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United States Patent Application 20170152565
Kind Code A1
Hart; Thomas C. ;   et al. June 1, 2017

METHOD FOR DIAGNOSING RENAL DISEASES OR PREDISPOSITIONS

Abstract

The invention provides a method of diagnosing a disease or a predisposition to contract a disease by assaying for mutations of uromodulin (UMOD) within a test subject or patient. The presence of a mutation in the UMOD supports a diagnosis of a disease or a predisposition to contract a disease within the patient.


Inventors: Hart; Thomas C.; (Potomac, MD) ; Hart; Patricia Suzanne; (Potomac, MD) ; Gorry; Michael; (Pittsburgh, PA) ; Bleyer; Anthony J.; (Winston-Salem, NC)
Applicant:
Name City State Country Type

University of Pittsburgh - Of the Commonwealth System of Higher Education
Wake Forest University

Pittsburgh
Winston-Salem

PA
NC

US
US
Family ID: 1000002454743
Appl. No.: 15/430171
Filed: February 10, 2017


Related U.S. Patent Documents

Application NumberFiling DatePatent Number
14269515May 5, 20149567638
15430171
12843714Jul 26, 20108759001
14269515
11112327Apr 23, 20057781164
12843714
PCT/US2003/033957Oct 23, 2003
11112327
60420768Oct 23, 2002
60430318Dec 2, 2002

Current U.S. Class: 1/1
Current CPC Class: C12Q 2600/156 20130101; C12Q 1/6883 20130101
International Class: C12Q 1/68 20060101 C12Q001/68

Goverment Interests



STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made in part with Government support under Grant Number DK62252 awarded by the National Institute of Diabetes and Digestive and Kidney Diseases. The United States Government may have certain rights in this invention.
Claims



1.-20. (canceled)

21. An oligonucleotide comprising a fragment of a uromodulin (UMOD) gene or the complement thereof, wherein the UMOD gene comprises a imitation selected from the group consisting of: (i) G>A at nucleotide position 1880 of the UMOD coding sequence; (ii) a deletion of the nucleotides at positions 1966 to 1992 of the UMOD coding sequence; (iii) T>C at nucleotide position 2086 of the UMOD coding sequence; (iv) G>A at nucleotide position 2105 of the UMOD coding sequence; and (v) G>T at nucleotide position 1744 of the UMOD coding sequence; wherein the oligonucleotide is detectably labeled.

22. The oligonucleotide of claim 21, wherein the oligonucleotide specifically binds to the UMOD gene comprising a mutation under high stringency conditions.

23. The oligonucleotide of claim 21, wherein the oligonucleotide does not specifically bind to the wild type UMOD coding sequence under high stringency conditions.

24. The oligonucleotide of claim 21, wherein the UMOD gene comprises a deletion of the nucleotides at positions 1966 to 1992 of the UMOD coding sequence.

25. The oligonucleotide of claim 21, wherein the UMOD gene comprises a G>A mutation at position 1880 of the UMOD coding sequence.

26. The oligonucleotide of claim 21, wherein the UMOD gene comprises a T>C at nucleotide position 2086 of the UMOD coding sequence.

27. The oligonucleotide of claim 21, wherein the UMOD gene comprises G>A at nucleotide position 2105 of the UMOD coding sequence.

28. The oligonucleotide of claim 21, wherein the UMOD gene comprises G>T at nucleotide position 1744 of the UMOD coding sequence.

29. A method of detecting a mutation in a UMOD gene, the method comprising: (a) contacting a UMOD nucleic acid obtained from a human test subject with an oligonucleotide selected from: (i) an oligonucleotide comprising a fragment of a UMOD nucleic acid sequence that specifically binds to a UMOD gene having a mutation selected from the group consisting of: (1) T>C at nucleotide position 2086 of the UMOD coding sequence; (2) G>A at nucleotide position 2105 of the UMOD coding sequence; and (3) G>T at nucleotide position 1744 of the UMOD coding sequence; (ii) an oligonucleotide that is the complement of the oligonucleotide of (i); (b) detecting hybridization of the oligonucleotide with the UMOD nucleic acid, wherein hybridization is indicative of the presence of a mutation in the UMOD gene.

30. The method of claim 29, wherein the UMOD nucleic acid is genomic DNA.

31. The method of claim 29, wherein the UMOD nucleic acid is RNA.

32. The method of claim 29, wherein the method further comprises generating a synthetic copy of the DNA or RNA of the test subject.

33. The method of claim 29, wherein the oligonucleotide is detectably labeled.
Description



CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application is a continuation of Ser. No. 14/269,515, filed on May 5, 2014, which is a divisional of U.S. patent application Ser. No. 12/843,714, filed on Jul. 26, 2010, issued as U.S. Pat. No. 8,759,001 on Jun. 24, 2014, which is a continuation of U.S. patent application Ser. No. 11/112,327, filed on Apr. 23, 2005, issued as U.S. Pat. No. 7,781,164 on Aug. 24, 2010, which is a continuation-in-part of PCT/US03/33957, filed on Oct. 23, 2003, and claims the benefit of U.S. Provisional Patent Application No. 60/430,318, filed on Dec. 2, 2002, and U.S. Provisional Patent Application No. 60/420,768, filed on Oct. 23, 2002. The contents of each of these applications are incorporated herein in their entirety by reference thereto.

INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY

[0003] Incorporated by reference in its entirety herein is a computer-readable nucleotide/amino acid sequence listing submitted concurrently herewith and identified as follows: One 89,394 bytes ASCII (Text) file named "727891_ST25.TXT," created Feb. 10, 2017.

FIELD OF THE INVENTION

[0004] This invention pertains to methods and reagents for diagnosing diseases or a predisposition to develop a disease.

BACKGROUND OF THE INVENTION

[0005] Medullary cystic kidney disease 2 (i.e., "MCKD2," Online Mendelian Inheritance in Man Ref. OMIN603860 (available on the Internet at: www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603860) and familial juvenile gouty nephropathy (i.e., "FJGN" Online Mendelian Inheritance in Man Ref. OMIM162000 (available on the Internet at: www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=162000) are autosomal dominant renal diseases characterized by juvenile onset of hyperuricemia, gout, enuresis, and progressive renal failure. Both conditions typically result in death, unless renal trasnsplantation is preformed.

[0006] Because clinical features of both MCKD2 and FJGN vary in presence and severity, definitive diagnosis of both conditions is difficult before the onset of significant pathology. As such, currently, both conditions generally cannot be treated early, and prophylaxis typically is not possible for these conditions. Accordingly, there exists a need for a more sensitive diagnostic method and reagents for diagnosing diseases, such as MCKD2 and FJGN, or the predisposition to develop such diseases

BRIEF SUMMARY OF THE INVENTION

[0007] The invention provides a method of diagnosing a disease or a predisposition to contract a disease by assaying for mutations of uromodulin (UMOD, also known as Tamm-Horsfall glycoprotein (available on the Internet at: www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191845) within a test subject or patient. The presence of a mutation in the UMOD supports a diagnosis of a disease or a predisposition to contract a disease within the patient.

[0008] The inventive method can permit diagnosis of diseases (e.g., MCKD2, FJGN, nephropathy, renal failure, hyperuricemia, gouty arthritis, enuresis, and the like) earlier than current methods, which can facilitate intervention and treatment of such diseases prior to the onset of significant pathology. In some applications, the method can identify a predisposition to develop such disorders even in a non-symptomatic patient. Furthermore, the method can be employed to screen a potential tissue donor or donated tissue or organs (e.g., a kidney or renal tissue) to minimize the risk to a transplant recipient of receiving donated tissue at risk for developing such disorders. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIGS. 1A and 1B depict the pedigrees of families studied. Family 1: more than 300 individuals have been genealogically identified over 7 generations. The kindred is too large to include in total; thus, the nuclear families studied have been indicated for this report. These families are from different parts of this extended kindred, and are indicated as subfamilies A, B, C, and D. In addition eight singletons were studied. Clinical findings in affected family members are consistent with a clinical diagnosis of FJHN in Family 1. Family 2: Clinical findings in this family are consistent with a clinical diagnosis of FJHN. Family 3: Clinical findings and renal biopsy/autopsy reports are consistent with a clinical diagnosis of MCKD2 (Thompson et al., Arch. Intern. Med., 138, 1614-17 (1978)).

