtccg cctggcctgg cctggtacca aatgtttata gacaggacga 60

gggtcgctgg aatcgcctcg ctcctttcag cttggcgcta aggcgcgaat ctcgatcctc 120

ctagtatttc tctggcgtct gtctctatct cagtctctgc ttttgtctct ttctccctcc 180

ctccgcccca gtctttccgt ctctttttcc tcgaatgcac gtggaattcg gaattgaaaa 240

ttgaggtcag aatctccctt tttcttccag ttatccgcgc cgctgcccca cgcctagcgg 300

cttggatctg catagacatc tatctacccg caacaagatc cgagctgcag aagcaaacct 360

aatctgtctc cgcaccatcc cctgctctgt agacccactg ccccatccca cgccacatcc 420

ttgaggttca agtagcgact ccagcggatg attcggagaa tgccctgctt tccaaaggcc 480

ccaacccgtg tttttatttt ctttttcctt tgcccgcttg accaactttg gtttctttca 540

gggcccggag gtgcctgcgc cgcgcttggc tttgctttcc gccgccccag gagacccggg 600

actgtggttt ccgctcgcca catcccagcc tggtgcgcac acaagagcct ggcgagcttc 660

cctcgcgcgc ttacagtcaa ctactttggg cctcggtttc cctgctcctt gtagatcaga 720

gaagggacgg gcgaaatgcc tgcgagggag ggttggcgaa tgggttggtt ggtggcaaga 780

ctgcagttct tgtacatgga cgggggttgg ggggtcaaca ctggaagaac tcctgcctga 840

cgccaagagc cacccgcttt ccagctcgtc ccactccgcg gatgtttacc caccttcatg 900

<210> SEQ ID NO: 128

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 128

tttggggcac ccaacccttc ccaagcctcg gttttcccga tcttgtggga tccttgcggc 60

gcgaatgggg ttggaagcac cttggaagct acagagtacc gggtcgggac aatttccggc 120

actgccccag ttcagtggtt tatagaaaat ttctttctct ctctcaggtc cactaagacc 180

gagagagaga gagaagtcga ctctggcaca cccgggcgag gggctgccgg gattcgggag 240

ctggcgcggt tgattttttc cgagaatcct ccacttgggg tgacgtcggg cagcgcgcgc 300

gggccgtgag gttaatgccc aggcttttct ctaaagcgtc cgggaatgat ccggcgaata 360

aaacgggtgt ctgcaaagtt aatgaattgt acaaggaggc tgagggtggg gacttcgacc 420

cggggagcca gaggcggttc tggtggacgc ttccccgtgc gcctaggggt gcgctgggct 480

ttcccagccg aggtctgcag 500

<210> SEQ ID NO: 129

<211> LENGTH: 2000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 129

ccagacagtt aaggtaaaac gttgaagtca agaggaagta gtgagtctgt tgccaactgg 60

atagggttgg tcctgtccca tctaaatgta ttagaattaa gtggctttta aaaatgagct 120

ggtcatcttc agcccacggg ctggccaatt tggaacttaa tgggcctttg cgtcctcctt 180

ccctgagcct ccttttattc cagacttctc agtgtgagtc tgtgcgtccc tccgacgatc 240

tcagggagtg gggtgccttc atctgcctgt tccctgttcc tcaggctgac gctcccgctg 300

tcctccccgc ctcccctcac tccttttctc cctcccttcc tccttgtggg gaggctcttg 360

gccagggtcc ctgagcccgg gcgggtgctg gcagaggacg cagaaggggt gaggtcacgt 420

ctcccttgag ccccgagccg ctggcttttc agagcctcgc cacaagccgg cggccagagc 480

cccagaccac acagaccgtg cgctcctccg ccctcccggc gccgccggcc tcgcccatgt 540

ctcagtacgc ccctagcccg gacttcaaga gggctttgga cagcagtccc gaggccaaca 600

ctgaagatga caagaccgag gaggacgtgc ccatgcccaa gaactacctg tggctcacca 660

tcgtctcgtg tttttgccct gcgtacccca tcaacatcgt ggctttggtc ttttccatca 720

tggtgagtga atcacggcca gaggcagcct gggaggagag acccgggcgg ctttgagccc 780

ctgcagggga gtccgcgcgc tctctgcggc tcccttcctc acggcccggc ccgcgctagg 840

tgttctttgt cctcgcacct cctcctcacc tttctcgggc tctcagagct ctccccgcaa 900

tcatcagcac ctcctctgca ctcctcgtgg tactcagagc cctgatcaag cttcccccag 960

gctagctttc ctcttctttc cagctcccag ggtgcgtttc ctctccaacc cggggaagtt 1020

cttccgtgga ctttgctgac tcctctgacc ttcctaggca cttgcccggg gcttctcaac 1080

cctcttttct agagccccag tgcgcgccac cctagcgagc gcagtaagct cataccccga 1140

gcatgcaggc tctacgttcc tttccctgcc gctccggggg ctcctgctct ccagcgccca 1200

ggactgtctc tatctcagcc tgtgctccct tctctctttg ctgcgcccaa gggcaccgct 1260

tccgccactc tccggggggt ccccaggcga ttcctgatgc cccctccttg atcccgtttc 1320

cgcgctttgg cacggcacgc tctgtccagg caacagtttc ctctcgcttc ttcctacacc 1380

caacttcctc tccttgcctc cctccggcgc ccccttttta acgcgcccga ggctggctca 1440

cacccactac ctctttaggc ctttcttagg ctccccgtgt gcccccctca ccagcaaagt 1500

gggtgcgcct ctcttactct ttctacccag cgcgtcgtag ttcctccccg tttgctgcgc 1560

actggcccta acctctcttc tcttggtgtc ccccagagct cccaggcgcc cctccaccgc 1620

tctgtcctgc gcccggggct ctcccgggaa tgaactaggg gattccacgc aacgtgcggc 1680

tccgcccgcc ctctgcgctc agacctcccg agctgcccgc ctctctagga gtggccgctg 1740

gggcctctag tccgcccttc cggagctcag ctccctagcc ctcttcaacc ctggtaggaa 1800

cacccgagcg aaccccacca ggagggcgac gagcgcctgc taggccctcg ccttattgac 1860

tgcagcagct ggcccggggg tggcggcggg gtgaggttcg taccggcact gtcccgggac 1920

aacccttgca gttgcgctcc ctcccccacc ggctcacctc gcctgcagct gggccacgga 1980

actccccggc cacagacgca 2000

<210> SEQ ID NO: 130

<211> LENGTH: 600

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 130

ctctctgggc cttaggaaaa tggaaatgac acctgtacct gcccttccag gactgacagg 60

aggggctgct ccatgaaacc tcactgctgc ggtcataatg tcattatctt ttgccttaaa 120

gggatttctt ctgcaccagc acctaaagtg gcagcccctt acccttggcc atcagctgga 180

ccctggtgct ctcctggagc ccaaaacctc tgttttgtgt tgcatcctgc tgaccagcca 240

cagtccacac ccatctgagt gtctgagcag aacagcccag aggccacacc aggatggctt 300

tccaccggtc accttccccc acccactcat aaaccctgcg tctctggggg agagggtggc 360

gaggtcccct ccccacatag atggaaacac tgaggcctga ttcatggtgc cccctgtgaa 420

gcgcctcatg gccagcaccg gggggcagca ggccagggcg gggacacata cccggttctc 480

gtcgtagatg atctgcacca ggctgcggtg cttcgactcg atgggcggcg gtgacacggg 540

cttctcaggc tcgggcggct tggcagcctc ctcctccagc tgttgctgtg gggagaggca 600

<210> SEQ ID NO: 131

<211> LENGTH: 400

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 131

cttgaaaact cccagccccc tttgtccaga tggggatgga ggtggccagg ctgccccgtt 60

gattgtgtgc cgaggagccc tccccgggaa ggctgtgatt tatacgcgca ggcttgtcac 120

ggggtgaaag gaagggccac tttttcattt tgatccaatg ttaggtttga aagccaccca 180

ctgctgtaaa ctcagctgga tccgcgggcc gtgattaaac acattgcccg ctttgttgcc 240

gagatggtgt ttcggaaggc gctgtgaatg cacttccctt tgcggggctc acacagacaa 300

gatgtgtgtt gcaaggatga ggcgcctgct cggcctccag cccagggccg ggaagggaga 360

aggtgctgtg cgtcgctgcc tgtgtcgccc gcggctctcc 400

<210> SEQ ID NO: 132

<211> LENGTH: 1200

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 132

cgcgtcaggg ccgagctctt cactggcctg ctccgcgctc ttcaatgcca gcgccaggcg 60

ctcaccctgc agagcgtccc gcctctcaaa gaggggtgtg acccgcgagt ttagatagga 120

ggttcctgcc gtggggaaca ccccgccgcc ctcggagctt tttctgtggc gcagcttctc 180

cgcccgagcc gcgcgcggag ctgccggggg ctccttagca cccgggcgcc ggggccctcg 240

cccttccgca gccttcactc cagccctctg ctcccgcacg ccatgaagtc gccgttctac 300

cgctgccaga acaccacctc tgtggaaaaa ggcaactcgg cggtgatggg cggggtgctc 360

ttcagcaccg gcctcctggg caacctgctg gccctggggc tgctggcgcg ctcggggctg 420

gggtggtgct cgcggcgtcc actgcgcccg ctgccctcgg tcttctacat gctggtgtgt 480

ggcctgacgg tcaccgactt gctgggcaag tgcctcctaa gcccggtggt gctggctgcc 540

tacgctcaga accggagtct gcgggtgctt gcgcccgcat tggacaactc gttgtgccaa 600

gccttcgcct tcttcatgtc cttctttggg ctctcctcga cactgcaact cctggccatg 660

gcactggagt gctggctctc cctagggcac cctttcttct accgacggca catcaccctg 720

cgcctgggcg cactggtggc cccggtggtg agcgccttct ccctggcttt ctgcgcgcta 780

cctttcatgg gcttcgggaa gttcgtgcag tactgccccg gcacctggtg ctttatccag 840

atggtccacg aggagggctc gctgtcggtg ctggggtact ctgtgctcta ctccagcctc 900

atggcgctgc tggtcctcgc caccgtgctg tgcaacctcg gcgccatgcg caacctctat 960

gcgatgcacc ggcggctgca gcggcacccg cgctcctgca ccagggactg tgccgagccg 1020

cgcgcggacg ggagggaagc gtcccctcag cccctggagg agctggatca cctcctgctg 1080

ctggcgctga tgaccgtgct cttcactatg tgttctctgc ccgtaattgt gagtccccgg 1140

gccccgaggc agcagggcac tgagactgtc cggccgcgga tgcggggcgg gaagggtgga 1200

<210> SEQ ID NO: 133

<211> LENGTH: 2000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 133

cttccgccgc ggtatctgcg tgcccttttc tgggcgagcc ctgggagatc cagggagaac 60

tgggcgctcc agatggtgta tgtctgtacc ttcacagcaa ggcttccctt ggatttgagg 120

cttcctattt tgtctgggat cggggtttct ccttgtccca gtggcagccc cgcgttgcgg 180

gttccgggcg ctgcgcggag cccaaggctg catggcagtg tgcagcgccc gccagtcggg 240

ctggtgggtt gtgcactccg tcggcagctg cagaaaggtg ggagtgcagg tcttgccttt 300

cctcaccggg cggttggctt ccagcaccga ggctgaccta tcgtggcaag tttgcggccc 360

ccgcagatcc ccagtggaga aagagggctc ttccgatgcg atcgagtgtg cgcctccccg 420

caaagcaatg cagaccctaa atcactcaag gcctggagct ccagtctcaa aggtggcaga 480

aaaggccaga cctaactcga gcacctactg ccttctgctt gccccgcaga gccttcaggg 540

actgactggg acgcccctgg tggcgggcag tcccatccgc catgagaacg ccgtgcaggg 600

cagcgcagtg gaggtgcaga cgtaccagcc gccgtggaag gcgctcagcg agtttgccct 660

ccagagcgac ctggaccaac ccgccttcca acagctggtg aggccctgcc ctacccgccc 720

cgacctcggg actctgcggg ttggggattt agccacttag cctggcagag aggggagggg 780

gtggccttgg gctgaggggc tgggtacagc cctaggcggt gggggagggg gaacagtggc 840

gggctctgaa acctcacctc ggcccattac gcgccctaaa ccaggtctcc ctggattaaa 900

gtgctcacaa gagaggtcgc aggattaacc aacccgctcc cccgccctaa tccccccctc 960

gtgcgcctgg ggacctggcc tccttctccg cagggcttgc tctcagctgg cggccggtcc 1020

ccaagggaca ctttccgact cggagcacgc ggccctggag caccagctcg cgtgcctctt 1080

cacctgcctc ttcccggtgt ttccgccgcc ccaggtctcc ttctccgagt ccggctccct 1140

aggcaactcc tccggcagcg acgtgacctc cctgtcctcg cagctcccgg acacccccaa 1200

cagtatggtg ccgagtcccg tggagacgtg agggggaccc ctccctgcca gcccgcggac 1260

ctcgcatgct ccctgcatga gactcaccca tgctcaggcc attccagttc cgaaagctct 1320

ctcgccttcg taattattct attgttattt atgagagagt accgagagac acggtctgga 1380

cagcccaagg cgccaggatg caacctgctt tcaccagact gcagacccct gctccgagga 1440

ctcttagttt ttcaaaacca gaatctggga cttaccaggg ttagctctgc cctctcctct 1500

cctctctacg tggccgccgc tctgtctctc cacgccccac ctgtgtcccc atctcggccg 1560

gcccggagct cgcccacgcg gacccccgcc ctgccccagc tcagcgctcc ctggcggctt 1620

cgcccgggct cctagcgggg aaaaggaagg ggataactca gaggaacaga cactcaaact 1680

cccaaagcgc atgattgctg ggaaacagta gaaaccagac ttgccttgaa agtgtttaag 1740

ttattcgacg gaggacagag tatgtgagcc tttgccgaac aaacaaacgt aagttattgt 1800

tatttattgt gagaacagcc agttcatagt gggacttgta ttttgatctt aataaaaaat 1860

aataacccgg ggcgacgcca ctcctctgtg ctgttggcgc ggcgggaggg ccggcggagg 1920

ccagttcagg ggtcaggctg gcgtcggctg ccggggctcc gcgtgctgcg ggcggggcgg 1980

gcccggtggg gattgggcgc 2000

<210> SEQ ID NO: 134

<211> LENGTH: 1000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 134

agtttgggga gccttttctc catttgagaa aaaacaaact tacagcgagg ggtgaggggt 60

tagggtttgg gattggggaa aatgtgggtg gggagccccc ccaaggaagt gaggaggggg 120

ctgcaaggat tacacctggg catacgtttc cctagaaatc acattcattg tatttttata 180

atttattcta aatctttcat gcgaagaaag tcagtagtga gtgttagtac tggtggccct 240

cctgatcaca cttgcatctc ttgagtgtgc cttaaaggtc ttgggaatgg aaaatataaa 300

aactgcttcg tgatgcgtca tctttatccc ccactccccc acccattcca atatattttc 360

tacttccagc ctaaattcgg ggccccctac cgaggccggc catgatcttg agggcggcat 420

aggggaggcc gcgctctgtc caccccagcc tggtgatgcc gttcgcttct tgtgcccggt 480

attgtgggct acatgccttt ccggcgtacg gagctgagcg tccaggccag tgcccctcaa 540

cctctcagta atgtttaccc gaggccgtcg tgcaatgaga ctattcgcat ggcattgtca 600

acgcggcggc gcgcgcgtct cggccctccg cggcttgcca gactgtcctg caaaccacct 660

cacccgtctc tttggcgcag gagactcagg ctgtaaccgg agaaaacact tcaccctgga 720

accctaactc aggtcctggc aaaagatgcg agaggaagac ttgctctctt aataaatctc 780

ggccgcccgc acatctggcc cctagacctg ctcggtagag gactggctgg tggatgcgcg 840

gtccaggccg tgggcactcg acccacctct attttccttc ccgaggcgcc cctggattac 900

cactttcggt ttgcgcttac atccgggatg tcgaatttcc cagggaatca taattatttt 960

atctataatt tattctaacc ccaaggttcc aagaaaatct 1000

<210> SEQ ID NO: 135

<211> LENGTH: 1100

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 135

acattccttc taaaatgtgg gctttctgtg tacatgggcg cgcattccca ggactcggtt 60

ccctgggtgg aattcaccca ggaatacaat cgattttctg aacctgcgta aggccacagg 120

cagctctgaa aatgaaagcg tttgctaagt gggggagatc tcaccgatcg aacgtttaaa 180

aatggctttg tcttcattca gctctcccga tttattctgt gttttacaaa tagaagctca 240

gagcttctgt cgcccagtcc ttgcatgact catggcggtg gccacacggg tttcagggat 300

aacgggatgt ttagaaaatc gctgcatatc ggagtttcct agcacgttcc atttatactg 360

aacgcaggcg gccgctgaaa atccagcctc gactcttgct aatgactggg taggaccctc 420

ggggtcctgc gacggtgctg gagggtgttc ccggctccga tgtggggagg cctgcgcggg 480

gactaggttc tcgagaggcg agcgggcgcg ccagagaacc cgagactgct gcggggccgg 540

atgcgggatc cctgggctgc ggttctacgc agaaacgcca atggccatgc ctccccagct 600

cctcccagcc ccagtcacta ggccggcgcc tggcccggag atcctcccag agccctggcg 660

gtgccatcat gccggagaag acaagctcgg ccccgctgga attcgctcca aacacagatg 720

ctcatttttg gaatattcta gaaaaataac aagatcttgt ttgtcgttat gattcacggg 780

aggtaactga tgggagggcc atttacatga gggcagacac tgtggggcga aggtgacttc 840

tggacgtagg ctttaaagta ggaacggctc caaattccca atatctccgg ccttaccggt 900

tgcaaatcgg acccctgcgg gaaaaccaga cacttctgtt tcgtggcttt cgggctgcct 960

ccagcccacg caggctcgtt tagtccccgt ggagtcagcc ccgagccttc ctagtcctgg 1020

aacaagggct ccaggtcgcg gccgcgggaa gccgccaaga gggcggggag tagggattcc 1080

ctccagctcc gcagggcatc 1100

<210> SEQ ID NO: 136

<211> LENGTH: 1500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 136

tcctcctcgg cctcagatgt cgtcccacct gcccacgagc agggaacctg gaacccactc 60

tcccggcagt ccccagcggg ttccgccacc cggcggccgc ccctgacacc gagtgggtgg 120

gaggaagagg cagctggcgg ggatgggcca ttgagacctc ttgaaaaata ttaaaagaca 180

ggatgggtag agatttctcc gggagaaagt tcgagggtgc atcgggtcgc ggctgggagg 240

agtacccgaa atgccagcag gagaaatgca acctgtttag gccacacctt caatccccga 300

ggctgtctgg agagactgcg tgcgggggac ttgccggcgt tcccacaccg cgcctgcaat 360

ccactcccgc ggctgcctgg cctctgccac tcgcggcttg aagccagtgg ctctcaagcc 420

ctcggccccg cggcggcccg cgcagccttc acccggcgcc ggcaccacga agcctggccg 480

cagtggactc cccgcagctc gctgcgccct ggcgtctccc gtcgaggagg gagggacgga 540

ggcctgagcc gggagctccc tggcggtggt cgggccgccc cccttgaggc ctgctccccc 600