[0010] FIG. 2 depicts the integrated physical and genetic map of the FJHN/MCKD2 candidate region on chromosome 16p. Genetic STRP markers and their relative locations are indicated on the left. Locations of significant linkage results (LOD scores >3.0) are indicated for 2 families in the current report (Family 1 and Family 2) and for five other studies (referenced 1-5). Nine known STRPs and nine novel STRPs were identified, localized and genotyped. Two novel STRP loci were identified in BAC2349B8; the position of these loci (2349B8(16)-2 and 2349B8(16)-1) are separated by 54,000 bp as indicated in FIG. 2, and the order of these are given in FIG. 3. Genetic loci identified in the region are indicated to the right of the figure.

[0011] FIG. 3 depicts the haplotype results indicating the minimal genetic interval on chromosome 16 segregating with the FJHN phenotype in Family 1 and Family 2. FJHN affected individuals are indicated by shaded symbols, white circle and squares indicate unaffected family members, slash indicates deceased. Genetic STRP loci genotyped are listed in positional order in the left column for each family. Haplotypes segregating with the disease locus are shaded. Individual II-5 from Family 2 is unaffected, but has inherited the disease associated haplotype for the interval D16S412-D16S3046, indicating this region does not contain the FJHN disease locus. The boxed region indicates the minimal haplotype region segregating with the FJHN in both families, indicating the FJHN gene is within the interval flanked by 2349B8(16)-2 and D16S3046.

[0012] FIG. 4 depicts the structure of the human UMOD gene. A. Genomic organization of the UMOD gene. The exons and introns are represented as vertical boxes and horizontal lines respectively. The sizes of each intron are given in bp. B. cDNA structure of the UMOD gene. The translation start and stop codon are labeled as ATG and TGA, respectively. The 5' and 3' untranslated regions are shaded gray. The arrows indicate the missense mutations identified in this study. The horizontal bar indicates the deletion identified in this study. C. Structure of the wild-type UMOD protein. The inititation met is amino acid 1. The signal peptide is shown as a black box. The EGF-like domains are shown as dotted lines. The ZP domain is shown as a gray box. The eight potential glycosylation sites are shown as Y. The missense mutations identified in this study are shown as arrows with the corresponding amino acid listed below. The 9 amino acid deletion is shown as a horizontal bar. Additional recent preliminary data suggest that additional exons, other than those depicted in FIG. 4, may exist.

[0013] FIG. 5 diagrams mutations in the UMOD sequence. The top sequence in each panel shows wild-type sequence (SEQ ID NO:1 to SEQ ID NO:4). The bottom sequence is from an affected individual (SEQ ID NO:5 to SEQ ID NO:8). Descriptions of each mutation are given for [genomic; cDNA; protein] in accordance with nomenclature guidelines. A. Affected individuals in Family 1 were heterozygous for a 27 bp deletion that results in the in-frame deletion of amino acids 177-185. [g.1966_1992de1; c529_555del; p.H177_R185del]. B. Affected individuals in Family 2 were heterozygous for a missense mutation that changes a conserved cys to tyr. [g.1880G>A; c.443G>A; p.C148Y]. Affected individuals in Family 3 were heterozygous for a missense mutation that changes a gly to a cys. [g.1744G>T; c.307G>T; p.G103C]. D. Affected individuals in Family 4 were heterozygous for a missense mutation that changes a conserved cys to arg. [g.2086T>C; c.649T>C; p.C217R].

[0014] FIG. 6. Alignment of the amino acid sequence of human UMOD (GenBank accession No M17778 (SEQ ID NO:9)) with the UMOD of bovine (GenBank accession No 575958(SEQ ID NO:10)), murine (GenBank accession No NM_009470(SEQ ID NO:11)) and rat (GenBank accession No. M63510(SEQ ID NO:12)). All 48 C residues are conserved and shown in bold with an asterisk. The arrows indicate the position of the missense mutations identified in this study. The 9 amino acids deleted in Family 1 are indicated in bold and underlined.

[0015] FIG. 7 depicts SEQ ID NO:1 to SEQ ID NO:8 discussed herein.

[0016] FIG. 8 depicts SEQ ID NO:9 discussed herein.

[0017] FIG. 9 depicts SEQ ID NO:10 discussed herein.

[0018] FIG. 10 depicts SEQ ID NO:11 discussed herein.

[0019] FIG. 11 depicts SEQ ID NO:12 discussed herein.

[0020] FIG. 12 depicts SEQ ID NO:13 discussed herein.

[0021] FIG. 13 depicts SEQ ID NO:14 discussed herein.

[0022] FIG. 14 depicts SEQ ID NO:15 discussed herein.

[0023] FIG. 15 depicts SEQ ID NO:16 discussed herein.

[0024] FIG. 16 depicts SEQ ID NO:17 discussed herein.

[0025] FIG. 17 depicts SEQ ID NO:18 discussed herein.

[0026] FIG. 18 depicts SEQ ID NO:19 discussed herein.

[0027] FIG. 19 depicts SEQ ID NO:20 discussed herein.

[0028] FIG. 20 depicts SEQ ID NO:21 discussed herein.

[0029] FIG. 21 depicts SEQ ID NO:22 discussed herein.

[0030] FIG. 22 depicts SEQ ID NO:23 discussed herein.

[0031] FIG. 23 depicts SEQ ID NO:24 discussed herein.

[0032] FIG. 24 depicts SEQ ID NO:25 discussed herein.

[0033] FIG. 25 depicts SEQ ID NO:26 discussed herein.

[0034] FIG. 26 depicts SEQ ID NO:27 discussed herein.

[0035] FIG. 27 depicts SEQ ID NO:28 discussed herein.

[0036] FIG. 28 depicts SEQ ID NO:29 discussed herein.

[0037] FIG. 29 depicts SEQ ID NO:30 discussed herein.

[0038] FIG. 30 depicts SEQ ID NO:31 discussed herein.

[0039] FIG. 31 depicts SEQ ID NO:32 discussed herein.

[0040] FIG. 32 depicts SEQ ID NO:33 discussed herein.

[0041] FIG. 33 depicts SEQ ID NO:34 discussed herein.

[0042] FIG. 34 depicts SEQ ID NO:35 to SEQ ID NO:57 discussed herein.

[0043] FIG. 35 depicts SEQ ID NO:58 to SEQ ID NO:87 discussed herein.

DETAILED DESCRIPTION OF THE INVENTION

[0044] The invention provides a method of diagnosing a disease or a predisposition to contract a disease by assaying for mutations of UMOD within a test subject. Any individual can be tested in accordance with the inventive method. Typically, however, the test subject (or patient) belongs to a family with a history of disorders such as, for example, MCKD2, FJGN, nephropathy, renal failure, hyperuricemia, gouty arthritis, and enuresis. Asymptomatic individuals from such families can be tested to assess whether they have a predisposition to contract such diseases or whether they might be a carrier of an allele that can cause the disease in their progeny. In fact, the method can be used prenatally to assess the propensity of a fetus to develop MCKD2, FJGN, nephropathy, renal failure, hyperuricemia, gouty arthritis, and enuresis after birth. Alternatively, the inventive method can be used to diagnose symptomatic patients, typically those exhibiting hyperuricemia, renal insufficiency, and/or enuresis. For such patients, the inventive method can provide earlier and/or more definitive diagnosis, which can facilitate earlier intervention and treatment. Furthermore, inasmuch as people in need of transplants often receive donated kidneys and other renal tissue from close relatives of family members, the inventive method can be used to screen donors or donated tissue to ensure that the recipient does not receive renal tissue that produces abnormal UMOD protein.

[0045] In one embodiment, the inventive method involves assaying genetic material obtained from a test subject. The genetic material can be, for example, DNA or RNA obtained directly from the test subject, or the genetic material can be copied or amplified from genetic material within the test subject's cells (e.g., via PCR, RT-PCR, or other suitable technique). For example, cells can be harvested from a urine sample to obtain genetic material. To ensure that sufficient quantity of genetic material is available for testing, typically genetic material amplified from cells obtained from the test subject is assayed in accordance with the inventive method. Desirably, a PCR or RT-PCR strategy is employed using primers flanking all or a portion of the UMOD gene, so as to amplify this sequence from the patient for the assay. Because MCKD2 and/or FJGN are autosomal dominant disorders, it is most preferred to amplify/copy both copies of the UMOD gene from the test subject, so that both can be assayed in accordance with the inventive method.

[0046] However obtained, the genetic material is assayed to detect a mutation in the UMOD gene (e.g., a mutation at least one of the two UMOD alleles). Any test able to detect mutations appropriate to the type of genetic material (e.g., gDNA, cDNA, RNA, etc.) can be used to this end. For example, a portion or substantially all of the genetic material can be sequenced, and the sequence compared to the wild-type UMOD sequence (see, e.g., GenBank Accession Nos. AY 162963 (SEQ ID NO:13), AY162964(SEQ ID NO:14), AY162965(SEQ ID NO:15), AY162967(SEQ ID NO:16), AY162968(SEQ ID NO:17), AY162969(SEQ ID NO:18), and AY162970(SEQ ID NO:19)) to detect any mutations (see, e.g., FIG. 5). Alternatively, the genetic material can be probed with a hybridization probe that is substantially specific for a predetermined UMOD mutation (e.g., via Northern or Southern hybridization, PCR, or other appropriate method, such as are well-known to those of ordinary skill in the field). For example, one known UMOD mutation associated with MCKD2 and/or FJGN is a deletion of 27 base pairs from exon 4 of the UMOD gene (see FIG. 6), and a probe designed to straddle this deletion can be employed to quickly assay for this mutation (e.g., via ELISA).

[0047] In another embodiment, the inventive method involves assaying UMOD protein obtained from the test subject. The UMOD protein can be obtained by any suitable method, such as in a urine sample or cells isolated therefrom. Thereafter, the UMOD protein obtained from the test subject is assayed to detect a mutation. For example, the UMOD protein can be purified (either partially or substantially (see, e.g., Tamm and Horsfall, J. Exp. Med., 95, 71-97 (1952)) and assayed via immunohistological techniques (e.g., Western blotting, ELISA, immunoprecipitation, etc.) using one or more antibodies recognizing known mutant UMOD proteins but not wild type UMOD protein. Alternatively, or in conjunction, the UMOD protein sample from the test subject can be assayed using one or more antibodies recognizing wild type UMOD proteins but not known mutant UMOD protein. Thus, in some applications, it can be possible to develop an immunological UMOD profile of a given test subject or even quantitatively determine the amount and/or type of mutant and wild type UMOD protein present.

[0048] As an alternative to immunological characterization, protein from a test subject can be assayed morphologically. In this respect, UMOD is known to be polymeric in its native form, composed of monomeric subunits of approximately 85 kD, with 30% of the molecular weight due to carbohydrates and the remaining 70% due to the polypeptide chain (Fletcher et al., Biochem. J, 120, 425-32 (1970)). Electron microscopy reveals that the high molecular weight aggregate is composed of thin, intertwining fibers with a zigzag or helical structure. Recent analysis indicates that the filaments consist of two protofilaments wound around each other, forming a right-handed helix (Jovine et al., Nat. Cell. Biol., 4, 457-61 (2002)). UMOD contains a zona pelucida (ZP) domain, which has been shown to be responsible for polymerization of ZP-containing proteins into filaments (Jovine et al.). UMOD also contains a high number of cysteine residues (48 per monomer), allowing for the potential formation of 24 intramolecular disulfide bonds. These cysteine residues are highly conserved across species (FIG. 6). Mutations of the UMOD protein can alter its primary and secondary structure and ability to associate and form its typical tertiary structure. Thus, in some applications, it is possible to compare the structure of UMOD from a test subject with that of wild type protein as a morphological assay for mutant UMOD protein.

[0049] Of course, it also is possible to employ both genetic and protein assays in conjunction with each other to detect mutant UMOD within a test subject. Regardless of the method of assay, however, a test result that supports the presence of mutant or abnormal UMOD genetic material and/or protein from the test subject supports a diagnosis of MCKD2, FJGN, nephropathy, renal failure, hyperuricemia, gouty arthritis, or enuresis within the test subject, if accompanied by other symptoms consistent with such a disease. A UMOD-positive result for a non-symptomatic test subject supports a diagnosis of a predisposition to develop such a disease.

[0050] The following example further illustrates the invention but, of course, should not be construed as in any way limiting its scope.

EXAMPLE 1

[0051] This example demonstrates the existence of four UMOD gene mutations that segregate with the disease phenotype in three families with FJGN and in one family with MCKD2. These findings provide direct evidence that MCKD2 and FJGN arise from mutation of the UMOD gene and are allelic disorders. Accordingly, it is possible to assay for UMOD mutations to identify a propensity to develop FJHN and/or MCKD2.

Patients and Methods

[0052] Pedigrees and Diagnostics

[0053] Study participants were obtained from four families. Family 1 was a large multi-generational family in which the disorder was traced back 7 generations. The family tree contains more than 300 members and was too large for the entire pedigree to be depicted. FIG. 1 shows the pedigree for selected portions of the family in whom the majority of samples were obtained. This family had a long history of hyperuricemia, reduced fractional excretion of uric acid, and renal failure, inherited in an autosomal dominant fashion, with clinical findings consistent with FJHN. Family 2 was a large multi-generational family that also segregated FJHN as a highly penetrant autosomal dominant trait. Family 3 has previously been reported to suffer from medullary cystic disease, hyperuricemia, and gout (Thompson et al., Arch. Intern. Med., 138, 1614-17 (1978)), inherited in an autosomal dominant fashion (see FIG. 1). A sample was obtained from one affected family member from Family 4. Family 4 was previously extensively described in the literature as suffering from familial hyperuricemia and renal disease but no medullary cysts, findings consistent with a diagnosis of FJHN (Massari et al., Arch. Intern. Med., 140, 680-84 (1980)). Family 5 was screened because family members had exhibited symptoms consistent with a diagnosis of FJGN.

[0054] Serum uric acid and serum creatinine measurements were performed, and 24-hour urine collections for uric acid and creatinine were obtained. The creatinine measurements were performed by the Jaffe alkaline picrate kinetic method (Tietz N W. Clinical Guide to Laboratory Tests, 3d edition. WB Saunders Company, Philadelphia, Pa.; 186-87 (1995)). The uric acid measurements were performed on the ADVIA 1650 Chemistry System. The uric acid determination method is based on the Fossati enzymatic reaction using uricase with a Trinder-like endpoint (Fossati, Clin. Chem., 26, 227-231 (1980)). Estimates of creatinine clearance, as determined by the Cockroft-Gault formula (Cockroft et al., Nephron, 16, 31-41 (1976)), were made using the patient's weight or ideal body weight, whichever was less. Renal insufficiency was defined as an estimated creatinine clearance less than 80 ml/min. Enuresis was defined as persistent bed-wetting after the age of 4 years.

[0055] Patients were considered to be definitely affected if they met the following criteria: (1) Hyperuricemia, defined as serum uric acid levels greater than 2 standard deviations (s.d.) above the age- and gender-adjusted norms for the population (Wilcox, J. Pediatr., 128:731-41 (1996); Mikkelsen et al., Am. J. Med., 39, 242-51 (1965)) or a history of gout and current treatment with allopurinol, and (2) Reduced fractional excretion of uric acid (<5% for men and <6% for women) or a reduced creatinine clearance of less than 80 ml/min. (In general, individuals with a creatinine clearance less than 80 ml/min will start developing an elevated fractional excretion of uric acid (Rieselbach et al., Nephron, 14, 81-87 (1975)), and as such family members with renal insufficiency could not have their fractional excretion of uric acid used as a determinant of FJHN). Family members were defined as clinically unaffected if the serum uric acid level was within 1 s.d. of the age and gender-adjusted norms for the population (Wilcox; Mikkelsen et al.).