ctctcggcct cgccaaatcc ctgaaagccc agtccccctt cgtcaccccg ggggcttcta 660

atcactcggt atcgatttcc ctaactcttt tcatcctgtt gaagacacat cttaaaacac 720

tccagcccgg agtgtgctct gggctttatc cacactaata aaatgattta cccttctctc 780

cgcgctctcc tcacagagga aaatcgttcg agccccggct atttgtgtgt gatcagtaaa 840

tatttagtgc gctgacatcc ttagctgggc ttcggatcga ttcggggccc accgggaggt 900

gcgcacggtc cgggcggggc cgcgccgagc tcgccgaggg ggctcctccc gccctcgccg 960

ccggccgctg atttacggcc cctgcaacca gctaaggggg gcgaaagcgc gcctggaaaa 1020

ttggcttttc aaccttttac ttttgacatt cagccacttc cccaggctct aattctcgcc 1080

cgcactcctc cctcccgccc tactaagggt tgccctgtgc gccctgcgag cccttccagc 1140

agcaacgcgc ggcgctcgcg ccccctcggc ccggggacca cctatcacag ccctgagccg 1200

cgacgcgggg aggccccggc ccctgctatg ggggtcgcct ccttcgagga gagatgctct 1260

ccgcccgccc acacctctga gggaggagag ggggtggaga agcccagagc tgcatctgct 1320

ggatgacgag ccgctctccc tgctaccctt tctccgaccc gtcggccttt ctcctactct 1380

ggagactgat cctcgacgtc catcgggccg gatggcgtcg ggtggaagcg ttactttcct 1440

cgcagaaaaa ctcctcctct ttcctaagat cagaaaaagc gcttagcttg gaattgttag 1500

<210> SEQ ID NO: 137

<211> LENGTH: 600

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 137

cctaggcatt ctcagcccgt tttgctggag ggggcatttg aggcctggcc agcttagcca 60

gcctacaagg agtgttactg gggtgaaaac agccagcggg gaccagtctg cttgtggccc 120

gccaggtgcc tgggatgggg aagcagcaaa tgcccacctt cctgcccaac cccctcctcc 180

ctcttcatgg ggggaactgg gggtggcagc ggctgccggg tgcgagcggg ctcaggcctg 240

tggccctgcc tgacgttggt ccccatcaag ccatgtgacg agaccaggcc acaagaaaga 300

ggtttcaaca agcgttatcg tttcctggaa ctccaactcg gcgacttccc cgaagaccgg 360

ctgtgcctgg cgggcgggct gcgcacagcg gggacaaggc tgcccccttc ctcctccgct 420

gcctccgcgg ccgcgtctat ctcagtctga ctacctggaa gcagcactcc accctccagc 480

ccagcggccc tcggctcagc tgccaggtca ccggcaaccc cgggagcggt ggggcagggg 540

ctgctccgcc agcctctgtg atgttcaggc cgggctgcac cagcccggga cccctaggtg 600

<210> SEQ ID NO: 138

<211> LENGTH: 700

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 138

gcactggttc ccctttacct gagccaacaa cctaccagga agtttccatc aagatgtcat 60

cagtgcccca ggaaacccct catgcaacca gtcatcctgc tgttcccata acagcaaact 120

ctctaggatc ccacaccgtg acaggtggaa ccataacaac gaactctcca gaaacctcca 180

gtaggaccag tggagcccct gttaccacgg cagctagctc tctggagacc tccagaggca 240

cctctggacc ccctcttacc atggcaactg tctctctgga gacttccaaa ggcacctctg 300

gaccccctgt taccatggca actgactctc tggagacctc cactgggacc actggacccc 360

ctgttaccat gacaactggc tctctggagc cctccagcgg ggccagtgga ccccaggtct 420

ctagcgtaaa actatctaca atgatgtctc caacgacctc caccaacgca agcactgtgc 480

ccttccggaa cccagatgag aactcacgag gcatgctgcc agtggctgtg cttgtggccc 540

tgctggcggt catagtcctc gtggctctgc tcctgctgtg gcgccggcgg cagaagcggc 600

ggactggggc cctcgtgctg agcagaggcg gcaagcgtaa cggggtggtg gacgcctggg 660

ctgggccagc ccaggtccct gaggaggggg ccgtgacagt 700

<210> SEQ ID NO: 139

<211> LENGTH: 300

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 139

tgtccgacag gcacacagag cgccgccagg cacggccctc attcttcacc ccgagctccc 60

gcaaggtcgg cgaggaggct ggagcagcgg gtaggaagcg ggccgaggct cccccgacgc 120

tgggccgcaa ctgtcatcgc agatccctga aaaacgagct ctgtaatcgt tgccgtcagc 180

gggtgtacaa ttgcagcctt atgtttcctg ccgctgttta ccttcctgag cggcgcccag 240

agatgcacac acgctgccct gaagcgggac gtgacctctg ggcacctgtg aggtcctggg 300

<210> SEQ ID NO: 140

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 140

gtcggctcct gcgctcccaa cggggtggcc gtttccttcc tcgcaccctc ttctctcccg 60

gtgcctgcgg tcccaccttc cagatacccc tcggagagtc cagctgagct ctcgccagag 120

ctttcccctt ccaacccgct cgacttgccc agatcccaag ctgggcttct ctctccatcg 180

ccccagaaag tgggtcttgg agaccgaggc aagaatttgg gcctccgctt ctgttccaga 240

ccccggaccc cttgccaaaa tgcggcagat gtgcagattg ggccgcgctt ggttcctggc 300

tgggtttatg gagcctgcgg ctgaggcagg ctccgcagac cccgagccag agtgggattt 360

aacggcggcc ggtgcgctgt gcttggtcaa ccccggtaac cgtcacgctg ctagtgatat 420

gaaaaaaacc tgccagcgtt ctgcttttct gccccgctgc agtctttagc acccgccagg 480

attctgtccg agtgtttgga 500

<210> SEQ ID NO: 141

<211> LENGTH: 1000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 141

tttagtgtgt gcataaaaca tcccagctaa tctcaaatag acttttcctg agcagaggct 60

gaaatttgca agtaatgcaa agaagactcc gggagagcgt cgccgatggt ggagcgggag 120

acgggcgtgg ggagccccac tgcagtgctg ggatcgaagt ggtgctgacc ccaagacctc 180

tcccctcctc ctcccccggg agcttctcca gggttatttg ggaaatgagg gggaactcca 240

atccctgaga aagcgctcag gggcttgctg aggtgagcgc aaatggaagc acaaggccgg 300

gctggccgtg ggctcagtaa ccagtcggct gcccggcttg cgccagcact aaatgctcga 360

tcagaaagag aaaaagaggc gcaataattc caaatttcag gaaaagtcaa atcggagagg 420

ggggacgcag gtctcttcag actgcccatt ctccgggcct cgctgaatgc gggggctcta 480

tccacagcgc gcggggccga gctcaggcag gctggggcga agatctgatt ctttccttcc 540

cgccgccaaa ccgaattaat cagtttcttc aacctgagtt actaagaaag aaaggtcctt 600

ccaaataaaa ctgaaaatca ctgcgaatga caatactata ctacaagttc gttttggggc 660

cggtgggtgg gatggaggag aaagggcacg gataatcccg gagggccgcg gagtgaggag 720

gactatggtc gcggtggaat ctctgttccg ctggcacatc cgcgcaggtg cggctctgag 780

tgctggctcg gggttacaga cctcggcatc cggctgcagg ggcagacaga gacctcctct 840

gctagggcgt gcggtaggca tcgtatggag cccagagact gccgagagca ctgcgcactc 900

accaagtgtt aggggtgccc gtgatagacc gccagggaag gggctggttc ggagggaatt 960

cccgctaccg ggaaggtcgg aactcggggt gatcaaacaa 1000

<210> SEQ ID NO: 142

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 142

catggtgctt caggaaggga ggggacgaga gccctgggct tgtggtgtcc acgtggacag 60

ctaatgagga gccttgccga tgaggagcat gcgttcccga cggggcggcc gaatgcggaa 120

ggagccgcca ttctctccgc cctgaccgcg ggattctctg cagcagatga gaaacggcgc 180

tgactcagca gggtccctcc caggccccga gcggtcatct ggtgaccccc gcgcttcccc 240

cacggcccag ccggagaagg gcaaagggaa gtcccggctc caaggcgcac ccagagatgc 300

ggtgcatgtg gcaggatggc ccagccccgt cggcagcccc agcttcctgc ccctggtttc 360

cttcctccca cgggctacag gcctctgatg agctttggaa agcaggaaac acacaggcta 420

gtaactatga atgggtccaa aaaacactcc ttattacttt aaactactta ggaagaagca 480

cagcgttgcc aaacgccaga 500

<210> SEQ ID NO: 143

<211> LENGTH: 1200

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 143

gcgcgggggg ccggaggatg gcggcctggg ggccctgcgg gggctgtcgg tggccgccag 60

ctgcctggtg gtgctggaga acttgctggt gctggcggcc atcaccagcc acatgcggtc 120

gcgacgctgg gtctactatt gcctggtgaa catcacgctg agtgacctgc tcacgggcgc 180

ggcctacctg gccaacgtgc tgctgtcggg ggcccgcacc ttccgtctgg cgcccgccca 240

gtggttccta cgggagggcc tgctcttcac cgccctggcc gcctccacct tcagcctgct 300

cttcactgca ggggagcgct ttgccaccat ggtgcggccg gtggccgaga gcggggccac 360

caagaccagc cgcgtctacg gcttcatcgg cctctgctgg ctgctggccg cgctgctggg 420

gatgctgcct ttgctgggct ggaactgcct gtgcgccttt gaccgctgct ccagccttct 480

gcccctctac tccaagcgct acatcctctt ctgcctggtg atcttcgccg gcgtcctggc 540

caccatcatg ggcctctatg gggccatctt ccgcctggtg caggccagcg ggcagaaggc 600

cccacgccca gcggcccgcc gcaaggcccg ccgcctgctg aagacggtgc tgatgatcct 660

gctggccttc ctggtgtgct ggggcccact cttcgggctg ctgctggccg acgtctttgg 720

ctccaacctc tgggcccagg agtacctgcg gggcatggac tggatcctgg ccctggccgt 780

cctcaactcg gcggtcaacc ccatcatcta ctccttccgc agcagggagg tgtgcagagc 840

cgtgctcagc ttcctctgct gcgggtgtct ccggctgggc atgcgagggc ccggggactg 900

cctggcccgg gccgtcgagg ctcactccgg agcttccacc accgacagct ctctgaggcc 960

aagggacagc tttcgcggct cccgctcgct cagctttcgg atgcgggagc ccctgtccag 1020

catctccagc gtgcggagca tctgaagttg cagtcttgcg tgtggatggt gcagccaccg 1080

ggtgcgtgcc aggcaggccc tcctggggta caggaagctg tgtgcacgca gcctcgcctg 1140

tatggggagc agggaacggg acaggccccc atggtcttcc cggtggcctc tcggggcttc 1200

<210> SEQ ID NO: 144

<211> LENGTH: 600

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 144

gggcgggttg ccacactgtc ccctttctgc atgggaggaa gggggctcga gaactgagtc 60

agccacacaa aacgaggatg gacagaactc ctgagtagcg agggtgcctg ccgggcgcga 120

ggaggagggg gaagacgagg aagacgagga ggaggaatag ggagcaccac atgacagagg 180

ggctgcctca gaccacaaag cgcttcctca tcctttcctc gccctttgat gccgccggca 240

acgtgactct gcgagcagcg gggcagacgc caggtctccc tcgcaggcgg gaaaggggct 300

ccaaggcggg tgctgccttg ctcgggtcac atggctacgt gggggccttg ctcaaattca 360

cttcctgcct tcattacaaa actgtcaaag gggatcgcac gtttgcaggg tgtcacccaa 420

gcattctggt tttgcaaacg acgctgtgcg gcaggcggtc tgatacctga tgagctcggt 480

gtggcggggt cggcagcatt tcctccgggg ttttgagctc tggccacttc tccttttgtt 540

ccacccaatc tcacccactt ctgggcttcg aggccagagt gtcttaacaa gggggcacgt 600

<210> SEQ ID NO: 145

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 145

gagcgagact ttgtctcaaa aaaaaaaaaa accaaataaa ttgaaagctg agaaattcag 60

agcacaagaa gacaagcgcg ccccctcttt tagctgtcaa catggcggag ccgtccctgg 120

tgacgcagcc tccaaaggcc tccctgtgcc ctcctgagac cgcaagaggg aaagtggcag 180

cgacagtgat cgtggtgtct ttgtggcggt tgtgttgacc tcactgaccc ccgaagtgcc 240

gctctagggt ctgtcctcag cggtgacccg gccgggtcga agggcagagt tccgctgtca 300

ctagccctcc acccgtcctg tgtgctggga tgccctcgcg gcgccgtcca cgccaccgcc 360

gccccctctt gtgggttctg tctcctccgt gtctaggatc ctcctgcatc cgtttttcct 420

tcctcccttc tctccctccg tctgtcttgc ccgcacctga ggttgtcgca gaggcgctga 480

gacgggccag caggagctgt 500

<210> SEQ ID NO: 146

<211> LENGTH: 600

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 146

tgctgtcccg gtcctgtcgc agtcctcaaa gatgctagag tgacagtcct ctaggggtag 60

agatggtcgt cctcccagga gaaggtggcc cggagacttg gaggtgggat caatcctgcc 120

agtcctggat caggaggcct ctgtcgggcg ccgcccccct tcctcctcca tcagcaacag 180

gcggcgccgg ccagcctcat agtcagcctc atccacactg accagcaggc gaacagcctc 240

ccggcccaca gcctctcgca gggcctcagt caggaacacg ccccgcaggg cctgcagcag 300

ggcgccactc aggtagtcgc cccagaaggc gtccagatag gagagctctg agaacttgat 360

gtcacaaacc acagagccca ggtcccttga gcgcagcact gcggtggcct gcccaaacac 420

gtccagctgc cgcgccagcg cctggggccg ccgggatgcc acgccctgct ccaaggctgg 480

cccatgctcg cagtactctg ctcgaacccg gagccggatg tctgcagggg aaggagggat 540

ttgtcaggga gggggccaac actagacaca cttatgggga acgccaccct tcctccctcc 600

<210> SEQ ID NO: 147

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 147

tgatgcccgg cccccagggg ggcagaggcg ccgccaccat gagcctgggc aagctctcgc 60

ctgtgggctg ggtgtccagt tcacagggaa agaggcggct gactgcagac atgatcagcc 120

acccactcgg ggacttccgc cacaccatgc atgtgggccg tggcggggat gtcttcgggg 180

acacgtcctt cctcagcaac cacggtggca gctccgggag cacccatcgc tcaccccgca 240

gcttcctggc caagaagctg cagctggtgc ggagggtggg ggcgcccccc cggaggatgg 300

catctccccc tgcaccctcc ccggctccac cggccatctc ccccatcatc aagaacgcca 360

tctccctgcc ccagctcaac caggccgcct acgacagcct cgtggttggc aagctcagct 420

tcgacagcag ccccaccagc tccacggacg gccactccag ctacggtgag ggcctgggcc 480

atcttggccc acttttcaga 500

<210> SEQ ID NO: 148

<211> LENGTH: 110

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 148

tttgggccac gaggcaagtt caaagcggga gacttttgtt ttataaaatg atggtgagca 60

gctccggttt tatgtcaaac atcagggttt cgtgcaggat ataaacattt 110

<210> SEQ ID NO: 149

<211> LENGTH: 800

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 149

tgcctgagcg cagagcggct gctgctgctg tgatccagga ccagggcgca ccggctcagc 60

ctctcacttg tcagaggccg gggaagagaa gcaaagcgca acggtgtggt ccaagccggg 120

gcttctgctt cgcctctagg acatacacgg gaccccctaa cttcagtccc ccaaacgcgc 180

accctcgaag tcttgaactc cagccccgca catccacgcg cggcacaggc gcggcaggcg 240

gcaggtcccg gccgaaggcg atgcgcgcag ggggtcgggc agctgggctc gggcggcggg 300

agtagggccc ggcagggagg cagggaggct gcagagtcag agtcgcgggc tgcgccctgg 360

gcagaggccg ccctcgctcc acgcaacacc tgctgctgcc accgcgccgc gatgagccgc 420

gtggtctcgc tgctgctggg cgccgcgctg ctctgcggcc acggagcctt ctgccgccgc 480

gtggtcagcg gtgagtcagg ggccgtctcc ccgaagaacg agcggggaga ggggaccacg 540

gggcgcggcg ggcagcctgt tctcgggcgg aggctctccg gggcgttgga aacctgcatg 600

gtgtaaggac ccgggaggag gcggggagaa attgattgtg ctgttctcct ccctctcttc 660

tctaacacac acgcagaaaa gtttaaattt ttgtgaagcg cttgcttacg tagctgcgga 720

gcgagcctct gcttcattac gagcggcata gcctttttca ggagtgattt ccactttctt 780

tgtgagagag ttgaccacac 800

<210> SEQ ID NO: 150

<211> LENGTH: 600

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 150

ttcaatttac actcgcacac gcgggtacgt gggtgttcgg ggtagggcac tgatctgggg 60

aaggtctccc ccccgcgacc caactcatct ttgcacattt gcagtcctcc ctcggtgcac 120

tcctggcggg gatctggcca gtgcagcgca ctgggaccga gggcagagcc cgcggagtga 180

ggccaggaga gacttcaggc ctctaaggac acagctgagg ctaaggctga gttgaacgca 240

gcccctcccg cggctcgtcc cctctccagt gtctctcccg taaggtgccg ctcccaacag 300

caatgggtcg agatgtagag gaaacactct gtacgttatt tttccgccca ccctttagcg 360

cctgaggaga cagacagtgt agactttagg gtacaattgc ttcccctctg tcgcggcggg 420

gtggggagcg tgggaagggg acagccgcgc aaggggccag cctgctccag gtttgagcga 480

gagagggaga aggaggtcca cggagagaca agaatctccc tcctcccacg cccaaaagga 540

ataagctgcg gggcacaccg cccgcctcca gatcccccat tcacgttgag ccggggcgcg 600

<210> SEQ ID NO: 151

<211> LENGTH: 1400

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 151

gcctgaagac catttcttcc tctcttaggg acctgctggt ctccagctga ttcggtccag 60

gaggaaaaac ctcccacttg ctcctctcgg gctccctgca aggagagagt agagacactc 120

ctgccaccca gttgcaagaa gtcgccactt ccccctccag ccgactgaaa gttcgggcga 180

cgtctgggcc gtcatttgaa ggcgtttcct tttctttaag aacaaaggtt ggagcccaag 240

ccttgcggcg cggtgcagga aagtacacgg cgtgtgttga gagaaaaaaa atacacacac 300

gcaatgaccc acgagaaagg gaaaggggaa aacaccaact acccgggcgc tgggcttttt 360

cgacttttcc tttaaaaaga aaaaagtttt tcaagctgta ggttccaaga acaggcagga 420

ggggggagaa gggggggggg gttgcagaaa aggcgcctgg tcggttatga gtcacaagtg 480

agttataaaa gggtcgcacg ttcgcaggcg cgggcttcct gtgcgcggcc gagcccgggc 540

ccagcgccgc ctgcagcctc gggaagggag cggatagcgg agccccgagc cgcccgcaga 600

gcaagcgcgg ggaaccaagg agacgctcct ggcactgcag gtacgccgac ttcagtctcg 660

cgctcccgcc cgcctttcct ctcttgaacg tggcagggac gccgggggac ttcggtgcga 720

gggtcaccgc cgggttaact ggcgaggcaa ggcgggggca gcgcgcacgt ggccgtggag 780

cccggcctgg tcccgcgcgc gcctgcgggt gccccctggg gactcagtgg tgtcgcctcg 840

cccgggacca gagattgcgc tggatggatt cccgcgggca gaggcagggg gaaggagggg 900

tgttcgaaac ctaatacttg agcttctttg caaagtttcc ttggatggtt ggggacgtac 960

ctgtataatg gccctggacc agcttccctg ttggagtggc cagagaagtg tgtaaaacac 1020

actagagggg cagggtggaa aaagagactg ccttcaaaac ttgtatcttt tcgatttcat 1080

tttgaaaaat aactacaaat ctattttaat tttacaaagt tagactcata gcattttaga 1140

tatcaatgtc ttcatttaac agaagtgaag atggagcaaa cgctcaatca gcgtctgtat 1200

ttattcgctc ctgttgtgcc agggtgcgtt tttgccgagc ggttgccttt ctttactcac 1260

aaaaccccct tgatgtctgt cctccacgtt ttacgaggga gagccggatc ttttgaagtt 1320

tgtatcatct aaagcaggta tattgggatg actatggata gaatttaacc tgaaaacact 1380

gaagttgaca gctgacaaag 1400

<210> SEQ ID NO: 152

<211> LENGTH: 250

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 152

tgcttcaacc ggaaatgtgg ttgaattacc cttacagtga acctgatcag tggtaacagg 60

agatgctaga acaggaaaag acaagtttcc cctttcctcc ctatcccatc aattactttg 120

aggtgtattt tttctttgca acccctccag agaagtcggc aatgtttaac gagcatgcct 180

gccaagtggc ttgccttata cctcattatg aagtgatact cagggccact aacacatcgc 240

acagcattgc 250

<210> SEQ ID NO: 153

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 153

tatgattccc tcgatttccc tcaatcttaa ccattgtgga tcacagcagg agggccagaa 60

agtgagcttc agcctggcac cgggacctca gcctctccct taaactttcc ctaatcctcg 120

gagctagtgt tactcaagtg actccacagt gttgcccgat cccttcagac atggccttga 180

tgatctccaa aactcatgct acctttgcca gcctaaagca tccactctgt gccccaaaac 240

gtgaatgtca aatacccttc aaggcagaag gctatttcta tttttgtttg tttctgttta 300

aggcaacaat caccaacatt tggtacacat gagccatcct gtgaaacatc aaggcgcttc 360

gttggcagca agtcaacttc ggtttcagaa gaaagctgca ctatttcctg aggttagagg 420

tttaaaccaa aacaagacaa ccacatttta accccaaatc tgccgactga gggtaaccat 480

gatccttcct tcacagcacc 500

<210> SEQ ID NO: 154

<211> LENGTH: 150

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 154

tactaaatca acccaaaccc gagaacccgg tcatggagaa ataaatgata gtaatctatg 60

ctgttcatct gttccatcac tcactcactc tcttgctgaa caagaaaggg ccacccatgt 120

agcaaaccac atgtaaagag ccgggaagac 150

<210> SEQ ID NO: 155

<211> LENGTH: 300

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 155

tattattttg ttcaaagtag acgggtatac taacatctgt gggcaagttt accacacgcc 60

acttaaaaca ggctaacagg gtcatatgcc aaaacgttca ggtttgcatt tttgaaaagc 120

tcagagatct gacagatgtg ttccggccgc gatttaacat gcggctccag tgagaaggaa 180

gcagatatga caaatggttc acttatttca gaactaaaac cccagaggag cagcctgagc 240

caaaaaggga agtgatcaat ggaaaagacg gtcgaatctg ctcacaggca aggcaagggg 300

<210> SEQ ID NO: 156

<211> LENGTH: 400

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 156

gcaggggtga ctggtcctct ctctctgcac ctcgcaggat ttctctggaa gatctgagcc 60

cgagcgtcgt gctgcacatg accgagaagc tgggttacaa gaacagcgac gtgatcaaca 120

ctgtgctctc caaccgcgcc tgccacatcc tggccatcta cttcctctta aacaagaaac 180

tggagcgcta tttgtcaggg gtaagtgcga ccctagaggc gatcgtctct gctgtctgtg 240

gaaaaaagag ctcctacacc caaagtgctt ctcagttgct gacacttgat ccaagctgct 300

aatttaatct aatgtgaggc tgagttttct gaatgtggga taaagtcgta gctaaacctg 360

cttctcaggg agtgcctttt atctgcaatg tttttcaaat 400

<210> SEQ ID NO: 157

<211> LENGTH: 10000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 157

gtctttcccg cccccttgtc taaactcaaa accgagtccg ggcgcgcctt gcagggcgcc 60

cgagctctgc agcggcgttg cgggctgaac ccatccggca caaactgcgg gccactggcc 120

cctcacacct gggagtttgc ggcgctggcc tgcagcccgg ggcccacgtg gcggaagctt 180

tcccgggcgc gcgctgcgca gccccgcggg gccggggaga caccgctcgg gagtcctccg 240

ctcggctgca gaatctttat cagctgcact ttaccgcagc cctggctagg acgctaggcg 300

gtggagcgcc ctatccaggt gcgccgccgc accatggatc accgcgcccg gtcccgcagt 360

cccgccatgg cctggggagg cccgaagccc ggggacagtg gccggcccat ctccggctcc 420

gcggaccccc ggctcaggcg ggagggcagg cgggtccctg caggccccca gggagcccgg 480

gagcctctct ctggcgtcat tcagtcccgg ggcaacctga agcgcggtag atattggaga 540

gggggcgtct gttgggggga cctggcgtca ttactgatgg ctagcaggga ggagggaacg 600

ggttgtcacc tcggcctcat aaggccgtga gtgagtagtc cagggcctct tcaggcattt 660

ttgaaactgg attaactagg ggggaaattg tagcactgaa gccaccgtga ctgtcttttg 720

cgctgtgtgg aaactccggt aaaactcttt gggcaacagt cttatcacca gctcttcaac 780

gtgtgcagcc cttctggtcc tgtccctgtt ctgggcccca ggaatgcaaa gcaggtccag 840

gcactgtgaa gaccctggcg gtggaggaag aggcttcccg gctgtggagg aagccagacc 900

cttacaacac aagacgagaa ccagacctgc gtgggggagc tctggatgct acaggggctc 960

aaggaggggt ggaggggcct tcccaggcca acccctgaac ggcttggaca agatgctcag 1020

atggacggga ggaacggcgt gtgggatggg ggagctggag gcgggtgggt ggggggggga 1080

ggatggggaa agcgctggcc cacccagtgt gggaggggta gaggaaaagc ccgcaggggc 1140

caggttggga ccccgtaggc cgggttagag ggcttggact tgatcctgac aggcgacagg 1200

gagacatatt gctacttatt atgtgcacag tggccagatc tctaaagaaa acaccatccc 1260

ccacccccac cccccatata gtaaaccagg tggtccgccc agtgctccca gggaggtgat 1320

gggaaatccc actccatacc ctgcggtgag gggttccatg ccctccacgt gtgcaactac 1380

tccgggccca gggaaacact gggccccatc cggtaacccc cggcccagtc gggtttccca 1440

gttcacatta taaccaaacg gtcttgccag ctagacagac agacacccct gacctgttta 1500

ccctgatcct ctgctctcag gattaatcac aacttgtcga agggggtggc ttccagtggg 1560

gtggaccgct ctgtcaatgc cagcgtgtgt ctagcatctc ctggggtggg ggtgtgggga 1620

agggaggtgt aggatgaagc cctagaagcc tcaggcaatt gtgatccggt gggctggata 1680

ctgaagccca cccctgcctt gacctcaatt ttcagtatct tcatctgtaa aatgggaaca 1740

acctgccttc ctcctagccc taaaggggct gctgtcaaga ttggctgaga tagctgtttg 1800

caagctgagc tcaatgaaag ttcattgtgt ccccctcagt cctatcccaa tatcgtctca 1860

ctgcaaaggt ggggggcagc ttaacttcaa gggcacttca aggatagcca ggtggctgtc 1920

agcccagctt tccaggatgg gagcaggatc ttgacagaag ggttgactgg gaggggcagt 1980

tgctggtttg ggcttcgtta ggttgcattt ttgtttgttg tcctttcatt tccctggggc 2040

agcacccctt cctgcaagct ccaggccttc ctctggaatg ctcctagagc ccaacctctg 2100

ctggtgcctg agcttaagcc aggccagcta aggggatcct ggattcacac ggcctcacag 2160

tcactcagat tgttagcaga agacaaaaat tacaagggga gggcgtcatg tgattcttac 2220

acaccctcca aatccagcag acaccttgga agccacaggt agcttcaaga aacccatttt 2280

acggatgaga acctgagatg gagaaaggac aactggagat ctctgagtct ctgagcccac 2340

actccctacc tccctgcacc tccaggcact ctgctggcag gatcttgggc aaatgcccac 2400

agctctctga gagtcagttt tcctgtctgt aaaatgggag tcataccttc ctcctatggc 2460

cggtgagaga ctaaattaaa ctatgtctgt caagacacct gaaactcctg gcacaattta 2520

ggttgccttc aagtggtcac agttgtcatt aggtggaagt caacacccca atcattgtaa 2580

aggtgcccat ataccccaag atccagatta cagctctcac agtttattat atacagcgaa 2640

aaaacacata acacaccttt gcccacattt acatgtattt tacggaccat gtttcacatc 2700

agtccgcatg cacatctgca cgtgtgtgca ttcggcagta tttaccaagc acctgccaag 2760

tgccagggcc tgtcctccgc acccggcgtg aactgtcctg gaccagtccc gggagccgcg 2820

gttctgacca gccgtgctga ccctggacga ctccatgagc tgttttgtga gaaagacacg 2880

ccatttgttt gcagagttct gacttctgag gggtcatgta gcacatgttt ggtagccaaa 2940

cgctgtcatt cacgaccagg agcgatggct gcaatgcctt tttctttgct ttgctttccg 3000

gtgccgggag ccttgcctcc cgccgccacc cctggtcagc tctgcgcaag aacgtcgttc 3060

tgtttggcag ccaggccgag acgcagcctg aatgtgagca ggaactcgga gaagggaagg 3120

gagagaatca gaaagaaggc ccgggaggga cccgggaagc agtgggaggt ctgcgccctg 3180

gagccccgcg agagcccgcc ggtttggcac gggctcctcc cgggccgccc ggcggtccaa 3240

caaaggccgg ccccgacacg cacccggtct tttgtgggag agaaacacaa agaagaggga 3300

aaaacacgga ggaggccaac agcaccagga cgcgggggcc aaccaggaac tcccggagcc 3360

ggggcccatt agcctctgca aatgagcact ccattcccca ggaaggggcc ccagctgcgc 3420

gcgctggtgg gaaccgcagt gcctgggacc cgcccaggtc gcccaccccg ggcgccgggc 3480

gcaggacccg gacaagtcct ggggacgcct ccaggacgca ccagggcaag cttgggcacc 3540

gggatctaat ttctagttat tcctgggacg gggtggggag gcataggaga cacaccgaga 3600

ggtactcagc atccgattgg caccagggcc aagggagccc aggggcgaca cagacctccc 3660

cgacctccca agctactccg gcgacgggag gatgttgagg gaagcctgcc aggtgaagaa 3720

ggggccagca gcagcacaga gcttccgact ttgccttcca ggctctagac tcgcgccatg 3780

ccaagacggg cccctcgact ttcacccctg actcccaact ccagccactg gaccgagcgc 3840

gcaaagaacc tgagaccgct tgctctcacc gccgcaagtc ggtcgcagga cagacaccag 3900

tgggcagcaa caaaaaaaga aaccgggttc cgggacacgt gccggcggct ggactaacct 3960

cagcggctgc aaccaaggag cgcgcacgtt gcgcctgctg gtgtttatta gctacactgg 4020

caggcgcaca actccgcgcc ccgactggtg gccccacagc gcgcaccaca catggcctcg 4080

ctgctgttgg cggggtaggc ccgaaggagg catctacaaa tgcccgagcc ctttctgatc 4140

cccacccccc cgctccctgc gtcgtccgag tgacagattc tactaattga acggttatgg 4200

gtcatccttg taaccgttgg acgacataac accacgcttc agttcttcat gttttaaata 4260

catatttaac ggatggctgc agagccagct gggaaacacg cggattgaaa aataatgctc 4320

cagaaggcac gagactgggg cgaaggcgag agcgggctgg gcttctagcg gagaccgcag 4380

agggagacat atctcagaac taggggcaat aacgtgggtt tctctttgta tttgtttatt 4440

ttgtaacttt gctacttgaa gaccaattat ttactatgct aatttgtttg cttgttttta 4500

aaaccgtact tgcacagtaa aagttcccca acaacggaag taacccgacg ttcctcacac 4560

tccctaggag actgtgtgcg tgtgtgcccg cgcgtgcgct cacagtgtca agtgctagca 4620

tccgagatct gcagaaacaa atgtctgaat tcgaaatgta tgggtgtgag aaattcagct 4680

cggggaagag attagggact gggggagaca ggtggctgcc tgtactataa ggaaccgcca 4740

acgccagcat ctgtagtcca agcagggctg ctctgtaaag gcttagcaat tttttctgta 4800

ggcttgctgc acacggtctc tggcttttcc catctgtaaa atgggtgaat gcatccgtac 4860

ctcagctacc tccgtgaggt gcttctccag ttcgggctta attcctcatc gtcaagagtt 4920

ttcaggtttc agagccagcc tgcaatcggt aaaacatgtc ccaacgcggt cgcgagtggt 4980

tccatctcgc tgtctggccc acagcgtgga gaagccttgc ccaggcctga aacttctctt 5040

tgcagttcca gaaagcaggc gactgggacg gaaggctctt tgctaacctt ttacagcgga 5100

gccctgcttg gactacagat gccagcgttg cccctgcccc aaggcgtgtg gtgatcacaa 5160

agacgacact gaaaatactt actatcatcc ggctcccctg ctaataaatg gaggggtgtt 5220

taactacagg cacgaccctg cccttgtgct agcgcggtta ccgtgcggaa ataactcgtc 5280

cctgtaccca caccatcctc aacctaaagg agagttgtga attctttcaa aacactcttc 5340

tggagtccgt cccctccctc cttgcccgcc ctctacccct caagtccctg cccccagctg 5400

ggggcgctac cggctgccgt cggagctgca gccacggcca tctcctagac gcgcgagtag 5460

agcaccaaga tagtggggac tttgtgcctg ggcatcgttt acatttgggg cgccaaatgc 5520

ccacgtgttg atgaaaccag tgagatggga acaggcggcg ggaaaccaga cagaggaaga 5580

gctagggagg agaccccagc cccggatcct gggtcgccag ggttttccgc gcgcatccca 5640

aaaggtgcgg ctgcgtgggg catcaggtta gtttgttaga ctctgcagag tctccaaacc 5700

atcccatccc ccaacctgac tctgtggtgg ccgtattttt tacagaaatt tgaccacgtt 5760

ccctttctcc cttggtccca agcgcgctca gccctccctc catccccctt gagccgccct 5820

tctcctcccc ctcgcctcct cgggtccctc ctccagtccc tccccaagaa tctcccggcc 5880

acgggcgccc attggttgtg cgcagggagg aggcgtgtgc ccggcctggc gagtttcatt 5940

gagcggaatt agcccggatg acatcagctt cccagccccc cggcgggccc agctcattgg 6000

cgaggcagcc cctccaggac acgcacattg ttccccgccc ccgcccccgc caccgctgcc 6060

gccgtcgccg ctgccaccgg gctataaaaa ccggccgagc ccctaaaggt gcggatgctt 6120

attatagatc gacgcgacac cagcgcccgg tgccaggttc tcccctgagg cttttcggag 6180

cgagctcctc aaatcgcatc cagagtaagt gtccccgccc cacagcagcc gcagcctaga 6240

tcccagggac agactctcct caactcggct gtgacccaga atgctccgat acagggggtc 6300

tggatcccta ctctgcgggc catttctcca gagcgacttt gctcttctgt cctccccaca 6360

ctcaccgctg catctccctc accaaaagcg agaagtcgga gcgacaacag ctctttctgc 6420

ccaagcccca gtcagctggt gagctccccg tggtctccag atgcagcaca tggactctgg 6480

gccccgcgcc ggctctgggt gcatgtgcgt gtgcgtgtgt ttgctgcgtg gtgtcgatgg 6540

agataaggtg gatccgtttg aggaaccaaa tcattagttc tctatctaga tctccattct 6600

ccccaaagaa aggccctcac ttcccactcg tttattccag cccgggggct cagttttccc 6660

acacctaact gaaagcccga agcctctaga atgccacccg caccccgagg gtcaccaacg 6720

ctccctgaaa taacctgttg catgagagca gaggggagat agagagagct taattatagg 6780

tacccgcgtg cagctaaaag gagggccaga gatagtagcg agggggacga ggagccacgg 6840

gccacctgtg ccgggacccc gcgctgtggt actgcggtgc aggcgggagc agcttttctg 6900

tctctcactg actcactctc tctctctctc cctctctctc tctctcattc tctctctttt 6960

ctcctcctct cctggaagtt ttcgggtccg agggaaggag gaccctgcga aagctgcgac 7020

gactatcttc ccctggggcc atggactcgg acgccagcct ggtgtccagc cgcccgtcgt 7080

cgccagagcc cgatgacctt tttctgccgg cccggagtaa gggcagcagc ggcagcgcct 7140

tcactggggg caccgtgtcc tcgtccaccc cgagtgactg cccgccggag ctgagcgccg 7200

agctgcgcgg cgctatgggc tctgcgggcg cgcatcctgg ggacaagcta ggaggcagtg 7260

gcttcaagtc atcctcgtcc agcacctcgt cgtctacgtc gtcggcggct gcgtcgtcca 7320

ccaagaagga caagaagcaa atgacagagc cggagctgca gcagctgcgt ctcaagatca 7380

acagccgcga gcgcaagcgc atgcacgacc tcaacatcgc catggatggc ctccgcgagg 7440

tcatgccgta cgcacacggc ccttcggtgc gcaagctttc caagatcgcc acgctgctgc 7500

tggcgcgcaa ctacatcctc atgctcacca actcgctgga ggagatgaag cgactggtga 7560

gcgagatcta cgggggccac cacgctggct tccacccgtc ggcctgcggc ggcctggcgc 7620

actccgcgcc cctgcccgcc gccaccgcgc acccggcagc agcagcgcac gccgcacatc 7680

accccgcggt gcaccacccc atcctgccgc ccgccgccgc agcggctgct gccgccgctg 7740

cagccgcggc tgtgtccagc gcctctctgc ccggatccgg gctgccgtcg gtcggctcca 7800

tccgtccacc gcacggccta ctcaagtctc cgtctgctgc cgcggccgcc ccgctggggg 7860

gcgggggcgg cggcagtggg gcgagcgggg gcttccagca ctggggcggc atgccctgcc 7920

cctgcagcat gtgccaggtg ccgccgccgc accaccacgt gtcggctatg ggcgccggca 7980