[0056] DNA-Marker Analysis

[0057] Genomic DNA was extracted from peripheral blood by standard methods using the QIAamp blood kit (Qiagen). Genetic linkage studies were performed for 90 individuals from two extended multigenerational families diagnosed with FJHN (Family 1 and Family 2, FIG. 1). Available family members were genotyped for STRP-type (Short Tandem Repeat Polymorphism) genetic markers spanning the candidate interval. In addition to 9 previously reported STRP loci, 9 novel STRP loci were developed from a 5.6-Mb physical map of the interval (FIG. 2, FIG. 3). These marker loci were PCR amplified by use of fluorescence-labeled primers, permitting genotyping by conventional methods (Hart et al., Am. J. Hum. Genet., 70, 943-54 (2002)). PCR products were detected by an ABI 377 fluorescent sequencer and were analyzed by GENESCAN 2.1 (Applied Biosystems).

[0058] Parametric Linkage Calculations: LOD Scores and Haplotype Analysis

[0059] Sub-localization of the candidate interval was achieved by means of genetic linkage studies and determination of the minimal region of overlap of haplotypes segregating with the FJHN trait in Family 1 and Family 2. Standard two-point and multipoint linkage analyses were performed using the VITESSE program (O'Connell et al., Nat. Genet., 11, 402-08 (1995)). Assumptions of the linkage analyses included autosomal dominant transmission, penetrance values of 95-100%, a disease allele frequency of 0.0001, and a phenocopy rate of 1%. To permit identification of haplotypes, a physical map of the FJHN candidate gene region was developed. This map permitted precise localization of known STRP markers within the region and allowed identification of novel STRP markers at desired locations spanning the interval.

[0060] Development of a Physical Map of the Candidate FJGN Candidate Interval; STRP and Gene Identification

[0061] To identify novel STRP-type markers spanning the candidate interval and to permit identification of all known and hypothetical genes within the interval, the development of a detailed physical/genetic map was initiated (Zhang et al., Cyto. Genet. Cell. Genet., 95, 146-52 (2001)). The final alignment contained 67 BACS that span a 5.6 million base region. This region contains two gaps across which a BAC sequence did not align. This contig was screened for all known genes, and STRP loci were identified through the NCBI Human Genome Sequencing website and GENEMAP 99 gene website [on the internet at www.ncbi.nlm.nih.gov/genome/seq and www.ncbi.nlm.nih.gov/genemap/] gene and STRP loci confirmed on the BAC contig were positioned on the new map. New STRP markers were identified using the Tandem Repeats Finder (Benson, Nucl. Acids. Res., 27, 573-80 (1999); and on the internet at c3.biomath.mssm.edu/trf.advanced.submit.html). Candidate STRP sites were then selected and primers designed using Oligo 4.0 software.

[0062] Several sources of information were used to identify genes in the candidate region: The Human Genome Project Working Draft at UCSC (on the internet at genome.ucsc.edu/), the Sanger Center's ENSEMBLE database (on the internet at www.ensembl.org) and Locus Link (Benson). NCBI BLAST (on the internet at www.ncbi.nlm.nih.gov/blast/) and ePCR were also used on the BAC contig sequence with the BLAST non-redundant and dbEST databases screened. A cDNA contig was made for each candidate gene using all information that was available at the time. The inclusion of all EST data provided for a more accurate representation of the gene. Intron/exon boundaries were determined manually using the consensus splice sequences indicated at GENIO/splice (internet site is genio.informatik.uni-stuttgart.de/GENIO/splice/). Primers for amplifying candidate genes from genomic DNA were designed using data obtained from the primary contig as well as from available NCBI data (accession numbers in electronic references; NCB Locus Link, NCBI Entrez) [NCBI Locus Link (on the internet at www.ncbi.nlm.nih.gov/LocusLinc/) for genes shown in FIG. 2--Locus ID Numbers are: XT1-64131 (SEQ ID NO:20), COQ7-10229 (SEQ ID NO:21), B/K-51760 (SEQ ID NO:22), G104-162074, GPRC5B-51704 (SEQ ID NO:23), GP2-2813 (SEQ ID NO:24), UMOD-7369 (SEQ ID NO:25), BUCS1-116285 (SEQ ID NO:26); NCBI Entrez provided at (www.ncbi.nlm.nih.gov/Entrez/) Gene Accession Numbers: XT1-XM 485032 (SEQ ID NO:27), COQ7-NM 016138 (SEQ ID NO:28), B/K-NM 016524 (SEQ ID NO:29), G104-XM_091332 (SEQ ID NO:30), GPRCSB-NM_016235 (SEQ ID NO:31), GP2-NM_001502 (SEQ ID NO:32), UMOD-NM_003361 (SEQ ID NO:33), BUCS1-NM_052956 (SEQ ID NO:34)]. By means of linkage and haplotype analyses, the FJHN candidate region was refined to about an 1.7-Mb interval. Five known genes were localized to this interval. Additionally, using an integrated bioinformatic and bench lab approach, one previously uncharacterized genetic locus was localized within the interval. All exons and intron-exon boundaries of four of these genes were analyzed by sequence analysis of genomic DNA from affected and unaffected family members from Family 1 and Family 2.

[0063] UMOD Exon Sequencing

[0064] The genomic structure of the UMOD gene was determined bioinformatically and was confirmed by sequence analysis. Oligonucleotide primers to amplify 11 of the 12 exons, including intron-exon boundaries (Table 1), were designed with Oligo 4.02 (National Biosciences). PCR amplification of the UMOD gene was performed as indicated in Table 1.

TABLE-US-00001 TABLE 1 Primer Sets for Exonic Amplification of Human UMOD Gene Primer (5'.fwdarw.3') SEQ SEQ GenBank ID ID Size PCR Accession Exon NO Forward NO Reverse (bp) Condition.sup.a Number 02-03 35 TCCTGCTCCAAATGACTGAGTTCT 36 TCAACCCAATGGAATGACCTCTTA 888 B AY162963 04-05 37 GGTGGAGGCTTGACATCATCAGAG 38 GGAATAGGGCTCAGATGGTCTTTG 1493 A AY162963 04-05.sup.S 39 GCCCTGGCCTCATGTGTCAATGTG 40 GGGTCACAGGGACAGACAGACAAT AY162963 04-05.sup.S 41 CGGCGGCTACTACGTCTACAACCT 42 GTAGCTGCCCACCACATTGACACA AY162963 06 43 ACCTCTGGACCTCAAGTAATCTGT 44 TGATGCCTACTGGCTGAGACAATC 940 A AY162964 07 45 ACCAGCAGATTTAGCTTTGAAGTC 46 GCTTGAACCAGGCAGTGCTTTGAC 475 A AY162965 08 47 AGCAGCATCCAGGCACTTGTCAGA 48 TGAGGCAGAAGAATCACTTGAACC 711 B AY162967 08.sup.S 49 TCCAAAGACCCCCTCTGAATTCTA AY162967 09 50 ATTTGAATCCAGGAAGTCTGACTC 51 GGCAAGCCACTGAAGTTCTCTGAG 612 B AY162968 10 52 GAGCGGCTCAGAGAACTTCAGTGG 53 CCCGTGTCCTGTGTTACATTCATC 529 B AY162968 11 54 GAGCCCCTGATGGGTCTGAAGTAG 55 TCTGAGCCACTCTCCTTATTTAGA 345 B AY162969 12 56 TAGATTGGGCACTTCACAAGAATG 57 ACAGCAGAACCCAGTCTCACTGAG 733 B AY162970 .sup.Sdenotes primers also used in sequencing reactions. Sequencing was performed with BigDye Terminator System form ABI. .sup.aThe standard PCR amplification for each exon contains: taq (0.025 U/.mu.l), 1x PCRx Enhancer Buffer, 25 nM each dNTP, and 1.5 mM MgS04 A = 5% PCRx Ehancer B = 1X PCRx Enhancer Buffer, no PCR x Enhancer. Cycling Conditions = 95-5'+94-30''/56-30''/72-90'' 35X+71-10'

[0065] Amplified DNA was purified with the QIAquick PCR Purification Kit (Qiagen) and was sequenced using the BigDye Terminator Cycle Sequencing Kit on an ABI 3700 DNA Analyzer (Applied Biosystems) by the Genomics and Proteomics Core Laboratories of the University of Pittsburgh. Sequence analysis was performed with Sequencher 4.1 software (GeneCodes).