gcctgccgcg cctcacctcc gacgccaagt gagccgactg gcgccggcgc gttctggcga 8040

caggggagcc aggggccgcg gggaagcgag gactggcctg cgctgggctc gggagctctg 8100

tcgcgaggag gggcgcagga ccatggactg ggggtggggc atggtgggga ttccagcatc 8160

tgcgaaccca agcaatgggg gcgcccacag agcagtgggg agtgagggga tgttctctcc 8220

gggacctgat cgagcgctgt ctggctttaa cctgagctgg tccagtagac atcgttttat 8280

gaaaaggtac cgctgtgtgc attcctcact agaactcatc cgacccccga cccccacctc 8340

cgggaaaaga ttctaaaaac ttctttccct gagagcgtgg cctgacttgc agactcggct 8400

tgggcagcac ttcggggggg gagggggtgt tatgggaggg ggacacattg gggccttgct 8460

cctcttcctc ctttcttggc gggtgggaga ctccgggtag ccgcactgca gaagcaacag 8520

cccgaccgcg ccctccaggg tcgtccctgg cccaaggcca ggggccacaa gttagttgga 8580

agccggcgtt cggtatcaga agcgctgatg gtcatatcca atctcaatat ctgggtcaat 8640

ccacaccctc ttagaactgt ggccgttcct ccctgtctct cgttgatttg ggagaatatg 8700

gttttctaat aaatctgtgg atgttccttc ttcaacagta tgagcaagtt tatagacatt 8760

cagagtagaa ccacttgtgg attggaataa cccaaaactg ccgatttcag gggcgggtgc 8820

attgtagtta ttattttaaa atagaaacta ccccaccgac tcatctttcc ttctctaagc 8880

acaaagtgat ttggttattt tggtacctga gaacgtaaca gaattaaaag gcagttgctg 8940

tggaaacagt ttgggttatt tgggggttct gttggctttt taaaattttc ttttttggat 9000

gtgtaaattt atcaatgatg aggtaagtgc gcaatgctaa gctgtttgct cacgtgactg 9060

ccagccccat cggagtctaa gccggctttc ctctattttg gtttattttt gccacgttta 9120

acacaaatgg taaactcctc cacgtgcttc ctgcgttccg tgcaagccgc ctcggcgctg 9180

cctgcgttgc aaactgggct ttgtagcgtc tgccgtgtaa cacccttcct ctgatcgcac 9240

cgcccctcgc agagagtgta tcatctgttt tatttttgta aaaacaaagt gctaaataat 9300

atttattact tgtttggttg caaaaacgga ataaatgact gagtgttgag attttaaata 9360

aaatttaaag taaagtcggg ggatttccat ccgtgtgcca ccccgaaaag gggttcagga 9420

cgcgatacct tgggaccgga tttggggatc gttcccccag tttggcacta gagacacaca 9480

tgcattatct ttcaaacatg ttccgggcaa atcctccggg tctttttcac aacttgcttg 9540

tccttatttt tattttctga cgcctaaccc ggaactgcct ttctcttcag ttgagtattg 9600

agctccttta taagcagaca tttccttccc ggagcatcgg actttgggac ttgcagggtg 9660

agggctgcgc ctttggctgg gggtctgggc tctcaggagt cctctactgc tcgattttta 9720

gatttttatt tcctttctgc tcagaggcgg tctcccgtca ccaccttccc cctgcgggtt 9780

tccttggctt cagctgcgga cctggattct gcggagccgt agcgttccca gcaaagcgct 9840

tggggagtgc ttggtgcaga atctactaac ccttccattc cttttcagcc atctccacta 9900

ccctccccca gcggccaccc ccgccttgag ctgcaaagga tcaggtgctc cgcacctctg 9960

gaggagcact ggcagcgctt tggcctctgt gctctttcct 10000

<210> SEQ ID NO: 158

<211> LENGTH: 100

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 158

tttttaatgc tcagagaagt tcgtattact gattcgggaa cactgagttt ttcagctcct 60

gtaaaactat tttcaggttt attttcaagt acattcttta 100

<210> SEQ ID NO: 159

<211> LENGTH: 400

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 159

caccctagag gcaaggacgg ggtctgtgtc aagaggcttc ccagagaagt gaaaactctg 60

caggtgcagc cgctgggaga gcatcaagaa gggcagggtg gaggggcagg gggcgaaggg 120

agggggtgaa gcccgcaccc tacccccaca tgaaactgat tccactaccc catctctgca 180

agcgtccaga ggcagagagg ccaacatttc ggggacagct tggaggcggg agatttaggc 240

agggctcctt aaacttttat gtgcatgaaa atcaggccaa tcacggggct cttgagcaaa 300

tggggacgat gattcagcag gtctgggctg aggcctcaga ttctgcactt ctaacaagtt 360

cccaggtggt agtgatgctg ccagtccaaa gaccacactg 400

<210> SEQ ID NO: 160

<211> LENGTH: 5000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 160

tgcttcagtg gggtaaactt gaaccgctga gaagacaagc agggagtcgg tctcgctgag 60

atttttacct gtggttctag gaacgcagag gcatgtgagt gttcaggctt tgcatagacc 120

actaagccac ttctaagaac aaggctacct gagccatttt gcaaaaatat gtacgtgccg 180

aggcttttcc tccccacacc tacctcaact ctttctgccg acacactgca cttttcaagg 240

gaacccaagt ttgggttcgg caagaattgt acgttgcaca ccgtgtgtga taattccagg 300

gaatttcaat cgcatcttgt cttccttcct aagcaaattc ggtgggaacc tggtgtggtg 360

tgatagaaaa agccccgagt tctctgtggt agaccacatc aatttcatgt gccagtctct 420

cagactccgg cttgcctctc tcaaggaagg gaacaatggt ttgcttggct tcactcctct 480

ctttcccccc aatttccaca tgggtatctg gctaaaaatg agttacaggt ttccttctgt 540

gagaattgca tggactgata aagtaccatc ccaggaagaa aacaaagatg ctgtcttccc 600

tttcggctca cagttgccgt tggggaggga acacacgctg taaattatag gcagccagaa 660

gtgaccgcat tgaccactgc gagtggccca gctatggcaa caggctgaga actctggggg 720

agagccattt gttggcaggg atggtgattc ttctagcatc aagctctaag atgatgacca 780

aacggtatca aaagaaatga tattttgcta cctctccggc ttgggtgaat gatgtggaca 840

gttaacctgg acaatttaaa cctttatgtt gatggatcac ttggatgaaa ttaaccagga 900

aattgccaag atttcacttg gccctctgac atcaaatctc aatattatat taccaaatta 960

gagattctaa agaaccctga gttcctttca ctgaaaggaa ggagtggaaa aacctttcca 1020

gatgatccct tttgagtctt ggtgcgagct caggccctcc ctacactgcc tccgtgaaag 1080

ctaaccgacc cttgttccta acctagcgca ggtcagctga gtgtccatcg ggcacaggag 1140

ccctgggctt gtccgggaga tagccagact cctgctattt cctgatgtct gcatagctca 1200

gcgtgtccct caccatcttt gccgttggcc agtaaggaga gccccagggg ccagcactgc 1260

acactgaaac ccaacctatt gctcaatgga atgcttaaaa atttcctgaa tctgccttcc 1320

tgagttgata aaataggaaa caatacacgt tctgaggggg tactgaaagc agagtaaagc 1380

caggaagatc ttttttttct gttattctat acaaatattg cttcctctgc ttgttagcag 1440

cccagaggaa atgcagccag ggagccgttt gcagcttttc accagtggcc ggtgtctctg 1500

tgttaccaac caaacgacgc tgcaagacta gtgactaacg cacgtctgca tgattcaact 1560

tcactaaaat tccctctgct gccagtaaag aagcacttga aaactcttta atttgaaact 1620

tgagcttggt taatgacttg ttttcttctc tttctcttta acttctctct tgccatctcc 1680

aacacacaca cacacacaca cacacacaca cacacacaca cacacacact ctctctctct 1740

ctctctctct ctctctctct ctctcatcaa gttttttaat ttcagggacc cggaaacata 1800

cagccccgtg cattcacaat agcatttgct gtgataaagt ggccggcaag ccctctgcat 1860

tcccctgctc acttagctgt atgaataaat aatgagtcac agatacaatt tgggtgctca 1920

agagagtttg tagccagaaa attaattatt ctcccatccc agcccactcc atctcagctt 1980

tgccaaacca tcaagataca ctttgcaggc actggtcaga gtgcgtgccc cgacgcacac 2040

ggcaatgcct ttgagacatt ttatgttatt atttttgttt gtttaagcac agccctcttt 2100

taccacgaaa gatacacaag acgcacatgc acacacatac tcacacactc acagctcaac 2160

cacagctttg tccatttcaa gaggctggtt tcaaaaatgg agacaggttt tccaccctgg 2220

ctgttcctat tcataagcct gtaatctaac gacttaagct gcgagaatgc ttaactcggg 2280

aaacttctct attgcccttt tccagagaga cctcggtatg ccacaatttg cttcctttct 2340

ctcttgaaag atgctggttg tctctttgca ttgaggctac aaggaaaaac acagcacagc 2400

cccatgctga tgattttaac ctaaccaagt ctgtcagtct cctgtactct ctgccttata 2460

gagacagctg ccttgccact ttggccctga agtccccagg ctggtgcaag gctatctgag 2520

agcctccgcc tcctgcccca cactggcacc agccctcctg gctggctctg tgcatgtgcc 2580

tgctaagccc cagggcaggc tgcattctgg gccacacagc atgccgagtt aaggataact 2640

cagacacagg cattccgggc aagggacagc aaaataaaac ccagggagct tcgtgcaagc 2700

ttcataatct ctaagccttt aaacaagacc agcacaactt actcgcactt gacaaagttc 2760

tcacgcaccg actgaacact ccaacagcat aactaagtat ttattaaaac atttctgaag 2820

agcttccatc tgattagtaa gtaatccaat agacttgtaa tcatatgcct cagtttgaat 2880

tcctctcaca aacaagacag ggaactggca ggcaccgagg catctctgca ccgaggtgaa 2940

acaagctgcc atttcattac aggcaaagct gagcaaaagt agatattaca agaccagcat 3000

gtactcacct ctcatgaagc actgtgggta cgaaggaaat gactcaaata tgctgtctga 3060

agccatcgct tcctcctgaa aatgcaccct cttctgaagg cgggggactc aatgatttct 3120

tttaccttcg gagcgaaaac caagacaggt cactgtttca gcctcacccc tctagcccta 3180

catctctctt tcttctcccc tctgctggat acctctggga ctccccaagc cctattaaaa 3240

aatgcacctt tgtaaaaaca aatattcaaa ttgttaaaga ttaaaaaaaa aaaaaaagcc 3300

agcgccgcct tggctgtggg ttggtgatgc tcaccacgct gcgaaaccct gtggtttgca 3360

ttcagtgtga ttcgtcctgc ctgctgacca ctatgctggg ttcagacttc tgacactgcc 3420

aggctaccca acttgtggtt ctgtggttgt ttatgaggcc caaagaagtt ttcacacaac 3480

ccaaattaca aatttaactg ttcccctttc cacagcccat ctcaattggt tcttgccaat 3540

catgtgactt aagtgatgtc aatttttttt tttcttttct gagcaatgcc cttccttccc 3600

tccacctgcc ctcccccagg ctgtgcaaga aaatagccga gtagactttg caagaggggg 3660

ggatgtagaa aaaagtgact cagtcactta ttatatctca atggtctttg ctgatttagt 3720

acaactcggc tcctgttgtt atttgtggtt tttggaacta ctgattattt tgataaagat 3780

ttcattgctg cttattcaat agtaattcaa cgctggcatc aagccgctgc tccgacagga 3840

tgtggatccc atcatttaaa atgctaggca tcagctccgg gagagttaag tccttggtaa 3900

cgtctatcat ggcataagtg aaactataaa agggaaaaat aaataaaaag aaatgttttg 3960

gtgagagtct gacccctaca acgggctggc aactcacagg tattttaaag cctgggaaag 4020

ggaaagaatt ttacttttga aataaaagga ctgttttaat gaaaccaaaa ttatgtggtt 4080

ttattccccc taaatggaca actttagtat gtatctcttt cagtaaagag ataaaatcat 4140

agtacagtct taacacacac acacacacac acacacacac acacacacac acaaattagg 4200

aagctaaagg aaaacaaagc agagagaatt tctgtatttg ggacaaagca gtggttactc 4260

tgcagatgtt tatttgtatt gtcacttggg aaagctccct gtattgcctt tctctagttc 4320

aattcaaatc aataggctaa tttacacctg taggtaaaac tacactttga gcacatgagg 4380

atgccacaat agaaggggaa ccaggaggag acacttctcc tggggctgac taatgaatat 4440

tatatagcgc gtcctctacc ttagaaagac atgcctgttt gaagatgcta aaaacaggat 4500

aattttgtaa gtgggcaaac cactgtggtc acacgtattt cattttccgg ccccactggc 4560

tttacctgct gacaactaaa acgtcatttt gttttgtagt tccaagatga agaaaggctt 4620

attttcctga tttactacct tattcatttg gctctgctct gcctacatcc gccatagcac 4680

tctgcgcacg tgaaatttcg acacataggg tcaagagaac ctgtgtgatg atgggttgta 4740

aatgccagtc ctggattcta agctgcagta gccagcacag gcacttcaga aaggctgaac 4800

tcccacaaca ctccctcggt tttccctcat ccacttaatt tcacacacac aaagacccac 4860

aacgatagta gcttccatgg cacaagtctt tcaaaaggaa cagacacaat ttttacttac 4920

tcctgttttg actaaagcag gaattgaaac tcaacagacc gctttctctt acacttgtga 4980

gaagttagct ggccacatgt 5000

<210> SEQ ID NO: 161

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 161

agggaaaaga gataacgaaa gaaagaaaga aaaaaaaaag ggccggcaat ttcatgtaca 60

tttgttttgg cattcgctga attctagaga tgaaaacaat ctcctgcttt taattcagtc 120

cacgtgcaac aaagttgtac gttgggagat ctggctttta ataagaacga ttaacaagcg 180

tttttgatca caggaagttg agaagagtcg ctgcttctaa gaatacaata aacattgact 240

agcagttaga cggtccatct ttctctatca gccgtttagc agcctctact ttgatttggg 300

gcaaatgcga gatgggacca ggagagagct ccccacaccc ccaccaccac gtgggcagtg 360

gttctgttcc agagcgcctt ccttcctgtc cagggaggca ggctgctgag gccgtttctg 420

ggcaagaggc cattgtcggg atatttgctt tagatagctt gcagctgggc tgagtgggtg 480

tttcattcag actcaacaca 500

<210> SEQ ID NO: 162

<211> LENGTH: 700

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 162

agcctggcgc acccgcccta atttgagtca gggaccctag gcgcctgcag ctccggttcg 60

ggttgagtgc ctcctgtcag gatgtgaagc tgctgtcccc cccgggggcc tccagcactg 120

ctgaggactc agcagtcagc ctctcctccc acttgggctc atttacagag agcatctcca 180

ggaatcagtc atggggaaag gggaaacgcg gagtgacaac acaacacgta gaaagttctc 240

tgccgccttg gtcaggcttg tcagcctcac agcccatcct gctcctgcgg gaggaaaagt 300

gagcagaact cagcccggag atgagccgca ggccggcagc ccctgcctct gccctgcttg 360

ttgtgactgc aatgcaaggc tctctgtagg tgcgggggat tcgggttaaa tgggtctcca 420

gtggtccagc gctcccagca aaggccgacc acaagaatta gcgggctagt tatttaccat 480

aaccatatac aaaaccacaa gcatcagcgt tccctcaaat acatccgaga cgctgtatat 540

ctctttatta aagcctgtca gggtttgtta ttgcacagct tggccttgaa ccccaactaa 600

accaggctgc ttgagcaaag aaccaagcaa tgcaagcatt caggcaggac cattataacc 660

ctgaggccaa aggcagaagc agggagagga gacgtcttcc 700

<210> SEQ ID NO: 163

<211> LENGTH: 500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 163

agaccagcct cggtcttcgg cctgcgggtt ctgcaaagtc aggctagctg gctctccgcc 60

tgctccgcac cccggcgagg ttccggtggg gaggggtagg gatggttcag ccccgccccg 120

ctagggcggg gcctgcgcct gcgcgctcag cggccgggcg tgtaacccac gggtgcgcgc 180

ccacgaccgc cagactcgag cagtctctgg aacacgctgc ggggctcccg ggcctgagcc 240

aggtctgttc tccacgcagg tgttccgcgc gccccgttca gccatgtcgt ccggcatcca 300

tgtagcgctg gtgactggag gcaacaaggg catcggcttg gccatcgtgc gcgacctgtg 360

ccggctgttc tcgggggacg tggtgctcac ggcgcgggac gtgacgcggg gccaggcggc 420

cgtacagcag ctgcaggcgg agggcctgag cccgcgcttc caccagctgg acatcgacga 480

tctgcagagc atccgcgccc 500

<210> SEQ ID NO: 164

<211> LENGTH: 17000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 164

cacgcgcccc ggcctggctg gaggggccaa cccagcgggg cccgcctgcc cgccggcctt 60

tctgtaactt tctctcttta aacttccaat gaatgaacgt gcctcttctt acggatttgt 120

ttagattagg gaatagattc ctcgctgata gcgttgcttt gcaaataaga cctcctatat 180

tattcaaacc aaacgagttt gtgtctttaa aggactatag cagccccatt ctatgttaag 240

ggttggctat tacaattatt atatgcttag ggaaaaaatg taagccccgt agtttgtgct 300

tttcttgatg tacagaaagg tttatcttag gtggataggt tttgttttgt ttcttaaatg 360

ggattttttt ggttcgtgtc tttgaagggc tgtttcgcga cgtcattaat gaactaatcg 420

gttttcagat ttcaagacgg tgtgtaattg atgtaaccac tgaggaattt cagtgcacac 480

cagactaaga ctcttccagc gcaggggatt ccagatgctt cttgggccct ctggaagcca 540

tggggatgtt tccagaccga aaggagggct ttgctgggga gcagatgtgc tgcctctccc 600

cgacccagga ttttgaggcc atgtttccgt taatctggac cgagagccct ctgggagagg 660

gaggcaggtc gtagggggcg ggggtgaggg ggagcgagat gaggtcgtcg ctggacgctg 720

ggctcccttg tcgttgtcct tttccccaga atccatggtc aggcctaggg agccacccct 780

gggtgctcga gatgagtccc caccctcact gaaggtcggt cactggatgt ttgtgtgcat 840

cgtaaggggc ccaccgaagt cccgaagcct tctcagggac cagcgagaaa gaggagcagg 900

cttgggagac agggaaggaa aatgcagggg aaagggctca cccctcgacc ccaggtaaaa 960

ttagaaggaa cgtgtggcaa cccaggtgca gctttggtcg ctcgctcaag gactttgcta 1020

gtcactacca ttaattaatt aatcactatc attaactacc aaggacaccg tttttattcc 1080

cctaaaagcg tcaccttgag gggaatggag aattgggcag cagctatgca aatcctggga 1140

caggagacac tgcctgagga ccctctctca ctcccaatcc cagaacccga agttatcccc 1200

gacaaccaag tccaagcaca tgaaccaaga cgatcagctt caggcagctc cttaccccca 1260

caagcggccc aggaggtggg cattatcccc cacccctggg atttctccat ccctccctct 1320

tctctcctgc gggagagaga gctgtggtca cccagttggg cgcgatggct ctggactaat 1380

ggggtctcta gacccagggc acaaaggcca atctgccagg ggttactgca tgtaatgaga 1440

taatcagaca tgttgaccaa cctaaaagaa aagactctcc cagggagtaa ctcccagtga 1500

aataatttat taaaaaaagc aaaaaagaga cataaatttc tctctactac ttgaggaaac 1560

agcaaacaga acgaattagg gtcttggcct ctgcaggaat aaattatttc cgacttggtc 1620

tggatacctg taattatttg taagctgtgg gtagtaatac tgtaattgtc ccccggtcct 1680

ttctggaagt agcaatgacc ccaaggacaa ttggtgacgt ctccacaggg tttacacatg 1740

gaaaggagtg aaaaatcgag gaattctttc agatagccca gaccaaaaat cctctcagcc 1800

atgaaaaggt catatatgtg atgctgggcc aagcggactt ttctggagta accatatcat 1860

aactgattgc ggatgtagac aagagcgtat aaaccaaata ggcttgaatc aacgcagtcc 1920

tggattttct gttgcctctg cttgctgggg cagtggaagt tcttaaactc cacttcagag 1980

gttggaaatt cttccccctc ccccacctcc ttagtgacaa ggtctctgat ctcctgctgc 2040

cactgcaata gcctctccca tcccgcgggg aacggccgga gttcttccct tgatctctcc 2100

cgagtcggct tccgctgggg atggatcgca ggtaggcgcc ggcgcggcct ggggaagaac 2160

agttgcggag catctgaagc ggaaaatcca agcagatgtg aggcgatccg ggcccgcctc 2220

gttcctcttg gggcctgaat ttcttccaga taagtttcct aatggaacat ttctaagagg 2280

tggggtacga ggcggcttgc tcgcacgcgc agtgggacag actgcgggtg gggacgtact 2340

gagaggtccg gacctcaatg cgtccgaccc gtctccacac cgcccttttc cagcccccag 2400

tctcctttca ttccctactc ttcaggctcc tttggggcca gtgggtgaac cgccatttag 2460

aacggtgcct cggactcggg ggtcgtgcgc tccatctctg cctcccccct ggggcccgcg 2520

aggctggtcc gggctttctg agctgggcgt tcggctttag gcccaatacc tggaccagga 2580

atttcttctc cccgcgccag aagggaaaga cataggaggt gtcccaatct gcggtcaccg 2640

ccgatgctcc tgaccactct agtgagcacc tgcccggtac ttttccattc caacagagct 2700

tccagcttca tactaactat cccacatacg gcctgtgggt attagctcta agtgtccttt 2760

tccgagggcc cgaggctccc cctccagcag ggagagctcc gggacggccc ccaccaaggg 2820

ttgggtttct tccttcacaa ttccacagag gcatccctgt ccttcctacc tgggaaacct 2880

cgaggtgcgg tgcccgtgta cttctggtac tttgcgtggt gccatcaggg accccagagc 2940

cacagctgcg tgtgtgtgtg gatgtgtgtg tgtgtgtgcg cgcgcgcgcg tgtacggcga 3000

aaggatgtgc ttgggggagc cgagtacaca acgtctgctt gggcagctgc tgggcaggcg 3060

ttgggcctgg aggtatctca cacccacgta tcttccagtc ttcaaacacg gcattgctct 3120

gcctcccgta gcgcgcttcg aacctgcctc gcggacacgt gaacagaggc tgtccctggg 3180

aagataagtg cgctttcccg taaaatccgg gaaatttgcc ttgaggaaag tttccgttct 3240

tgttacttgt cgggtttctc ccacttccac ttagccatgt ttctgcgatc tgggtaatcc 3300

ctttcaagcc caggaggaat tctcccgggt ccataattga gggtcggaag ccgtgggggt 3360

gagaaacgca ttaaatcctc ccgaagccca ggaggtgcca gagcgggctc agggggccgc 3420

ctgcggaagc tgcggcaggg gctgggtccg tagcctctaa ccccttggag ctccttctcc 3480

cagaggcccg gagccggcag ctgtcagcgc agccaggagc gggatcctgg gcgcggaggt 3540

gggtccgact cgccaggctt gggcattgga gacccgcgcc gctagcccat ggccctctgc 3600

tcaagccgct gcaacaggaa agcgctcctg gatccgaaac cccaaaggaa agcgctgtta 3660

ctctgtgcgt ccggctcgcg tggcgtcgcg gtttcggagc accaagcctg cgagccctgg 3720

ccacgatgtg gactccgcaa ggggctaggg acaggcaggg ggagagcccg ggtttgcgca 3780

caccttccag cccctggagg gagcctgctc ggcttcgaac gccttcgaac ttttgacctt 3840

caaaggagtc cctggaaaag gtcaggagcg cctgctgcag gcacggttgc cgaaggccag 3900

gccttcctgg cgcaggggag ggccagggga gggaagcgga tactcagtcg ctgtccgacg 3960

gcgagttttc ggagcagcag gctcatgatc ccgggccagt ggcgagagca gtgacaccga 4020

gaacccaaat ctccgcgccc ccatccgcgg cccggtgtcc tcccggcccc tgctgacctc 4080

caggtcacgc accccactgc tccacggctc tgcagcctgt ggcacacggc cgagagtccc 4140

cacatgatct cgacgccaag gtaaggaatt gccctgcgtc ctctgagcct gtctctggcc 4200

tggggggccg ggaaagctgc actcctggaa gaggtggggt tatgtgaccg ccgctgcagg 4260

ggtgcgcgga ggactcctgg gccgcacacc catttccagg ctgcgggagc cggacagggg 4320

agggcagagg ggggacaaaa ggactcttta ggtccaaaat gaccctgaag gagagtccag 4380

aatgcccagt ggccgcgtct gcaacggagt cttctttctc caattgcctt ctgccccatc 4440

accatgggcc ccacctgcgc cacctgcgcc caccctgtga ccctggctca gcgaccttgg 4500

cccttaatcg cccaacgccg attcctcaaa attccggctg cgctgaatcg ggctgctttt 4560

gccgccgccc cggcagttgg gccctgtttc cgccggcgcc ctgggagagg cctcaccact 4620

cggctgggct ccctggcccc tcccttcccc tggcctgagc gcccctgcgg cctcccgctc 4680

ctcctgagaa ggcgacaatc tctttgcacc ttagtgtttc gaggacagaa agggcagaag 4740

ggtcacttcg gagccactcg cgccgttttc acgtgtgtgt gtaatggggg gaggggggct 4800

cccggctttc cccttttcag ctcttggacc tgcaacaccg ggagggcgag gacgcgggac 4860

cagcgcaccc tcggaaggct cgatcctccc cggcagggcg cctggccaac gagtcgcgcc 4920

gcctcctctc ggccgcgcct gctggtgacc ttcccgagag ccacaggggc ggcctcggca 4980

cccctccttc cctcgccctc cctgccgccc atcctagctc cggggtccgg cgaccggcgc 5040

tcaggagcgg gtccccgcgg cgcgccgtgt gcactcaccg cgacttcccc gaacccggga 5100

gcgcgcgggt ctctcccggg agagtccctg gaggcagcga cgcggaggcg cgcctgtgac 5160

tccagggccg cggcggggtc ggaggcaaga ttcgccgccc ccgcccccgc cgcggtccct 5220

cccccctccc gctcccccct ccgggaccca ggcggccagt gctccgcccg aaggcgggtc 5280

tgccataaac aaacgcggct cggccgcacg tggacagcgg aggtgctgcg cctagccaca 5340

catcgcgggc tccggcgctg cgtctccagg cacagggagc cgccaggaag ggcaggagag 5400

cgcgcccggg ccagggcccg gccccagccg cctgcgactc gctcccctcc gctgggctcc 5460

cgctccatgg ctccgcggcc accgccgccc ctgtcgccct ccggtccgga ggggccttgc 5520

cgcagccggt tcgagcactc gacgaaggag taagcagcgc ctccgcctcc gcgccggccg 5580

cccccacccc ccaggaaggc cgaggcagga gaggcaggag ggaggaaaca ggagcgagca 5640

ggaacggggc tccggttgct gcaggacggt ccagcccgga ggaggctgcg ctccgggcag 5700

cggcgggcgg cgccgccggg ttgctcggag ctcaggcccg gcggctgcgg ggaggcgtct 5760

cggaaccccg ggaggccccc cgcacctgcc cgcggcccac tccgcggact cacctggctc 5820

ccggctcccc cttccccatc cccgccgccg cagcccgagc ggggctccgc gggcctggag 5880

cacggccggg tctaatatgc ccggagccga ggcgcgatga aggagaagtc caagaatgcg 5940

gccaagacca ggagggagaa ggaaaatggc gagttttacg agcttgccaa gctgctcccg 6000

ctgccgtcgg ccatcacttc gcagctggac aaagcgtcca tcatccgcct caccacgagc 6060

tacctgaaga tgcgcgccgt cttccccgaa ggtgaggcct caggtgggcg gccggggacg 6120

ctggggagcc cggcggcccc ggcccaggcg ggaagcgcaa gccagcccgc ccagaggggt 6180

tgccgcggcc tggcgtccag agctggggcg tctgagggag gttgcgtgag ggtcttcggc 6240

ttcggcgctg gcttggggcg aggggccagg gccttggcgg cccaggcgac caaaccctct 6300

cctggtccag ggctgggtga gggcgaatta cgaattgttc caggggcagg cagtccccca 6360

gcccgcacgg ccagcgagtt ctttctggtt ttgttctttc tccctttcct ccttccttcc 6420

ttcgccagtg cattctggtt tggtttggat ttttttctct ctttctttcc tttctttctt 6480

tctttctctt tctttttctt tctttcttcc tctttctttc attctcccct tccttccttc 6540

cttggccccc tctctccctc cctccttcct tccttccttt gccaatgcat tggtttgttt 6600

tctttccttt tctgctttcc ttcctttctt tggaagttca ctctggtttt gctttctttc 6660

tttccccatc ccttcctttc tttatccctc cttcccttcc tccttttctt tctacgattc 6720

cctttatttt tccttcattc ctccctcttt ttgtctcttc tggaggaggt gaaggagggt 6780

cagcttcagg cgctgcgagt cagcggggat cacggtgagg cccaagcact gcaggctgag 6840

gccacagagc gaacacttgt gctgagccgg gccctctcgt gaggctgggg tgcgggaagt 6900

ccgggcagga gagacccgcc cccgccgttg ctgagctgag acccggctga aagagagggg 6960

tccgattaat tcgaaaatgg cagacagagc tgagcgctgc cgttcttttc aggattgaaa 7020

atgtgccagt gggccagggg cgctgggacc cgcggtgcgg aagactcgga acaggaagaa 7080

atagtggcgc gctgggtggg ctgccccgcc gcccacgccg gttgccgctg gtgacagtgg 7140

ctgcccggcc aggcacctcc gagcagcagg tctgagcgtt tttggcgtcc caagcgttcc 7200

gggccgcgtc ttccagagcc tctgctccca gcggggtcgc tgcggcctgg cccgaaggat 7260

ttgactcttt gctgggaggc gcgctgctca gggttctggt gggtcctctg ggcccaggag 7320

ctgggagggc tgcgccggcc tctggagccc cgggagccag tgccgaggta gggagacaac 7380

ttccgccgca gggcgccgga cggtcggggc agagcaggcg acaggtgtcc ctaggccgca 7440

gggcgcttcc atagcgccat ccccaccagg cactctactc gaaatcggaa agctcgacct 7500

tttgcgttcg cctctgccaa gcctgttatt tgtgctggcc gctgggtctg gagctgcgct 7560

tctcggcccc tccccggtgg agcgcagagg gctggtctgc aagcgcggcc tccagccccg 7620

cggctccccg gcccaggagc caggcgcggg ctgacccggg agcacccggc agcggagggg 7680

gctggaagcg gaccctaggc ctctcctgtg ccacccggcc ctaccgcgcg gccgcggggc 7740

gctctcctct cgggcgcagc ggtccttcag cccagggcag gttcctccct ttcctactcg 7800

gaacgtggca aagatacccc agtcccagcc cctccagctg agagctgttg cccaaggtcg 7860

tcgctacttg tccgctcaat ggtgacccct tggcagagaa ctagggatga ttccactccg 7920

gttgatgttt taggggaaat taaaagaaca ttcggttttc tgagtctcct tccggggagg 7980

cgtggtggta actggtttgc tgggaagagc cgttccttaa ccgcatgcaa caaagcaggt 8040

gtggaatccg gacgagaggg cactcactgc cttctgcccc ctttggaaat agaaaaagcc 8100

ttcgaagcag caatccaaag atcaaatgat ttgcggtcaa tgatttcaat taaaccagaa 8160

attagtaagg gagggccgag aagacacggc tgctcagaag ctgttcgctg tttgagggat 8220

ttcccggaga gcctgttaaa agatgcgaag tggtgggtgt accgctcagc cacctttaaa 8280

ccggctctgt gcgttctggc tctggaaagc aagtctccag gcatttgggc tcagaattgc 8340

tgggccccga gtttgggcgg gggtggtcct tctgggggtc aggccttgag cagcttgcac 8400

tggtggcagg tttgggagca gttgaggggc ttcctgtgtg tcttttggag ggggtgaccc 8460

tggaagttgg cactctggaa gggagctgtt tggccctaga gttttggaaa gggccctgaa 8520

cctgttcggt ccccctcgga aagggaaggg agcagtggct tagtccctcc ctcctccatt 8580

cgtgcaatgc ctggggtagg ggtagacctg gagccggtgg actcatatcc ttggaattcg 8640

tcaggacagc tgctccgggg ccttggccct cagtcagtct ggggctgagg agtagggaag 8700

ctgggaactt ggggcagagg aagaagatgc gtttagaaag acctccatta tgcaaactgg 8760

agtccattta tgcaaactgg tcacccttcc agtagctcca aagagtggca gtggagtggc 8820

atcttgattg atttaacctc ttctcagggg acctgggtct gcgagggagg atatggctgc 8880

ggggttggaa taggatctgt ctgagctgcc agggtcaggg tggtggccct agggaggttt 8940

tagggccagg gtggtcccgg gctgtggcag gggctctcag atcgcctcgg gctctcagct 9000

gcaaggtgaa aaataccatg aggaattgat ctgccaaggg cggtcttgtc tcaaagcaag 9060

tggattgctg gggtaaagaa tctagagacc agcttaggac tctgggagga agaaaaaaaa 9120

aaaaagaata gcatagtcct aaggaactgc aaggatcacc agattaaccc ttcatacctg 9180

gggaaattaa ggccagacat gacacaggcc tttcccaagg ctctgtagca agggcaatag 9240

caggccagtt gctgccactg cggtcctgtg gggcatgttc tcactccact gcacccagga 9300

ggctgccagc ctctgttcct tttaacatag atctcctcag ttgttaagac agaaagagga 9360

actcagaggg gtccctgtgt gcaaggcaga gggagaccac cagaaccagg gtaagcaccc 9420

cacttggtag ccagttcaag gacttgggga tgttttcaac atttacagcg aggtttgagg 9480

ccccattgtc atgcagcgct actcggcctt ggtctcctta tctgtaaaat gggcccatta 9540

gcaatgcaca gggttgctgt gatgaagggt gaggtcccac aagcaaaagc tgtgcagtga 9600

ggggggaatc ctaagcattg ttcctatgcc attcacccct tcctgtgagc tccccatatt 9660

ccctggctca aaggagtctt gaatggcagg gatggaggac tcactgcctg gactttgaag 9720

acccctgctt tctgggtgac caccttttct tccctttgac agtgaactaa tacattggag 9780

gtagatagtg ctgggaagag gacaggagac cacggctgac tttggacatg ggctcgaaat 9840

tgataacttg atgagtcttg gagggtggtt aagataagct cggggctggg gcagcgctga 9900

ggtctgatgg tcagccagcc ctccccaaag tgtggccctc cgttctggag ataggggctt 9960

tggaaactgc aaaagcgtcc tggcaggcca gctctggttg ctccctggcc atagctgctc 10020

tgactacagg cagcaggacg caggtcggcc tctgcccatc ggaggtcaga ggcagggcct 10080

ccagcaccag actcagcagt gccactgcaa acctggcaca acaggctggt cccaggactc 10140

agctcagcag tgaagttgga aaccaaggtt gagtctcccc atctcccttt ccccaacccg 10200

aaagacccaa gatgggtgtg ggtgaaagag ggagaaagaa ttgctactcc agaaactgtc 10260

atttgcccac acgaaacgag gtggggttca aggtctgaac tcttccagtg cctgggtgcc 10320

tttgggttta aattcagctg caggtgcccc catcaccact tccacctgag cacaccacga 10380

gaagccaggt tatcttagaa actgtttccc ggaatcaaag cgacttgatt tggagagttg 10440

ggtgaggaga aactcacccc tatacccctc agggcgtcag agatgtgagg caattctcta 10500

cctccgctgg aaaaaatgca gatttattaa aggtcgactg tttagcagaa caacgtagat 10560

tttttacaac gctttccccg tctctgcttt gaagcctgcc aggctgcagc tggggatcca 10620

ggagggaaag cccgcaggcg cagaggggac aatccgggaa gtggtaaagg ggacacccgg 10680

gcacagggcc tgtgctttcg ttgcaggcga ggaagtggag cgcgcgctgc agattcagcg 10740

cggggctaga ggaggggacc tggatccctg aaccccgggg cggaaaggga gcctccgggc 10800

ggctgtgggt gccgcgctcc tcggagccag cagctgctgg ggcggcgtcc gaactcccca 10860

ggtctgcgca cggcaatggg ggcaccgggc cttctgtctg tcctcagaat acgtaggata 10920

cccgcgggcg acaagccggg ccaggctagg agcctccttc cctgcccctc cccatcggcc 10980

gcgggaggct ttcttggggc gtccccacga ccaccccctt ctcacccggt ccccagtttg 11040

gaaaaaggcg caagaagcgg gcttttcagg gaccccgggg agaacacgag ggctccgacg 11100

cgggagaagg attgaagcgt gcagaggcgc cccaaattgc gacaatttac tgggatcctt 11160

ttgtggggaa aggaggctta gaggctcaag ctataggctg tcctagagca actaggcgag 11220

aacctggccc caaactccct ccttacgccc tggcacaggt tcccggcgac tggtgttccc 11280

aagggagccc cctgagccta ccgcccttgc agggggtcgt gctgcggctt ctgggtcata 11340

aacgccgagg tcgggggtgg cggagctgta gaggctgccc gcgcagaaag ctccaggatc 11400

ccaatatgtg cttgcgtgga gcagggagcg gaagaggcag ccggtcctca ccctcctctc 11460

ccgccacgca catatccttc ttgacttcga agtggtttgc aatccgaaag tgagaccttg 11520

agtcctcaga tggccggcaa cgcgccgagg tcacgctccc cagaaacacc cctctcccct 11580

cccctacccc agctccccct ggggcgggtg gtaattgggg gaggagaggc cgcaggcagg 11640

gaaggggtgg gaaagccaga gagggaggca caaagtgatg gcagcccggc aaacactggg 11700

gcttcgggct gggccgcgct cgtttaatcc cacaaaaatc ccattttgga ggtgagaaat 11760

agaggttaga ggtcgggccc ttctggagat cagaccgagg agacgggccc agctggcgtc 11820

ttaaagcaag gagggggagt cgggaggagg tgagacccct gcacccaggt ggggctccca 11880

aaccgttctg gatttaccac actcccaggt ccgattttcc atggagggct ggggttaggg 11940

actggcacct tcttgttgtt aaccgcattt gatattcaca agaaccctgt gaggagactt 12000

tgtcaccgtt tttagatgcc tgaggttgcc ggaggggcag tgagagaatc gtctaacctg 12060