Results

[0066] Clinical Findings

[0067] Over a five-year period, clinical testing was performed on 72 members of Family 1. Thirty-one met strict criteria to be considered affected (hyperuricemia with reduced fractional excretion of uric acid or renal insufficiency), 22 were diagnosed as normal, and there were 10 unaffected spouses. For nine family members, a certain diagnosis could not be made. Thirty-four individuals suffered from hyperuricemia and 28 suffered from renal insufficiency. The pedigrees for families 2 and 3 identify all individuals who suffered from hyperuricemia or renal insufficiency.

[0068] Renal Biopsies

[0069] Pathologic samples were obtained by kidney biopsy in three members of Family 1. All three biopsies revealed histological changes of tubular atrophy and interstitial fibrosis. Global glomerulosclerosis was present, and there was no evidence of glomerulonephritis. In Family 2, a biopsy specimen of an affected female at age 39 years revealed widespread tubular atrophy. In Family 3, several autopsy specimens were obtained. The first was that of a 34-year-old man, revealing by report, tubules ensheathed by a dense acellular hyaline material (Thompson et al., Arch Intern Med., 138, 1614-17 (1978)). Medullary cysts were present. In another family member, autopsy studies again revealed sheathing of the tubules by fibrous tissue. In case three, tubules were ensheathed by dense acellular hyaline material (Thompson et al.). In Family 4, biopsy samples revealed focal tubular atrophy with interstitial fibrosis and lymphocytic infiltration. In summary, all biopsy specimens revealed focal tubular atrophy with interstitial fibrosis. Autopsy reports revealed tubules ensheathed by dense acellular hyaline material. Interstitial deposits of PAS-positive material also have been identified in medullary cystic kidney disease (Zager et al., Lab. Invest., 38, 52-57 (1978); Resnick et al., Lab. Invest., 38, 550-55 (1978)). Immunostaining of these deposits was found to be markedly positive with antibody to Tamm-Horsfall protein.

[0070] Physical Map of the Candidate Interval

[0071] Existing genetic and physical maps of the FJHN/MCKD2 candidate interval were generally poorly integrated and identified relatively few polymorphic genetic markers (STRPs) spanning the interval. This was problematic as a key marker (D16S3056) was uninformative in the families studied. The development of an integrated physical and genetic map of the FJHN/MCKD2 candidate interval (summarized in FIG. 2) permitted precise orientation of the results of previous linkage studies, to precisely localize known genes to the candidate interval, and to develop novel STRP loci. The availability of novel STRP markers permitted refinement of the candidate interval by haplotype analysis. The location of eight known and eight novel STRPs are shown in FIG. 2. Oligonucleotide primers and conditions used to amplify these STRPs are shown in Table 2.

TABLE-US-00002 TABLE 2 Primer Sets used in the amplification of STRP loci. Primer (5'.fwdarw.3') SEQ SEQ STRP.sup.a ID ID Size STRP Relative Locus NO Forward NO Reverse (bp) Type Position.sup.b D16S499 58 TCTCACAGTTCTGGAGGCTGGAAG 59 GGTGGACCCTAATTGCATAGGATTG 210 CA Repeat 238,700 D16S501 60 TGTCCTCTAGGGGAAGAGATGTCT 61 AGGTCAGGGACCTAGTAACTACTC 260 CA Repeat 305,100 481E9(16) 62 CCAGAGCCCTACAGGAGTGTACTG 63 CAAGACCAGGGGATCACAGTAACT 320 Di 362,700 449G13(16) 64 CAGCCTGGGCAACAGAGACTC 65 AGGCGCTAAATTCAGAGCAAATAG 300 CA Repeat 1,784,000 419L9(16) 66 GCTGTAATGGTGCTGTGTAAATCT 67 AAGAATCCTCCAGACTTCATACAC 218 CA Repeat 1,983,000 626G11(16) 68 ATCAGCTTAGCAGACATCTCTTCC 69 CTTGTAGTCCCAGCTACTCAGTGG 292 CA Repeat 2,019,000 234B8(16)-2 70 CACGAGAATCCCTTGAACCTG 71 TGGCTCTCCACTCAGAGATTC 214 Penta 2,050,000 2349B8(16)-1 72 CTGTGGCTGGCTTGTTTCACTCAG 73 TTGGGTGGAGGCAATCCAAGTGTC 201 CA Repeat 2,133,000 363E6(16) 74 TGTGTTATTGGTGAAATGCACATA 75 GGTGGCTCATGCCTGTAATTTGAG 355 Di 2,250,000 D16S3041 APPLIED BIOSYSTEM LINKAGE MAPPING SET, PANEL 73 270 CA Repeat 2,310,000 D16S490 76 TGACAGGCACATAGATTATTATGC 77 CGTACCCGGCTGATTATTTTAGAT 357 Tetra 2,390,000 D16S3036 78 AGATAGGGGTCTAGTTTCATTATC 79 ACAAAGCTGGACATATCACACTAC 310 CA Repeat 2,450,000 2380F24(16) 80 AGGCTGGTCTCGAACTCCTGACCT 81 GGGACTACAGGTGTGTGAATTTGA 272 Di 2,730,000 D16S3046 APPLIED BIOSYSTEM LINKAGE MAPPING SET, PANEL 22 110 CA Repeat 3,650,000 D16S3045 82 AGGACGGCTGAATGTCTGTCATCA 83 TTGGGGAGTCCCTAAATGACTTTA 180 CA Repeat 3,790,000 14O15(16) 84 GGCAGAAATGGCACATCTTAACTA 85 CAGCCTGGGTGACAGAGTGAGACT 234 CA Repeat 5,040,000 D16S403 APPLIED BIOSYSTEM LINKAGE MAPPING SET, PANEL 73 150 CA Repeat 5,820,000 D16S412 86 ACCCAGTAGAGACCCATCTTACTC 87 ACCCAGTAGAGACCCATCTTACTC 180 CA Repeat 5,952,000.sup.c .sup.aSTRP size indicates the region that the PCR amplified band will be in. .sup.bRelative position refers to the locus location on the BAC contig alignment sequence .sup.cThis position determined using the Human Genome Project data from June 2002 Amplifications performed using standard Amplitag Gold Conditions

[0072] The consensus candidate interval for most reports, including the present linkage data, support a candidate interval located in 16p13.11 (D16S499) to 16p12.2 (D16S403). It is apparent from FIG. 2 that, while all linkage intervals reported for FJHN and MCKD2 map to chromosome 16p, not all overlap.

[0073] Linkage Analyses

[0074] Results of genetic linkage analyses localized the gene for FJHN in two of the families (Family 1 and Family 2) to an overlapping interval of about 1.7-Mb (FIG. 2). For Family 1 the gene was localized to an interval of about 3.8-Mb delineated by 2349B8(16) to D16S403 (Z.sub.MAX=12.5 @ D16S3041, .theta.=0.01) and for Family 2 the linkage interval was .about.17-Mb between D16S404 and D16S3046 (Z.sub.MAX=3.2 @ D16S3041, .theta.=0.00); D16S404 extends about 14-Mb telomeric to D16S499. These findings were consistent with four (Dahan et al., J. Am. Soc Nephrol., 12, 2348-57 (2001); Hateboer et al., Kidney Int, 60, 1233-39 (2001); Scolari et al., Am. J. Hum. Genet., 64, 1655-60 (1999); Stiburkova et al., Am. J. Hum. Gen., 66, 1989-94 (2000)) of the previous 5 reports of linkage for FJHN to chromosome 16p. The present candidate interval did not overlap that of the fifth study (Kamatani et al., Arthritis Rheum., 43, 925-29 (2000)) possibly reflecting genetic heterogeneity (they are the only group to study Japanese FJHN families).