gtgttcctac cacagtccag gccctgtgtc ctgggctgga cccacagccc ctgccaccac 12120

ccagaggaag gcgcgaagct ggctgcctcc tttacgggtc tcccttaggt gccctcatga 12180

agggggacgg ccacctcaca gtgcaggaac tatctccccg tttgctccca aatagtcttc 12240

ttggtgtggt gctgtctatg gtctgtgacc tgcatctgga gttaccccca ggaccagctt 12300

cggaagagga gggatcgctt ggaggccgtg cagtgtgagg aacggcaggc agggtgtggg 12360

accaacatgc acacactcgc aggtgctggg gccagggagg aatgaggcgc tggctccctt 12420

tccctccatt tctccctggg ggtcccagca acctggccat ccctgacttc caacagcaca 12480

gcgtccccac aggtcctgca gtgctctgca ggggtgcagg gagctcccct ccccccagcc 12540

gcaacctcac cttcctcacc cccacccctc cggcaggaaa ccacaggctg ggttggggac 12600

ccctggtgct ccaagagagc agtgagtgct gggagccgct aaccccgagg cgcctagcac 12660

agactcttct caccccttat ttctgaaata aagcccttcc ttaggtccag atgaggacca 12720

cgtgctcagt gcctcacttt cgtgggagtg tatatcactt tacagtatca agacaatttt 12780

ctttcgttac aaatctttat ttagtctctg cgtttagacc aaagtagatt tttatgggct 12840

gagtgaaaaa acctcgcccg cattggtttc tgatggaaca gctggcagcg ccacggcccc 12900

gggtggggtg gcctagaggc aggggtgctt gggaggaaca tctagcaccc gaccacctcc 12960

accaggtggg aaagggacgt ttgcaccaaa tctccgccgg caaagcagag gctttgggga 13020

attacagaaa aactataatg atctaaaaga gaacaagtta tcttgaactg tgcgggtatt 13080

tgaatcatac agaaaattgt cctgtgtgcc caatgcactt ttgcatgtag agccagggcc 13140

ttcgaggaag ctttcaggag atcccgggca gcggagtctg gtctggagtt tcatttccgt 13200

aggtgcagat ttctccccaa gtcttcccgc catgggcttt gcaagaagcc agggcccaga 13260

ggccacgctc accgttaaca ctgcacaggg caaaggtggc tccaggacaa ctgcccaacc 13320

ccaggaacga cccagcagca gagaaaagga cagctgccag ggtgcctttg tcgctttttg 13380

gaaatcagaa ttcctgggtc cttagttaag tcttacttca ccaaatccca ggaccttcac 13440

attttggttc ttgccattgc taacagttgt aaatgctgcc gccacgaggc ctgggaggaa 13500

ggacccgctg gtgagagcac agggagtgct gctgtgatca cggtggtgat gcggggtgag 13560

cgcgatttcc cgggattaaa aagccaccgc tgcccccgtg gtggaggctg ggggcccccg 13620

aataatgagc tgtgattgta ttcccgggat cgtgtatgtg gaaattagcc acctcctcag 13680

ccaggataag cccctaattc cttgagccca ggaggagaaa ttaaaggtca tcccttttta 13740

aattgaggaa tagtggtttt ttttaacttt ttttttttta ggtttttagt tgccgaatag 13800

ggaagggttt gcgaagccgc tgccctgggc cgaggtgcat tttacgcttc cagaggtcga 13860

ggcctccaga gaccgcgatg cccagggcgt tcccggggag gctgagagac ccagggtgct 13920

ctgggtgact gcacggcgac tcctcgggaa cccactcgtg gctgcccgct tggaagggct 13980

ttgcggcccc gggaacgatc tccaggatct ccacggctgg tcaggttccc cgtccctcgt 14040

atcccgcgct gcccgggggc tcctgccttt ggttcagtgc tcgcggcacc accgcactca 14100

ggacggcagt ggggggctgg ggctggggct gggcctggcc cagcgtgggt tggggcgggg 14160

gacgcgccag cagcgcccgc agctcgctcc gcaggggtcg cagccagggg tcgggagcta 14220

ggctcgtggg ccgggagacg ccgggcgcgt tgtcctccgg ggaggttggg gtgcaggcgg 14280

tgcaccgacc ctcgccatct ggcgctgcag ccaccagcca cggcgcttag tggagggtct 14340

gcggccaggc tcccggcgga aagattccgg ggagggctcg ggggttgtcc cagcccgcgc 14400

taagcgccgc agcctcgccc ggctttcctg cttcctcgga ctgtgcaggg gaagcctggg 14460

gtctcgcggg gcgcagcagt caggtcgagg gtgcagcagg aggggagtcc tgacgggcag 14520

gtccctcttt cccctggtgc gcaacactgg ttggtagctt ttgcggaggt ggtgaagaag 14580

ggcaggaggc ctgttgagcg gaggagtccg gggatcccta attatgtgac aggagaccct 14640

ttccagttcg gcctgtggcc catccctctc tcaccgccgg cagattggag tctgctctcg 14700

gggagccccc aggtaaaccc ctcacaggga gaaggtttcg gattggaagg aggaccgcgc 14760

tcgtggggcg cctgtgagag ctgggaagcc caaggggtag cgtgtagggg gttttttatg 14820

cgggaggagc tgcctcctgg gcggcgggga ctttctgtct cagcctgtct gcctttggga 14880

aaacaaggag ttgccggaga agcagggaaa gaaaggaggg agggaaggag ggtccttggg 14940

ggaatatttg cgggtcaaat cgatatcccc gtttggccac gagaatggcg atttcaaagc 15000

agattagatt actttgtggc atttcaaata aaacggcaat ttcagggcca tgagcacgtg 15060

ggcgacccgc gggagctgtg ggcctggcag gctcgcacag gcgcccgggc tgccggccgc 15120

tgcggggatt tctcccccag ccttttcttt ttaacagagg gcaaaggggc gacggcgaga 15180

gcacagatgg cggctgcgga gccggggagg cggcggggag acgcgcggga ctcgtgggga 15240

gggctggcag ggtgcagggg ttccgcgtga cctgcccggc tcccaggcat cgggctgggc 15300

gctgcagttt accgatttgc tttcgtccct cgtccaggtt taggagacgc gtggggacag 15360

ccgagccgcg ccgggcccct ggacggcgtc gccaaggagc tgggatcgca cttgctgcag 15420

gtagagcggc ctcgccgggg gaggagcgca gccgccgcag gctcccttcc caccccgcca 15480

ccccagcctc caggcgtccc ttccccagga gcgccaggca gatccagagg ctgccggggg 15540

ctggggatgg ggtggtcccc actgcggagg gatggacgct tagcatgtcg gatgcggcct 15600

gcggccaacc ctaccctaac cctacgtctg cccccacacc ccgccgaagg ccccaggact 15660

ccccaggcca cctgagacct acgccagggg cgcctcccga gcgtggtcaa gtgctttcca 15720

atctcacttc cctcagcagg ttccacccag cgcttgctct gtgccaggcg ccagggctgg 15780

agcagcagaa atgattgggc tgctctgagc tctgaagcat tcggccgctg tgtgtgtgca 15840

aggggcgcaa ggacggagag acagcatcaa taatacaata ttaacaggag cacttgtcca 15900

gagcttactg caagccacat tcagttccgg accttattga cttccccctc ccatctagag 15960

tggattctgg tttttcaatt tgttttgttt tgttttttgt ttgtttgttt gtttttgaga 16020

cggagtctca ctctgtggcc caggctagag tgcaatggcg cgatctcggc tcactccaac 16080

ctccgcctcc cgggttcaag cgattctccc gcttcagcct cccgagtagc caggattgca 16140

ggcacccgcc atcatgcctg gctaattttt gtagagacag ggtttcaccc aggctggtct 16200

cgatctcctg acctccgatg atccgcccac ctcagccttc caaagtgttg ggattacagg 16260

cgtgagccaa cgcgtcctgc cttgattctg tttttaactc cattttttag aggaggaaat 16320

tgaggcacag agaggttaaa taacatgtct aaggtcacac agcaaggggt ggagcggagt 16380

tagcccactg gcctagctct agagcccacc cggataacca gaacttggtg aggcctccgg 16440

gctcttgctt ggtttggagc caggtgctta gcgccccgag cccggggcca ttcaccctgc 16500

aggagctgca cgcgcccctg acctcggctt ttccctggca gcagaggggc tttgcgggtc 16560

ggccgggtag ccctgagcac agctcgccac ttccaggtgg gctgttggcg ctggctgggg 16620

acacatcccg atctttcaaa tgccctttac agagcctcat caacgacccg attcattccc 16680

ccctcctgtc atttgtctct gccatcgaaa aatgcctacc gagagctgct ctgcatttcc 16740

gccctctatt ttgtgtttta ctttaaaata ataataaaaa aaatgttggc tgcaggacgc 16800

catgacttag gtcagcgagt cagccgctag ctctgcattt ccaaaaagca gatcttttca 16860

caactctctt gccccaagtg ccctggtgtg gtttattttt taaaatgcat gcctgcggaa 16920

gagaagaccc ggggaatatt cgaaaccccg agcttttaca acataaagcg catggtgtgg 16980

ccgcggcgag taatggcgct 17000

<210> SEQ ID NO: 165

<211> LENGTH: 1500

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 165

caaatcactt gaactcaagt tcaagaccag cctgggcaac atggtgaaac cacatctcta 60

caaaagtaaa gaaaattagc caggcatggt gctgtgtgcc tgtagttcca gctactcctg 120

gggaggtcga ggctgcagtg agccgcaatc acgccacttg tactccagcc tgggcgacag 180

agcaagtccc catctcaaaa aaaaaaaaaa aaaaaaaaaa aaaaggctgg gtgtggtggt 240

cccagatact cagaggctga aaagggagga ttgcttgagc ccaggagttc aaggctgcag 300

tgagctgcga tcacatcaat gcactccatc cagcctgagc aatggagtga gaccctgact 360

atatttaaaa aaaaaaaaaa taggaagaaa caactcaacc acagggctag tatgttactc 420

ggttataaaa tgataaagcc ctaaacagag aattagcccg tttccagaag aggccaagaa 480

cagatgatac agctgaactg aactcctgcc tgtacagctc gttttctaca agattccaga 540

cctggaagat gatggcatcc agcccccatt gaagcacctc gaacaagaaa aacgccgagt 600

ccgaagagcc aggccttgaa cacacgattc ctgtctataa ataactcccc ctggggaata 660

aaaagcagga tccaaggcag gaaacccgag ccgtggaatc tggtaagttc ttaggaaacc 720

cactcacggg cctgagtccc ccgtggaagc ggcgacttcg gcacctggac acccgagtcc 780

ccagagcccc gggcggccgc gcgtccctac ctgcaggcct gataccggcc gcggagcgct 840

cctggccccg ctcccgccag gctccgggac cgctgaaacg cacccagggg ggtgaaggcg 900

tagtcgccaa ggacagcgca gatggcagcg gaggcatggg agccggaacc taccgtggca 960

aagggccagg tcgggacgcc cctcggcgca gccccaaatc ctgcccgcgc cccagccccg 1020

ctcaggccgc gcccctgcca cctctggcca cacgggctga gacgtctggc tcctgcacag 1080

cgcacttccc gctgcccttc tccactggct gctcaggccc tgcctcgcca gcacggcatc 1140

cgcgggggat ccctacctgt cctttagggc ttgcctcata ggtcaaacgt cacctcccag 1200

ggaggtatgg cctgccccct ggccaggtgg gccccttcca cgctcgcctg caacaccacc 1260

cacccacctt gataactgct tgtaaaggtt gtactgcttt cccccttgag actgcaaacc 1320

ttcaagggca ggaaatgggt ctgttttcct ggcaaaataa tgaagttggc ttaaggtttt 1380

gctgaataaa atgagtgaca gacaaaagta gccaaatttg gcactcctga tgggttattt 1440

gatgaaggag gtgcaatgta tgggcttaac tagttattct ggatttcttt ccccatgtta 1500

<210> SEQ ID NO: 166

<211> LENGTH: 200

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 166

caaggccggt gcacgcggac ccgaggattc ggtagatgtc cccgaagacc cgctgccgct 60

ctaaggcggt ggaagcgaga ttctccggaa acccagggaa tccgatgctc gcacaggacc 120

aaagcccgag gccgcgggga ccacagaggg acggagaagc cgggactcct cacatcccac 180

atccggcagg ggaagcccag 200

<210> SEQ ID NO: 167

<211> LENGTH: 2000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 167

ctgataataa agttttacca ttttataatt taaaaatgta aatatggagt tgggcatggt 60

ggttgggagg ctgagaccag aagatcgctt gagcccaggg gtttgagacc agcctgggca 120

acatgcagaa accctgtctc tacaaataaa aaattagcca agcgtggtag cacgcacctg 180

taatcccagc tactcgggag gctgaggcag gagaatcgct tgagcctggg aggtggaggc 240

tgcagtgagc tgagactgta ccactgcact ccagcctggg tgacagagtg aggctctgtc 300

tcaaaaaaac aaaacacaaa aaaacaaaca aaaaaaagca aatatatgta aaaataggaa 360

gtgcggtttc ccaaaatgag gtctgtaaac aactgatcta gaaaatgttc tggaaaaagt 420

aaaaaaggat caggatctga ggtcaactga cctctccctg cgctctggac aggcaaacag 480

gcaaggttcc ctctgaggcc gtagcggctt ctcgtgggcg agtccctgtt cgcaggtgac 540

gtgtggacca cgctcttccg aagcgtctgg cctgtgtgct ctcggggagg ggacgcaggt 600

cagcccacct agccgatggc taacaagtca gtttgttttc tgaacggaag cttaaaccta 660

gaaaagtaac tgggttgggg tgggggtgta gccacatgca gtaaaagcac tgcctgtctg 720

tataacaacg acctgatgaa aaaaggaacg cgtgaaatgg ggagtgttag ggcgtcacaa 780

actccagtgt ggttgaaatg aaagcagaaa gcaaatggca agctggcttc cccttccagc 840

ttttcacaac cctgccttgc tcatggtcag ccccaagcac gggcggaaga aaggactgga 900

ggggagggaa aggggtgggg agcgagggta ccagaggcgt gggaggacgg ggacaaaggg 960

gcagcaaggg accggcggaa aggaaagtcg gcgttagctg gattggaaac agtccagaca 1020

gaacgatggg ctctgctgcc tccgggtggg gcaccaagcg gggagcgggg ccacgaggca 1080

ggggacagtg aagcaccatg cagcgcccac cagccggcag cgcccaccag cctgcgctgc 1140

gctgcacatg gtacccgcgg ccccagctgg ccagtgtgtg gcggagatga gaccctcgtg 1200

aagagactaa gcggccacag cagggggaag ggttgctcac ataaccccat actgctcaca 1260

ctacgaggtt aactgccgtg agatctgcct gcagccagca gaaacccgtt ctaggaaaac 1320

gttgcccagt gacttcagtg agtgccactg acccgggcgc ctccgccccg gcgtccggca 1380

gcagcaccga ttgcgcagga ggcaccttgc aaacaacctt tcctgatccg cgctgcagtt 1440

cccaggccgg ttgcagccgt ttcacagaga ctgcgcacac aaagcgtctc cgtgccctgc 1500

cattcacctt tcgacacagc cgcaacccct cttttcagtg ttaaaacctg gcgccaaaag 1560

gaacatgcga tgtgacgtgt tacctctgcg catgcgccgg gcattcccag cgccccgaac 1620

ctgatgaacg cgcggtgggg accccaggct tccgtgcttt cgttttcctg gaagctacgt 1680

gtcctcagtc tacatattgt tacctggaaa ataaagtttt ctcctttttt cttcctttgt 1740

taacaggcag aaggtgtagg ctgcaggttt cgggcctaag agagggcatg gctggcgaca 1800

cggagtagac tcctagatga cataacggag gcgagtctgc accggggact cggcattagg 1860

aggaggcaga ggaaaagccc accaccgtgg ccgagggaga tctagcaagc agcttgcagg 1920

gggtgaagtg tgtgcaaagc aggctgagac ctgtccagta tcgaaacacg ccgcggtggt 1980

caagcaggct ttaccatgct 2000

<210> SEQ ID NO: 168

<211> LENGTH: 700

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 168

tgaggctcaa aacaggtgtc tgtgagcttc acaggcggta aggccgtgtc tacatggccg 60

ggacatgcat cccggggctg cccctgccgt gctgcccgag tgcacggggg atgaggacct 120

gacaaggcca ttgatcttgc gggagcttcc tgaactactc cagcgtgaaa atcttccaga 180

aggattctcc acagggcaat gaggcaagaa atttacagct tagcctgatt aatgggccag 240

gcagttaaga gttctttgcc aagctatgag cataatttat agtcatcacg gcaggaggaa 300

aggccacata actcacatcc ttaaagggcc cttagaacaa gagacacgcc ggatcattga 360

aaacgtctcc actcctggcg ccaaaagaga tcggcacgtt tctgggtatt ctggtcaaag 420

aacagggagt ctggattaat atacacggca gaaaaaagcg aagaaaagac acacaggtca 480

tatatttctg actgatattc cgtttgttgt tttcggaggg acttggtatt tatttaacca 540

cattctcact tgacacgccc cctccccaca ccttgtaaat gccttcctct ttagccgagt 600

catttttcat cacatagaat tgaaatgttg ccaggaaggc ggtttatgag attgtagaaa 660

tggcactaga gaaagcagtg tgaaaagagg cctagaacgt 700

<210> SEQ ID NO: 169

<211> LENGTH: 600

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 169

tctctacatg ctatctacta aaaacttagg caaggaaatg catcagacca aacaccccac 60

agcacagaga accgaccggc cattgctttc caatctccgc aaacctaacc attgctggaa 120

gaaatcttac tcacagtgca cagacagtag gtattttatt gaagataaac atatagtgga 180

acaaaccaaa ttacccccat ttgagttacg tgagcactca gttctcagcg tggatgtccc 240

acaaatcaag tcaacatttg cgtcccatta ccagcagcca cttgccgagt atctcttcgc 300

ttccactggg actgcctggc atccctgatg ctaaggagcc actgaagagc ctccaaatgt 360

ctgacattca caaacgcatc ttttgctttg acccgaccct tcaacctctc cgagtctgct 420

gccttttctc agacacacat ccaggcaccg ttagggatag ttagagaatc tgaaaattca 480

gaagcgctcc gaaaagcctt tccaaaagta atccacagca ctcaacagtg aatttagaaa 540

ccccaatttt tttctgagtt tgaagttttt aagccttgcg gatggttgga gtaggaaaaa 600

<210> SEQ ID NO: 170

<211> LENGTH: 1100

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 170

tcagacaagc tctgtgcagt cggaattttt taaagatgca ctgtcacttg aggaagacag 60

gtgatcttcc tgcggcacaa atagaagcaa agagatttct cttcttctct gtagagcaac 120

acaattgata aatggccgat aatctccacc aaattggcag cagtaggctg cccgaaggca 180

gcaggcatat tcgtctttgt gaattgtttt actatgatgc tgtcacattt ccaggaataa 240

gacggttaaa atgatatatt gttgtggttt ggcatttgca gctttgctct gacttccctg 300

gtaactgcca acatctgcaa attattatgt gcttaaaaaa aaaatcaacc gccaccgcag 360

gctgccccca cggtccctgg ctgggccagg cctcctgcca ggccacaggg cagagttctt 420

ggaccaggag gcagcagggt caaaacccag gttgcctagg aagcccccaa agacagttat 480