[0075] Candidate Gene Evaluation; Mutation Analyses

[0076] Integration of all known linkage reports for FJHN with the present linkage data identified an interval of minimal overlap (<0.3-Mb) from 2349B8(16) to D16S3036 for the present linkage results with those of Dahan and co-workers (see FIG. 2) [Dahan et al., supra]. This gene identification approach identified 1 known gene (B/K protein; NM_016524) and one hypothetical gene (G104; XM_091332) in this common interval. Direct sequence analysis of genomic DNA from affected and unaffected family members from Family 1 and Family 2 for coding regions (including intron-exon junctions) of the B/K gene and the hypothetical gene G104 did not identify any alterations of DNA that would account for the FJHN trait in either family.

[0077] Because the definitive diagnosis of FJHN can be problematic (particularly in milder cases and in younger individuals), and incorrect diagnosis of family members can directly affect the boundaries of the candidate gene region, the present analysis proceeded using only linkage and genotype data from Family 1 and Family 2. Thus individuals who could not be diagnosed as affected based on the diagnostic criteria stated above were excluded from the present analysis. Similarly, individuals who did not have both normal renal function (calculated creatinine clearance greater than 100 ml/min) and a serum uric acid level within 1 s.d. of the mean adjusted for age and gender (Wilcox; Mikkelsen et al.) were excluded from the analysis to refine the candidate interval.

[0078] Haplotype analysis permitted the identification of the smallest common haplotype segregating with the FJHN trait in Family 1 and in Family 2 (FIG. 3). The present sequence analysis had excluded the known (B/K protein) and hypothetical gene (G104) from the interval 2349B8(16)-D16S3036, to permit refinement of the candidate interval to about 1.2-Mb, from D16S3036-D16S3046. This revised candidate interval contains 4 genes: butyrl coenzyme A synthetase 1 (BUCS1); glycoprotein 2 (GP2); G protein coupled receptor, family C group 5, member B (GPRCSB); and UMOD. Sequence analyses of GPRCSB and UMOD were performed for genomic DNA from affected and unaffected family members. No coding region polymorphisms were detected in the GPRCSB sequence data. To determine the genomic organization of the entire UMOD gene, all available UMOD mRNA and EST data were aligned to identify any possible splice variants. Using bioinformatic approaches, the genomic structure of the UMOD gene was determined (see FIG. 4). This approach led to the identification of 12 UMOD exons, which is one exon more than previously reported (Pennica et al., Science, 236, 83-88 (1987)). The novel exon identified by the present approach and supported by EST data is exon 2. Exons 1 and 2 are non-coding with the ATG start site in exon 3. Based upon EST data, there appear to be alternate 5' transcription start sites so that transcription either begins with exon 1 and proceeds to exon 3 or transcription begins in exon 2 and proceeds to exon 3. In either case, the resultant protein is identical.

[0079] UMOD sequence analysis was undertaken on Families 1 and 2. Results of sequence analysis revealed 2 different mutations in exon 4 of UMOD in Families 1 and 2 (FIG. 5A, 5B). Mutations are described according to nomenclature guidelines (Antonarakis, Hum. Mutat., 11, 1-3 (1998); Den Dunnen et al., Hum. Mutat., 15, 7-12 (2000)). In each family, (g.1966_1992del in Family 1 and g.1880G>A in Family 2), the UMOD exon 4 gene mutation segregated completely with the disease phenotype. To evaluate the possible involvement of UMOD mutations in MCKD2, sequence analysis on 3 affected and 5 unaffected family members from a smaller family segregating MCKD2 (Family 3, FIG. 1) was conducted. Analysis of this family identified a third novel mutation (g.1744G>T) in UMOD, also in exon 4 (FIG. 5C). To evaluate the generality of UMOD mutations in FJHN, we performed mutational analyses on an affected member from an extended kindred previously reported (Massari et al., Arch. Intern. Med., 140, 680-84 (1980)). This analysis revealed a fourth novel mutation (g.2086T>C) in exon 4 of UMOD (FIG. 5D). Affected individuals in family 5 contained another mutation (g.2105G>A, c.668G>A, p.C223Y).

[0080] The specific UMOD gene mutations in Family 1, Family 2 and Family 3 each segregated in affected family members (FJHN in Family 1 and Family 2; and MCDK2 in Family 3). None of these mutations were identified in any of the 100 control chromosomes tested. Sequence analysis of the UMOD gene in 50 Caucasian controls (100 chromosomes) did reveal the presence of two silent polymorphisms within UMOD Exon 4. A previously reported synonymous SNP (Pirulli et al., J. Nephrol., 14, 392-96 (2001)) located at C174, has a T allele frequency of 82% and a C allele frequency of 18% for our samples. A novel synonymous SNP located at V287, has a G allele frequency of 87% and an A allele frequency of 13%. No polymorphisms affecting the translation of UMOD were detected in any of the 100 control chromosomes examined.

[0081] Genotype-Phenotype Correlation

[0082] For Family 1, 36 family members carried the mutation and 26 family members did not. Thirty-two of 36 (89%) genetically affected individuals suffered from hyperuricemia (as defined in Methods, supra). Twenty-eight of 32 (88%) genetically affected family members had an estimated creatinine clearance less than 90 ml/min when measured after the age of 18 years. Ten of 36 (28%) individuals carrying the UMOD mutation suffered from enuresis. The fractional excretion of uric acid was less than 6% in all genetically affected men and less than 5% in all genetically affected women with an estimated creatinine clearance greater than 70 ml/min. (The fractional excretion of uric acid increases in patients as renal function declines (Rieselbach et al., Nephron, 14, 81-87 (1975))). Thirty-two of 36 individuals carrying the UMOD mutation met the strict clinical criteria required to be diagnosed as affected. The remaining four individuals were women who had normal serum uric acid levels despite low fractional excretions of uric acid. Two of these women had mild renal insufficiency. The serum uric acid levels remained normal or borderline on testing over several years in three of these women. Five family members who did not carry the UMOD mutation had serum uric acid levels which were elevated but which were not greater than 2 standard deviations above the mean.

[0083] In family 2, nine of nine patients with the mutation suffered from hyperuricemia, and 9 of 9 patients suffered from renal insufficiency. In Family 3, 2 of 3 family members carrying the mutation suffered from hyperuricemia, and all three affected family members suffered from renal insufficiency.

[0084] These data are surprising given that recently one study has excluded UMOD as a candidate gene for a large Italian family segregating MCKD2 (Pirulli et al., supra). Although this study reports that the entire UMOD coding region was sequenced, this was performed with different primer sets than those used in the current study. Methodological differences in sequencing of exon 4 might account for the different results, however, other possibilities must be considered. Deletion of an entire exon could result in PCR amplification of only the wild type allele, masking the presence of a mutation. Pirulli et al. did not analyze the non-coding exons 1 and 2, nor the 5' regulatory region of UMOD. It is possible that mutations in exon 1, exon 2 or the regulatory region could result in loss of UMOD production (Salowsky et al., Gene, 293, 9-19 (2002); Flagiello, Mutations in brief no. 195. Online. Hum. Mutat., 12, 361 (1998)). Alternately, genetic heterogeneity may exist with another kidney specific gene located in the candidate interval.

[0085] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0086] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0087] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Sequence CWU 1

1

87127DNAArtificialDNA UMOD Sequence portion from Fig. 5 1tccgtgtcag gcgcaccgca ccctgga 27227DNAArtificialDNA UMOD Sequence portion from Fig. 5 2ccgcctgtcg cccggtctcg gctgcac 27325DNAArtificialDNA UMOD Sequence portion from Fig. 5 3atggatggca ctgtgagtgc tcccc 25424DNAArtificialDNA UMOD Sequence portion from Fig. 5 4atggccgaga cctgcgtgcc agtc 24527DNAArtificialDNA UMOD Sequence portion from Fig. 5 5tccgtgtcag gcgagcagcg agtacgg 27627DNAArtificialDNA UMOD Sequence portion from Fig. 5 6ccgcctgtcg ccctgtctcg gctgcac 27724DNAArtificialDNA UMOD Sequence portion from Fig. 5 7tggatggcac tatgagtgct cccc 24824DNAArtificialDNA UMOD Sequence portion from Fig. 5 8atggccgaga cccgcgtgcc agtc 249640PRTHomo sapiens 9Met Gly Gln Pro Ser Leu Thr Trp Met Leu Met Val Val Val Ala Ser 1 5 10 15 Trp Phe Ile Thr Thr Ala Ala Thr Asp Thr Ser Glu Ala Arg Trp Cys 20 25 30 Ser Glu Cys His Ser Asn Ala Thr Cys Thr Glu Asp Glu Ala Val Thr 35 40 45 Thr Cys Thr Cys Gln Glu Gly Phe Thr Gly Asp Gly Leu Thr Cys Val 50 55 60 Asp Leu Asp Glu Cys Ala Ile Pro Gly Ala His Asn Cys Ser Ala Asn 65 70 75 80 Ser Ser Cys Val Asn Thr Pro Gly Ser Phe Ser Cys Val Cys Pro Glu 85 90 95 Gly Phe Arg Leu Ser Pro Gly Leu Gly Cys Thr Asp Val Asp Glu Cys 100 105 110 Ala Glu Pro Gly Leu Ser His Cys His Ala Leu Ala Thr Cys Val Asn 115 120 125 Val Val Gly Ser Tyr Leu Cys Val Cys Pro Ala Gly Tyr Arg Gly Asp 130 135 140 Gly Trp His Cys Glu Cys Ser Pro Gly Ser Cys Gly Pro Gly Leu Asp 145 150 155 160 Cys Val Pro Glu Gly Asp Ala Leu Val Cys Ala Asp Pro Cys Gln Ala 165 170 175 His Arg Thr Leu Asp Glu Tyr Trp Arg Ser Thr Glu Tyr Gly Glu Gly 180 185 190 Tyr Ala Cys Asp Thr Asp Leu Arg Gly Trp Tyr Arg Phe Val Gly Gln 195 200 205 Gly Gly Ala Arg Met Ala Glu Thr Cys Val Pro Val Leu Arg Cys Asn 210 215 220 Thr Ala Ala Pro Met Trp Leu Asn Gly Thr His Pro Ser Ser Asp Glu 225 230 235 240 Gly Ile Val Ser Arg Lys Ala Cys Ala His Trp Ser Gly His Cys Cys 245 250 255 Leu Trp Asp Ala Ser Val Gln Val Lys Ala Cys Ala Gly Gly Tyr Tyr 260 265 270 Val Tyr Asn Leu Thr Ala Pro Pro Glu Cys His Leu Ala Tyr Cys Thr 275 280 285 Asp Pro Ser Ser Val Glu Gly Thr Cys Glu Glu Cys Ser Ile Asp Glu 290 295 300 Asp Cys Lys Ser Asn Asn Gly Arg Trp His Cys Gln Cys Lys Gln Asp 305 310 315 320 Phe Asn Ile Thr Asp Ile Ser Leu Leu Glu His Arg Leu Glu Cys Gly 325 330 335 Ala Asn Asp Met Lys Val Ser Leu Gly Lys Cys Gln Leu Lys Ser Leu 340 345 350 Gly Phe Asp Lys Val Phe Met Tyr Leu Ser Asp Ser Arg Cys Ser Gly 355 360 365 Phe Asn Asp Arg Asp Asn Arg Asp Trp Val Ser Val Val Thr Pro Ala 370 375 380 Arg Asp Gly Pro Cys Gly Thr Val Leu Thr Arg Asn Glu Thr His Ala 385 390 395 400 Thr Tyr Ser Asn Thr Leu Tyr Leu Ala Asp Glu Ile Ile Ile Arg Asp 405 410 415 Leu Asn Ile Lys Ile Asn Phe Ala Cys Ser Tyr Pro Leu Asp Met Lys 420 425 430 Val Ser Leu Lys Thr Ala Leu Gln Pro Met Val Ser Ala Leu Asn Ile 435 440 445 Arg Val Gly Gly Thr Gly Met Phe Thr Val Arg Met Ala Leu Phe Gln 450 455 460 Thr Pro Ser Tyr Thr Gln Pro Tyr Gln Gly Ser Ser Val Thr Leu Ser 465 470 475 480 Thr Glu Ala Phe Leu Tyr Val Gly Thr Met Leu Asp Gly Gly Asp Leu 485 490 495 Ser Arg Phe Ala Leu Leu Met Thr Asn Cys Tyr Ala Thr Pro Ser Ser 500 505 510 Asn Ala Thr Asp Pro Leu Lys Tyr Phe Ile Ile Gln Asp Arg Cys Pro 515 520 525 His Thr Arg Asp Ser Thr Ile Gln Val Val Glu Asn Gly Glu Ser Ser 530 535 540 Gln Gly Arg Phe Ser Val Gln Met Phe Arg Phe Ala Gly Asn Tyr Asp 545 550 555 560 Leu Val Tyr Leu Asp Cys Glu Val Tyr Leu Cys Asp Thr Met Asn Glu 565 570 575 Lys Cys Lys Pro Thr Cys Ser Gly Thr Arg Phe Arg Ser Gly Ser Val 580 585 590 Ile Asp Gln Ser Arg Val Leu Asn Leu Gly Pro Ile Thr Arg Lys Gly 595 600 605 Val Gln Ala Thr Val Ser Arg Ala Phe Ser Ser Leu Gly Leu Leu Lys 610 615 620 Val Trp Leu Pro Leu Leu Leu Ser Ala Thr Leu Thr Leu Thr Phe Gln 625 630 635 640 10643PRTBos taurus 10Met Lys Cys Leu Phe Ser Pro Asn Phe Met Trp Met Ala Ala Val Val 1 5 10 15 Thr Ser Trp Val Ile Ile Pro Ala Ala Thr Asp Thr Ser Ser Ala Lys 20 25 30 Ser Cys Ser Glu Cys His Ser Asn Ala Thr Cys Thr Val Asp Gly Ala 35 40 45 Ala Thr Thr Cys Ala Cys Gln Glu Gly Phe Thr Gly Asp Gly Leu Glu 50 55 60 Cys Val Asp Leu Asp Glu Cys Ala Val Leu Gly Ala His Asn Cys Ser 65 70 75 80 Ala Thr Lys Ser Cys Val Asn Thr Leu Gly Ser Tyr Thr Cys Val Cys 85 90 95 Pro Glu Gly Phe Leu Leu Ser Ser Glu Leu Gly Cys Glu Asp Val Asp 100 105 110 Glu Cys Ala Glu Pro Gly Leu Ser Arg Cys His Ala Leu Ala Thr Cys 115 120 125 Ile Asn Gly Glu Gly Asn Tyr Ser Cys Val Cys Pro Ala Gly Tyr Leu 130 135 140 Gly Asp Gly Arg His Cys Glu Cys Ser Pro Gly Ser Cys Gly Pro Gly 145 150 155 160 Leu Asp Cys Val Arg Glu Gly Asp Ala Leu Val Cys Val Asp Pro Cys 165 170 175 Gln Val His Arg Ile Leu Asp Glu Tyr Trp Arg Ser Thr Glu Tyr Gly 180 185 190 Ser Gly Tyr Ile Cys Asp Val