ggatagagct gggagcccga aacacatgcg gcagtctctc agtttccagg taccggttct 540

cacatcatcc atgcatgtgt ttgaggaaaa acaaaaaaaa attgatggtt gccaaaaaca 600

aaaatgcttc catatcaaag tttatcagtg tcaatgtcaa gagacttctg gttcgtagac 660

tcattttggc ttgaggccac cagaagtgaa ctctggtttc taaatgcaga agcagaggca 720

ctggccgatc atggaagatg cagggaactg ttcaagaggc ccaagcctgg tgctcagaaa 780

cttggcagga tcaagcatct cgcccaggaa ttcatcccct gcttgtctaa gccggctggc 840

tctcgtgact gactcggaac aacagagcag atgtttgcgt gggaggcaag cctcacccaa 900

catctgtcct gcggcgggaa ggcctgggtg ttcacagata gagctggagt tccccggtgg 960

gtggcacaga caattagctg gggctgcctc acatgtaatc taattacagg ggaaacaggc 1020

tcaaacaccg ggtgataagc agcgcaactg tttcgggtga ctctgtaatt tttcctccat 1080

taattttctc cataacgcac 1100

<210> SEQ ID NO: 171

<211> LENGTH: 250

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 171

gttgcctggg atatgcttat atcaaaaact tacgtgtcac ttacctagca tttgcatttc 60

actgggcctc ctaaattctg tgtggtaacc gactgccacc ggacatgctg tttacttctc 120

tatcctcacg cagccagttg ccacattcaa cataacactg caaatattgc cggtggatcc 180

tgacttcctc gtggacccta ctgtgtcggg aaaaacaaac aaacgaaccc tggaaggaaa 240

caccatgagt 250

<210> SEQ ID NO: 172

<211> LENGTH: 600

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 172

tcataaatat ttccaaatgt attcctattt gtctctacag agtctaacag acataaatag 60

cgaattgaag gttctgtctt aaaacccagc agaaagaaaa acaatgacca gaaaaaaaaa 120

acaattgtct ttggcttccc aagaacagca tcggatttca actggaacca cagatggtcc 180

gttgatagaa gcgactactt tttagctctg gaggacgaca aaaggaacca gcttcttcct 240

gtgggtgtca cagcgaggtc gcctggccac atcaggtacc agagcgagcg ccctcacctg 300

ataggccctg tacaacctca gccacagcac tgtcaggagg aacacgcgga actagcaacc 360

taggagggta aaggcggagt tgggagggaa cacgaggcag gcaggtcggc tggctgctga 420

gctacaggct gcactcctag gacgtctacg tgtaattgag aaaaataaga caaaaataac 480

ttactgtgca ggcaattaat tctggttggc atagcgatcc tcttaagtta aagggaatga 540

gcatgagatg aagagaagta agaggcagaa agaattatgc aagagcaaca tcagagtgga 600

<210> SEQ ID NO: 173

<211> LENGTH: 2000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 173

acgccgagcc gcctctgcag gggaaaccga agcagatgtg gtgagataat acatccaacc 60

ctgagtgcta ctctaacctg ccagaggcgg agggttctca gtgagatgaa agcattacag 120

atgcgttaga tctaagggag gggcctgcag atgcgcagct ggcagagaaa ccagggaggg 180

gctgaactgt cagtcgcgac caccagggat ctgaatcagt tcaccgacag ccttggggac 240

attcaccttg ggctccacaa cctgtcagaa atgcccccaa gcccaaaggc gtcgagagaa 300

tggccaggtt gtttcagatt gacacatatc ctaatgtaca agtcagccca cacaccccac 360

gtgcactgag cgtctcttgt tgttcacccc aaataaactc tgccggaact ggggcgggac 420

tcgcaggggc ggagaagggg ggagacgggc agagggcaga agtggatggt gagaagagcc 480

aatggagggg ccccgtgaga gtgagcaagg ctgcacccct aaccgacgtc ctggggctac 540

tgtacaaaca aagaaccaca ggctgggagg ctgaacaaca gacctgcact ctctcgcagc 600

tcggaggctg caggtctgaa atcgaggggc tgacagcgct ggtttcctct ggaggctgcg 660

agggagaaac cgtcccctgc ctctcccagg ctctggggtg agcccttcct ggcatcccgg 720

gctcattgta gatggatcac tccaatctcc atggcttctc agggcttccc tccatgcacc 780

tcaaatctct ctctccttcc ttttgtaagg atgccagtca ttggatttag gttcacctta 840

aatccaggat gatctcatct aaattacatc tgcaaaaaga ccctttttcc aagtaagttg 900

acattcacag gtacctgggg ttaggattgg acatatcttt tgcaggggtg cagggggctg 960

ccactgagcc cgctgcacag ggtgacctgg gccaagggcc cttcactttc acttcctcat 1020

tggcaagctg ccctgtgttt ggactgggtc gaggctgtca accttgctgc ccctcggagt 1080

cccccctggt gtcccccaaa cagattctaa gctgctttcc tggggctgga ggccaggcat 1140

tgggattttt taaagagctt cccagcaggt gagcagcctt tcatgggtat caggagacct 1200

tcctggcaaa tgtggtgaag gtccttcctc ctgagcgatg ccttagaccc aggagcccag 1260

ggaggctgct cacctgatcg ttaggacagg agcagtggaa acctctggcc tcagaccccc 1320

tggaggaatc cctccctcta agactctggg actggtgcac gcaaggagct atcgtgaaca 1380

ttgctcccaa ctggccgctt gcttgtcccc cggctcccct tggccccagt ggcggctttg 1440

cctgaattag agggcgtgag agccacctgt gtctcagcac tgcaattaaa gcaggaagcc 1500

ctttcggaag cagccgtgtg caccagcctc ccatgggtgg agcagagcaa accacccact 1560

tctgccctct gcccttcttc ccttttctcg acaccctgcg gccccccagt ttcagcagag 1620

tttatttggg gtgaaaaaca agagatgctc agcgcctgtg ggatgtgtgg gctgactcgt 1680

acattaggat gtgtgtcaat ctgaaataac ctggccgtta tatggatgcc ttggggcttg 1740

gggggtttct ggcagtctgt cgagcccgag gtgaatgtcc ccaaggctgc tggtgaatca 1800

gatccctggc gttctccgtt ggcagttcag cccaacagtt tctctgccgg ccgtgcctct 1860

gcaggtccct cctctgatct gattggatta atatttgaat caatagactg agtcaagcag 1920

aatgtgggtg ggcctcatgc aatcagctga agccctgaaa agagcaaaag ggctgcccct 1980

tcccccgagg aggagagaac 2000

<210> SEQ ID NO: 174

<211> LENGTH: 200

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 174

gaatgttcaa agaaagagcc ctccttgcct tcctcttctt ccacccctgc cctctgcaga 60

ctggggttct gtagaccccc aaagtaagtc cgccacaccg gaaggaagtg agttacacag 120

gggcccacat gggaaccgct ttttgtcctg tcttggtggg aaaatggcca cgaccccagc 180

ccaggctctg ccacgccaca 200

<210> SEQ ID NO: 175

<211> LENGTH: 400

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 175

aggcagcagg gttaggactt caacatacaa cttttggggg gagatgtact tcagcccata 60

acacaccacg tgggaggata acaccgattt cagagcttgc agaggaagcc gccaggaact 120

ccagtgagac atcagccccc aggtgcctgt caggcacgcc gggctgtggg gggcacctgg 180

gcccatctga gtaacggagg cgcatccgca cttcccccag gagtacattt ttagaaccca 240

cagcgccata aaccaaagac aaggagactt cctggtgccc cgtcagcttc tggaggcgac 300

gttctcggct gacagctctg gcagcctccc ctgtaggtga gagacaggta aatgggactc 360

ttgcttccaa aacggaacag ggtaaaaatt ctcaagcgtt 400

<210> SEQ ID NO: 176

<211> LENGTH: 300

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 176

ttaaagggga gtggttgtat gaagagttcc tcagtcaaag gtgtgcagct gggaagccca 60

ccccacctaa gagggaggtc tgacaaactg tccacactga accactcaga cctgcatcag 120

ggccccgttt cttccataag ccgccaagta cagccctgag tcaactgaac tcaggcctgg 180

gaggcttccc aaagctgact tgactcagct ttgaactgaa atgaccgtac catgacaacc 240

ctgatgaaaa gctaaactga gcccaattat tcaacagtaa aattcagttg gtctcactca 300

<210> SEQ ID NO: 177

<211> LENGTH: 450

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 177

tgctaccagc tgcttgggct tgggcaagtc accctagctc tcagatgtca tctgtaaatg 60

atgacaatgc caatgtggca ctgttctgag agtcagacag aacgtatgtg tgcttcacat 120

atggtgctca tgaagtgcta tcattatcta aggaaaacag aaaacgaagt tcagagtctc 180

tctaaacgca tgacaccaga ccaacaggga gtttcaaaaa ataggtctga agtaaatcaa 240

ttctcctggt ctcaatacac tgaaaacaaa ctattagggg actgaccgaa cccaccttag 300

gaaccacctt acgtcacctt ctgtctctac tgcaaaaccc tcccttaata ctgttcaaat 360

acgctgacaa tccagatcca tatccaatgg aaccagcaat catgcctgtg tgccagcaat 420

gtcagggagg gaagccgatc tctgatgaat 450

<210> SEQ ID NO: 178

<211> LENGTH: 1300

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 178

caagcctgtg gtagggacca ggtcagagta aacaggaaga cagctttcgg ccaggcggtg 60

cacctcggtg ccggtgagtg tgagcgtgtg tgcgtgtgca cgtgtgcaga tgtgtgtgga 120

cgctcccttc tccgcagcag ctcctgaccc cctgcaggtg accctcagcc agccccaggg 180

ctgcccccac tctcccctgt ggacacctac ctcatttggg gtgaagtggg gggactgggg 240

tgtgaggggt gctttggggg gcacacttcg acccctctct ctgcaggcca agtcctgagg 300

ctcagtttcc tcctctgtgc cccggcgacg tggtgcaggc ctcgcgagtg acgtgagggt 360

tcatgaccca ggtgtgggca gccagccctt cacgggaggc cacccacctg gccacagtgc 420

ctgggaattt aggtcgggca ctgccgatat gtcgccttcc acaaggcggg cccgggcctc 480

tgctgaccgt gcaccggtcc tggggctggg taattctgca gcagcagcgc agcccatgcc 540

ggggaatttg cgggcagagg agacagtgag gcccgcgttc tgtgcgggaa ctcccgagct 600

cacagagccc aagaccacac ggctgcatct gcttggctga ctgggccagg cccacgcgta 660

gtaacccgga cgtctctctc tcacagtccc cttgcgtctg gccagggagc tgccaggctg 720

caccccgcgg tggggatcgg gagaggggca gtgtcgccca tccccggaag gctgagcctg 780

gtgcagccag ggagtgaggg ggcgggaagc cggggtgctg ccctgagggt gccccgacac 840

gctctcctgg ggccctgagc ggctgccacg tgcgtccagg gttctggcca cagggtgggc 900

aggggccctg tgctcctcac tggaggcccc tgaggctctg gaactgagac catccacccg 960

ccggccccct ctcgccggct ccggcacccc tgcctactgt gacttcctgc cccggactcg 1020

ctctgccagc ttggggcaaa ccacttccct ctggggtttt cacttccctc tttcccaagt 1080

ggggaaagac cacctgtccc cgacccagaa agggcccctg cccgagggca gcagcagtgc 1140

caggctggca tgtgaggctt ggggcaggcc cggcccccag aggcacaggg cgatgctctg 1200

tgggacgctg tgtcgtttct aagtacaagg tcaggagagg agccccctga ccccggaggg 1260

gaggagaggc agggcaggaa accgccacca tctcagccca 1300

<210> SEQ ID NO: 179

<211> LENGTH: 200

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 179

gcccactgtg ggtgtgcccg tgtgtgtggc tgtgaggcgt gagtgcaggc gtgaagtgtc 60

tgggagtggg agcgggcatg agtgtgtgcc acgggcctgc tgttgggtcc ttggaggcca 120

cggttgcccc tgaagggact gcaagctctt ttttgatttg tagttatttg agaagtctat 180

acaggaagaa aattaaaccg 200

<210> SEQ ID NO: 180

<211> LENGTH: 1000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 180

agcgcccagc gcagggccgg gacccagagt ggactctacc gtggggctgc ctcaaagaaa 60

tctcagcaaa cacaggaagc cagcccaccc gtgcagccat ggggccagga agcccgccct 120

ttaccaagtc atttgggcat tttttctctg tgctaacagc ccagatggag ccatagcctc 180

aacctctgtg ttctgataac accaagctgg gacgccggag ccatgcaggg gacagtgccc 240

ggcctgaggc tgcagcctgg gtctggatgc ctttctaatt cagggcctcc tcatggcctg 300

gttccataaa tggtcaaatg cagcctgaca gcgcagcctc ctatcagcgc tgggctccgt 360

accgccacac agcccacata ccccgttccc caggagacgc ccgcaggtgg gcagcgtcac 420

tcccacccgc cgagcacacg ctgtccccgt ctcgtgtccc gaggagccgg aagcagctgc 480

ttcctcccag cctgaaagct gcacctcggg ctgcactcgg ctccccgaac ccgccctccg 540

ctgccctgca attcgccaag ggagctaccc ttcccatata aaaatttcac ctccatttcc 600

ttgtagagaa gaaacatttc tgacagcaag gaagattcta atttgaaaag caagtgattc 660

atctcccggt gccaaacagc agacgcaggc gttaccagtc tgggtggggc gcccgagctg 720

gggacctggg gtcctctggg aggggcaaga aggcagcgat gctggccccc gcctccatct 780

gcccatccca tctgcttcca cacaccgccc tgccgtagct gcttgcagcc cttctctgtc 840

agtttctcca tcttttggtt tggtgataaa tgagagttcc catcgggtgt gccaccctct 900

gtgtgacggg gagcagagaa gaccctgcgt ccaagtcctc ctgggggaag agcgaagatg 960

ctgggaccag ccccagctgt cagggggtct ccaatcccag 1000

<210> SEQ ID NO: 181

<211> LENGTH: 300

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 181

cgcacacaca gcacagacgc ctgcatcttc ccatgcgtgg tttctgctct tgcctctctg 60

ggtttttgtt tcacttcggt cgagtttttg gtggtgttga gcggatagcc ggggaagttg 120

gagtcttgtt tgtggccgcc tcgtgctcgt gtctgtatct aagatcctca ggctgctcct 180

ttttgggtaa ggtctgttgc ttctctagga acagtgacgg tggcagagcc cgtggcccct 240

ctctcctgtc ccagagccaa gctgtttcct ctccccactc ccgggcaccc tgcgggcaag 300

<210> SEQ ID NO: 182

<211> LENGTH: 5000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 182

aagaggaaat tcccacctaa taaattttgg tcagaccggt tgatctcaaa accctgtctc 60

ctgataagat gttatcaatg acaatggtgc ccgaaacttc attagcaatt ttaatttcgc 120

cttggagctg tggtcctgtg atctcgccct gcctccactg gccttgtgat attctattac 180

cctgttaagt acttgctgtc tgtcacccac acctattcgc acactccttc cccttttgaa 240

actccctaat aaaaacttgc tggtttttgc ggcttgtggg gcatcacaga tcctaccaac 300

gtgtgatgtc tcccccggac gcccagcttt aaaatttctc tcttttgtac tctgtccctt 360

tatttctcaa gccagtcgat gcttaggaaa atagaaaaga acctacgtga ttatcggggc 420

aggtcccccg ataaccccca gctgcagatc gaggcctagt gcgagcacag gtccccccag 480

acccttccca gtgcccacca accggcggcc taggccaggt agaactggca gcgcctcccc 540

tgctgcaaca ccaggctctg gtagaaactt cagaaaacat gcaccggcaa aaccaaggaa 600

gggtggctgc gtcccgggtt cttccgcgca gctgtgtgta cacgcatgca cacacccaca 660

cgcacacacc cacgtgcaca cccccatgca cacgcaccca cttgcacgcc catgcacgca 720

cacacgcgcg tgcacccatg cgcacgcacc catgcacaca cacgcgcgca cacacccacg 780

tgcgcaccca catgtacaca cccacgtgca cacacccacg cgtacacacc cacgcgcaca 840

caccgctgtc cccagccgtg cagaacgatc ctccctgagt ccccggctcc gacccacacg 900

cagcactcgc taaacgcttc ccacgcagtc gttttgctgg gttgcgcttc acccacttct 960

cagagggggc ggccgaggca gaggtgtcgg ggatcgagca gctccgggcc tcaggggtcg 1020

ccccgccacc gttttccttt cccagatgct gggacggggg cagggagggg ctccccaggc 1080

tgaacccgac taggtcaccc tagaagcgag gcgagcttct cttctgtttt tcttcggcgc 1140

ccctgagccc ctgacagtgc ccaagctgcc catgggattg gattcgccag agcctcctac 1200

gcagacccca cccagggcca aagccaaccc caagccccac caccttggtg gtgtgggatg 1260

aaaagtgagc catcgagaga tggggtcccc ccacccccaa cccctccaag gacaaaggcg 1320

ggctgggaag cacccgcttt cacgtccgcc cctgcccggc tttcctagcg gaattggcgc 1380

cggcatcagt tgggggttgt gggatcagtg aggaatcccg tggggtcgcc tccatttatc 1440

agttgtgtgg ggttgggcga gcacccctag ccccagccca ggcgatcagg gcgcgaagcc 1500

cactggacgc ggatttggga ttaggacggg ggtgacagcc aggaggaccg cacctgccct 1560

ccccactcct gccgctccac ccctgccccc accgcaacac caaggtctcc accaggaaga 1620

tgggggtggg gaaaggacgc ggggtggggg ggggtgcggg gagagaggac acagggtcgg 1680

aagggtgagg ggtagtggca gaggcggagg ccgaggccac gcagctgcgg ggcgcaggga 1740

ggggcagagg aggggcgttc agatgggaac ctagtccaga cccgtcgggg ccctcgtgtg 1800

cggctcgtta tcctggaacc agagaggctg gagacccttg gcttgtctgg agcggaaccg 1860

tagtgtccaa tagagtgtgt ggggctcagc cctaaagcta aacattcttt atttcctgat 1920

gaccatgggg gcggagcggg ggaaaagccc tggccttata gtttagaatt ttataaaagg 1980

aaaggcgtgg ccactgacaa tttgcgcttc aggagtccca gagtgaccgc ctggctcgga 2040

gcagggaatg agggggtcct taactctgag atttgttttc tgagagacaa aggtgatggg 2100

tgaggcggct aagcctctga ttctctatag gtggcggtca ttcatttcag aacatgaatg 2160

gattcagtaa ataaacatga tagaaaaatg ccacaagccc taggcccatt ggagtggact 2220

ggacagtctg ttcccagtgt gtccctcagc ctcggtcccc cacccttccc ggagccctgg 2280

gggtcacaca catccctcct ggctgcctag cctgtgcccc ccgattcccc ccctccccgc 2340

cccgcgcgtg cacacacaca cacacacaca cacacacaca cacacacacc acacagcacg 2400

aggcgacaga gatatgagag agagcgagcg agagaggacg ggagagagag ggagtgcaag 2460

tgtgcgctgg gggtaacccg tgcatgcatg cattgggggt aacaggctgg agctcagatc 2520

cctcccccag cccccagcag gggggactgc aggctcctgg tctgagtggg gagctgggcc 2580

ccctggacag aggactgggc tgcggggtca ggaatgggca cacttcctaa ctgcaggaca 2640

ctctaagggc tttggtcatg cacacgcagc caagagaagg tgtcgctggc acacagcctt 2700

ccaggagcgg acttggagac ctcgccaagg accaggactc cccagcactc acactccctt 2760

aggcgctgaa gtccagagga cagaggttga gggcagagct cctgggagca ccagtggaag 2820

taggagggct gggctggaaa acctccccca acctcctatt gcaaagaggc tccagccagc 2880

agcctccaca ccccagtgat cttttaagat gcaaatctgc gccatcattt atttcctcag 2940

tgccttctcc agctcctggg atgcacactg cccgtcccca ggcccagaga cctgaccacc 3000

ctcattcctc cctcagccca ccctggggtc tctccaccag ctgacagcct tcctgcagtc 3060

ccctccccga atgctgctcc ctgaggccct cctggacacc tgcagggcag gcacagcccg 3120

cgggacctca cagcacttgc tccgggcaga gctgcagttt ggccaagttg ccagctccgt 3180

gtgggcaggg gccctggcct gtggctgcca catcccgggt gggggcacgg cctttcctgg 3240

cgtggatgct gagcaaacgt agggggaagg ggagtgaatg aggagagcca ggtagctcag 3300

gggctgaggc ctcactgagc agggtcccgc gtgaccggtc cccaccgctg acggttcctg 3360

gggtaacact caggacaggg agaggcaatg gaaagagacg tggccgccct cgcatcctgc 3420

agctcccgca ctcccagcct cccagcctcc cacccagccc cccagagccc accagtgacc 3480

ccgcccactg ggtcctcaga tggctcccac gggatctcct gccttgatct cctgtccaca 3540

tggaggtgaa gtgggttgct ctgaatgagg ggtgccgagc ctagggcgca gcccactctc 3600

ctgggtccgc agcatcacgc agcccggacc acaggctcct tacaagaatc ggaagggtcc 3660

ctgcaatcgc ccttcgcact gaggcttcct actgtgtggt gtaaaaacac aggcttgtcc 3720

tcccttgctg cccacggggc tggagccgcc tgaaaatccc agcccacaac ttccccaaag 3780

cctggcagtc acttgaatag ccaaatgagt cctagaaagc gagagacgag aggggaatga 3840

gcgccgaaaa tcaaagcagg ttcccctcct gacaactcca gagaaggcgc atgggccccg 3900

tggcagaccc gaacccccag cctcgcgacc gcctgtgacc tgcgggtcaa ccacccgccg 3960

cggctccacg ccgtgggcac agactcaggg agcaggatga gaaagctgag acggcgcagc 4020

cacggcccgg tgccttcacg cgcacagcga cacagcccca gccagcgggg cccacgctaa 4080

ggcggaatcc cacagaagcc tacagagcga gcgcgcgcct gtgcttccca aaacggaatg 4140

gaaccaaggt gacttctaca gaacgatctg aagccctggc tggcccttat gctagtctct 4200

tgggagcgtt ccaaatgcag ctcaatatta cttacttgac ttttatcttt cctccctggt 4260

tcgtggtatt tataactggg tcatctttta actatttgca acgtagcttc aggggagagg 4320

gggagggctt tataaataac ctgtattatt attatgcagg ttgattctgt tccctgagct 4380

aaagggaaca tgaaaataca tgtctgtgac tcatgccccc ccacccccac tccagggtgt 4440

gctgaggagt ctctcagctg ccccggggtc ctcgagcagg ggagggagaa aggctggcgc 4500

tgcgccctcc atcgcgtgaa gccaggggat tttgctctgc gacaagctga cttggctctc 4560

gtattgtttg cagaatcacc cagttccaag gcagtccctg cgggcaggtg cagctgtgcg 4620

ggagcttcag tcctgtcccc aacacccagg cagtaatggt tccagcacgg aaggtctacc 4680

tacctcccac tgcacagccc gagggctgtc ctggaggcac agccatccgt ccctgggtgg 4740

gcaggcacgt ttatgacccc cacccccacc cccacccccc acgcgagtca gcacgttcca 4800

tactcgggtg atcgtgctca tcccctggtc atgtcatcgg gatctgagtg ccatccgagc 4860

agagagctgt ggcccggtgc cgggggtgga cttcatctat tccagggaac caaggatgca 4920

tgatttgcaa acaaaaccag aagcgcaagc catctcctcg cctcccctga tagccgtgct 4980

gcggagcctg agtgctggag 5000

<210> SEQ ID NO: 183

<211> LENGTH: 400

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 183

tgcgtttagt gtaaaaatat caggtgtggc tgcacggagt gaaaaatcac aggctccacg 60

gagccgggag gcctgctgcc ctgccctctt gctttgatga ggaaatggcg accgcagaag 120

gaaatgtagc agcaccggca accggcatcc gtggggccac gccgggctgc ttcccagggc 180

cctccagcca agcagccaca ggaaagagta gatgttgatc ccaagctagg actgaggagt 240

ccgtccctaa gagccgaggg agtcaggtgg gcgaaactgg ccgcatgtct gggtacaact 300

gctcagggtt tctcatctgc tgaatcacca agctaggttc tgaagccagg cgtgagtgag 360

caggactgga gcaggattct gggaacaatc ttttccctcc 400

<210> SEQ ID NO: 184

<211> LENGTH: 293

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 184

aggtggaggt tgcagtgagc cctcctcccc tcctccccct tcccttccca cctcccatgc 60

ccccctttct tcctcccact cccctcccga ggccccgctt attctcccgg cctgtggcgg 120

ttcgtgcact cgctgagctc aggttctggt gaaggtgccc ggagccgggt cccgccttcg 180

gcctgagcta gagccgcgcg ggcggccggc ttcccccaaa ccctgtggga ggggcatccc 240

gaggaggcga ccccagagag tggggcgcgg acaccttccc tggggagggc cag 293

<210> SEQ ID NO: 185

<211> LENGTH: 474

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 185

ccttccagat gttccagaag gagaaggcgg tgctggacga gctgggccga cgcacgggga 60

cccggctgca gcccctgacc cggggcctct tcggagggag ctgagggccg cgttccttct 120

gaaagcggga cgcgggaggg gtggaggctg cggggagccg gggtcgcaca cgaataaata 180

acgaatgaac gtacgagggg aacctcctct tatttccttc acgttgcatc gggtattttt 240

cgttattgta aataaaacgg ttccgagccg tggcatcgag agggcgtctg gagttcaggg 300

aacgcgtggc ccccgcccgg gagcaccgcg cagcgctcgc ctctcgccct tcaagggggt 360

ccctgcccgg agcctgcgcc cccggagagg aaggggctcg aggggcttgg gtgccgcagc 420

gcgtccttcc gtagaaaagg cttgcgtcag tatttcctgc ttttacctcc tgag 474

<210> SEQ ID NO: 186

<211> LENGTH: 346

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 186

cagtatttcc tgcttttacc tcctgagtat tggaatattc gagtaaaccc tggagtttca 60

gcgccagcgc acgcctcttc atcagggcag cgcgtcgcga gcgcgctggt tccccggggc 120

ctcccggcca cggacaccgc tctagccagg gccacggcga ggccgccgag cagcacctca 180

gagacctgcg tgagttctaa agcctggggc tactacaatt ctgctcatct gtttgtcctg 240

tgaaatgatt cagggacatg aaaatgcctt cccactgact tgcgtcctgt cttagcctgg 300

acttgtcccc ttgggaacac gggccaggcc cctctgttcc tgaagt 346

<210> SEQ ID NO: 187

<211> LENGTH: 2000

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 187

catacatggt tattagaaaa ggcatctcat ccaaatgtgg tggctcgtgc ttgtaatccc 60

agtgcttcag gaggccaagg gaggaggatt acttgagcct aagagtttga gaccagcctg 120

ggcaacacaa caagaccttg cctctacaaa aaacttaaaa actagctggg tatgatggtg 180

cacacctgta gtcccagcta cttgggaggc ggaggcgggc agatcgcctg aggtcaggag 240

ttcgagacca gcctggccaa catgatgaaa ccccgtctct actaaaaata caaaaattag 300

ccgagtgtgg tggtgcatgc ctgtaatccc agctactcag gaggctgagg caggagaatc 360

acttgaaccc gggaggcgga ggttgccatg agccgagatc acgtcactgc actccagcct 420

gggtgacaga gcacaaaaga caggcatgac tttgtactta actgctcagc tttgtaatca 480

ctgggggccc agatgctcac ttggattcta actttgttgg catctgggcc taaaagccgt 540

gatgcaggtg agcaatgatg cagagggctc tgtgcgcctg gcgggctctg tttgcctgct 600

gggctctgtg cgcctgctgg gctctgtgcg cccgggaagg tgcggccacc ctcacgcgga 660

aggcggccag cggatcccgg tgcgcgcagc tcccagcgct ggggttccag cgccccgcct 720

cttcctatag caaccagcgg gacctgccgt cccccggggc accccgaggg gtctgcgccc 780

gcttctttcc gaaacgggaa ggcgctgggg gctcggcagc cagagggacg ggttcaggga 840

gcgtccggtg agcctaagac gcgcctttgc cggggttgcc gggtgtctgc ctctcactta 900

ggtattagga accgtggcac aaatctgtag gttttcctct gggggtgggc ggaggctcca 960

aaccggacgg ttttctcctg gaggactgtg ttcagacaga tactggtttc cttatccgca 1020

ggtgtgcgcg gcgctcgcaa gtggtcagca taacgccggg cgaattcgga aagcccgtgc 1080

gtccgtggac gacccacttg gaaggagttg ggagaagtcc ttgttcccac gcgcggacgc 1140

ttccctccgt gtgtccttcg agccacaaaa agcccagacc ctaacccgct cctttctccc 1200

gccgcgtcca tgcagaactc cgccgttcct gggaggggaa gcccgcgagg cgtcgggaga 1260

ggcacgtcct ccgtgagcaa agagctcctc cgagcgcgcg gcggggacgc tgggccgaca 1320

ggggaccgcg ggggcagggc ggagaggacc cgccctcgag tcggcccagc cctaacactc 1380

aggaccgcct ccagccggag gtctgcgccc ttctgaggac cctgcctggg ggagcttatt 1440

gcggttcttt tgcaaatacc cgctgcgctt ggacggagga agcgcccacg cgtcgacccc 1500

ggaaacgaag gcctccctga tgggaacgca tgcgtccagg agcctttatt tactcttaat 1560

tctgcccgat gcttgtacgt gtgtgaaatg cttcagatgc ttttgggagc gaggtgttac 1620

ataaatcatg gaaatgcctc ctggtctcac cacacccagg gtgacagctg agatgcggct 1680

tctccagggt ggagcctcct cgttttccag agctgcttgt tgaagtcttc ccagggcccc 1740

tgacttgcac tggaaactgc tcaccttggc atcgggatgt ggagcaagaa atgcttttgt 1800

tttcattcat cctagtgttc ataaaatgga aaacaaataa ggacatacaa aaacattaat 1860

aaaataaatt aatggaacta gatttttcag aaagcacaac aaacacaaaa tccaagtatt 1920

gccatgtcag caacacattc ctactttaag ttttatgaag ttaattggag tagtggagaa 1980

caaaagtgga tgtggggcag 2000

<210> SEQ ID NO: 188

<211> LENGTH: 149

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 188

gctggaccag aaagtgttga gtacctgctc atgcgtgcaa gaggaggagg gaggagcaca 60

tcactgaact tcacatgaaa ttggataccc gggattagag acagtagagg gttttggtga 120

aatcagatac acattgcaaa gcagcacac 149

<210> SEQ ID NO: 189

<211> LENGTH: 146

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 189

ggtcgagttt ttggtggtgt tgagcggata gccggggaag ttggagtctt gtttgtggcc 60

gcctcgtgct cgtgtctgta tctaagatcc tcaggctgct cctttttggg taaggtctgt 120

tgcttctcta ggaacagtga cggtgg 146

<210> SEQ ID NO: 190

<211> LENGTH: 133

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 190

cctcgtgctc gtgtctgtat ctaagatcct caggctgctc ctttttgggt aaggtctgtt 60

gcttctctag gaacagtgac ggtggcagag cccgtggccc ctctctcctg tcccagagcc 120

aagctgtttc ctc 133

<210> SEQ ID NO: 191

<211> LENGTH: 95

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 191

ctgttgcatg agagcagagg ggagatagag agagcttaat tataggtacc cgcgtgcagc 60

taaaaggagg gccagagata gtagcgaggg ggacg 95

<210> SEQ ID NO: 192

<211> LENGTH: 127

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 192

tgcaggatat ttggcaaggt ttcttactgt tccaagtttt ttttccgaaa acctcccttg 60

aaacttttgt gcttacttgt ggtaacatac ccataatata ccctcttaac catttctacc 120

ggcacag 127

<210> SEQ ID NO: 193

<211> LENGTH: 104

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 193

tgaatcagtt caccgacagc cttggggaca ttcaccttgg gctccacaac ctgtcagaaa 60

tgcccccaag cccaaaggcg tcgagagaat ggccaggttg tttc 104

<210> SEQ ID NO: 194

<211> LENGTH: 127

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 194

ccgttatatg gatgccttgg ggcttggggg gtttctggca gtctgtcgag cccgaggtga 60

atgtccccaa ggctgctggt gaatcagatc cctggcgttc tccgttggca gttcagccca 120

acagttt 127

<210> SEQ ID NO: 195

<211> LENGTH: 144

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 195

ccaggcaaga tggcttatgt ctttaatctc agctgtttgg gaagccaagt ggaaagattg 60

cttgaggcca ggagttcaag accaacctgg ataatgtaag aagacctcgt ctctataaaa 120

aattaaaaat tggctgagca tggt 144

<210> SEQ ID NO: 196

<211> LENGTH: 110

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 196

gacccagacg atacctggaa attatttgct catgtggcag tcactgttga ttgcctaccc 60

aaagccatta ctccttctcc ccacctaaca gaagccgagt tttgttcagc 110

<210> SEQ ID NO: 197

<211> LENGTH: 101

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 197

ccacatcctg gccatctact tcctcttaaa caagaaactg gagcgctatt tgtcaggggt 60

aagtgcgacc ctagaggcga tcgtctctgc tgtctgtgga a 101

<210> SEQ ID NO: 198

<211> LENGTH: 88

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 198

tgagctcaca ggtctggaaa tggtctgaat agaaaggatt ggtctccgga ggaaagcata 60

ctcttcctat taccagaacc ctgtgggg 88

<210> SEQ ID NO: 199

<211> LENGTH: 128

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 199

attctccaca gggcaatgag gcaagaaatt tacagcttag cctgattaat gggccaggca 60

gttaagagtt ctttgccaag ctatgagcat aatttatagt catcacggca ggaggaaagg 120

ccacataa 128

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Patent Valuation

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20.0/100 Score

Market Attractiveness

It shows from an IP point of view how many competitors are active and innovations are made in the different technical fields of the company. On a company level, the market attractiveness is often also an indicator of how diversified a company is. Here we look into the commercial relevance of the market.

72.0/100 Score

Market Coverage

It shows the sizes of the market that is covered with the IP and in how many countries the IP guarantees protection. It reflects a market size that is potentially addressable with the invented technology/formulation with a legal protection which also includes a freedom to operate. Here we look into the size of the impacted market.

73.88/100 Score

Technology Quality

It shows the degree of innovation that can be derived from a company’s IP. Here we look into ease of detection, ability to design around and significance of the patented feature to the product/service.

42.0/100 Score

Assignee Score

It takes the R&D behavior of the company itself into account that results in IP. During the invention phase, larger companies are considered to assign a higher R&D budget on a certain technology field, these companies have a better influence on their market, on what is marketable and what might lead to a standard.

14.98/100 Score

Legal Score

It shows the legal strength of IP in terms of its degree of protecting effect. Here we look into claim scope, claim breadth, claim quality, stability and priority.

Citation

Patents Cited in This Cited by
Title Current Assignee Application Date Publication Date
Methods for detecting a target nucleic acid in a sample F. HOFFMANN-LA ROCHE AG 24 April 1992 08 September 1999
Methods for identifying methylation patterns in a CpG-containing nucleic acid THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE 28 July 1998 13 March 2001
Reaction mixtures for detection of target nucleic acids ROCHE MOLECULAR SYSTEMS, INC. 25 April 1995 08 September 1998
Homogeneous methods for nucleic acid amplification and detection ROCHE MOLECULAR SYSTEMS, INC. 02 May 1991 30 November 1999
Homogeneous assay system F. HOFFMANN-LA ROCHE AG 06 August 1991 15 November 2006
See full citation <>

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