Ser Leu Gly Gly Trp Tyr Arg Phe Val 195 200 205 Gly Gln Ala Gly Val Arg Leu Pro Glu Thr Cys Val Pro Val Leu His 210 215 220 Cys Asn Thr Ala Ala Pro Met Trp Leu Asn Gly Thr His Pro Ser Ser 225 230 235 240 Asp Glu Gly Ile Val Asn Arg Val Ala Cys Ala His Trp Ser Gly Asp 245 250 255 Cys Cys Leu Trp Asp Ala Pro Ile Gln Val Lys Ala Cys Ala Gly Gly 260 265 270 Tyr Tyr Val Tyr Asn Leu Thr Ala Pro Pro Glu Cys His Leu Ala Tyr 275 280 285 Cys Thr Asp Pro Ser Ser Val Glu Gly Thr Cys Glu Glu Cys Arg Val 290 295 300 Asp Glu Asp Cys Lys Ser Asp Asn Gly Glu Trp His Cys Gln Cys Lys 305 310 315 320 Gln Asp Phe Asn Val Thr Asp Leu Ser Leu Leu Glu Arg Arg Leu Glu 325 330 335 Cys Gly Val Asp Asp Ile Lys Leu Ser Leu Ser Lys Cys Gln Leu Lys 340 345 350 Ser Leu Gly Phe Glu Lys Val Phe Met Tyr Leu His Asp Ser Gln Cys 355 360 365 Ser Gly Phe Thr Glu Arg Gly Asp Arg Asp Trp Met Ser Val Val Thr 370 375 380 Pro Ala Arg Asp Gly Pro Cys Gly Thr Val Met Thr Arg Asn Glu Thr 385 390 395 400 His Ala Thr Tyr Ser Asn Thr Leu Tyr Leu Ala Asp Glu Ile Ile Ile 405 410 415 Arg Asp Leu Asn Ile Arg Ile Asn Phe Ala Cys Ser Tyr Pro Leu Asp 420 425 430 Met Lys Val Ser Leu Lys Thr Ser Leu Gln Pro Met Val Ser Ala Leu 435 440 445 Asn Ile Ser Met Gly Gly Thr Gly Thr Phe Thr Val Arg Met Ala Leu 450 455 460 Phe Gln Ser Pro Ala Tyr Thr Gln Pro Tyr Gln Gly Ser Ser Val Thr 465 470 475 480 Leu Ser Thr Glu Ala Phe Leu Tyr Val Gly Thr Met Leu Asp Gly Gly 485 490 495 Asp Leu Ser Arg Phe Val Leu Leu Met Thr Asn Cys Tyr Ala Thr Pro 500 505 510 Ser Ser Asn Ala Thr Asp Pro Leu Lys Tyr Phe Ile Ile Gln Asp Arg 515 520 525 Cys Pro Arg Ala Ala Asp Ser Thr Ile Gln Val Glu Glu Asn Gly Glu 530 535 540 Ser Pro Gln Gly Arg Phe Ser Val Gln Met Phe Arg Phe Ala Gly Asn 545 550 555 560 Tyr Asp Leu Val Tyr Leu His Cys Glu Val Tyr Leu Cys Asp Thr Val 565 570 575 Asn Glu Lys Cys Arg Pro Thr Cys Pro Glu Thr Arg Phe Arg Ser Gly 580 585 590 Ser Ile Ile Asp Gln Thr Arg Val Leu Asn Leu Gly Pro Ile Thr Arg 595 600 605 Lys Gly Gly Gln Ala Ala Met Ser Arg Ala Ala Pro Ser Ser Leu Gly 610 615 620 Leu Leu Gln Val Trp Leu Pro Leu Leu Leu Ser Ala Thr Leu Thr Leu 625 630 635 640 Met Ser Pro 11642PRTMus musculus 11Met Gly Ile Pro Leu Thr Trp Met Leu Leu Val Met Met Val Thr Ser 1 5 10 15 Trp Phe Thr Leu Ala Glu Ala Ser Asn Ser Thr Glu Ala Arg Arg Cys 20 25 30 Ser Glu Cys His Asn Asn Ala Thr Cys Thr Val Asp Gly Val Val Thr 35 40 45 Thr Cys Ser Cys Gln Thr Gly Phe Thr Gly Asp Gly Leu Val Cys Glu 50 55 60 Asp Met Asp Glu Cys Ala Thr Pro Trp Thr His Asn Cys Ser Asn Ser 65 70 75 80 Ser Cys Val Asn Thr Pro Gly Ser Phe Lys Cys Ser Cys Gln Asp Gly 85 90 95 Phe Arg Leu Thr Pro Glu Leu Ser Cys Thr Asp Val Asp Glu Cys Ser 100 105 110 Glu Gln Gly Leu Ser Asn Cys His Ala Leu Ala Thr Cys Val Asn Thr 115 120 125 Glu Gly Asp Tyr Leu Cys Val Cys Pro Glu Gly Phe Thr Gly Asp Gly 130 135 140 Trp Tyr Cys Glu Cys Ser Pro Gly Ser Cys Glu Pro Gly Leu Asp Cys 145 150 155 160 Leu Pro Gln Gly Pro Asp Gly Lys Leu Val Cys Gln Asp Pro Cys Asn 165 170 175 Thr Tyr Glu Thr Leu Thr Glu Tyr Trp Arg Ser Thr Glu Tyr Gly Val 180 185 190 Gly Tyr Ser Cys Asp Ala Gly Leu His Gly Trp Tyr Arg Phe Thr Gly 195 200 205 Gln Gly Gly Val Arg Met Ala Glu Thr Cys Val Pro Val Leu Arg Cys 210 215 220 Asn Thr Ala Ala Pro Met Trp Leu Asn Gly Ser His Pro Ser Ser Ser 225 230 235 240 Glu Gly Ile Val Ser Arg Thr Ala Cys Ala His Trp Ser Asp Gln Cys 245 250 255 Cys Arg Trp Ser Thr Glu Ile Gln Val Lys Ala Cys Pro Gly Gly Phe 260 265 270 Tyr Ile Tyr Asn Leu Thr Ala Pro Pro Glu Cys Asn Leu Ala Tyr Cys 275 280 285 Thr Asp Pro Ser Ser Val Glu Gly Thr Cys Glu Glu Cys Arg Val Asp 290 295 300 Glu Asp Cys Ile Ser Asp Asn Gly Arg Trp Arg Cys Gln Cys Lys Gln 305 310 315 320 Asp Ser Asn Ile Thr Asp Val Ser Gln Leu Glu Tyr Arg Leu Glu Cys 325 330 335 Gly Ala Asn Asp Ile Lys Met Ser Leu Arg Lys Cys Gln Leu Gln Ser 340 345 350 Leu Gly Phe Met Asn Val Phe Met Tyr Leu Asn Asp Arg Gln Cys Ser 355 360 365 Gly Phe Ser Glu Ser Asp Glu Arg Asp Trp Met Ser Ile Val Thr Pro 370 375 380 Ala Arg Asn Gly Pro Cys Gly Thr Val Leu Arg Arg Asn Glu Thr His 385 390 395 400 Ala Thr Tyr Ser Asn Thr Leu Tyr Leu Ala Asn Ala Ile Ile Ile Arg 405 410 415 Asp Ile Ile Ile Arg Met Asn Phe Glu Cys Ser Tyr Pro Leu Asp Met 420 425 430 Lys Val Ser Leu Lys Thr Ser Leu Gln Pro Met Val Ser Ala Leu Asn 435 440 445 Ile Ser Leu Gly Gly Thr Gly Lys Phe Thr Val Arg Met Ala Leu Phe 450 455 460 Gln Ser Pro Thr Tyr Thr Gln Pro His Gln Gly Pro Ser Val Met Leu 465 470 475 480 Ser Thr Glu Ala Phe Leu Tyr Val Gly Thr Met Leu Asp Gly Gly Asp 485 490 495 Leu Ser Arg Phe Val Leu Leu Met Thr Asn Cys Tyr Ala Thr Pro Ser 500 505 510 Ser Asn Ser Thr Asp Pro Val Lys Tyr Phe Ile Ile Gln Asp Ser Cys 515 520 525 Pro Arg Thr Glu Asp Thr Thr Ile Gln Val Thr Glu Asn Gly Glu Ser 530 535 540 Ser Gln Ala Arg Phe Ser Val Gln Met Phe Arg Phe Ala Gly Asn Tyr 545 550 555 560 Asp Leu Val Tyr Leu His Cys Glu Val Tyr Leu Cys Asp Ser Thr Ser 565 570 575 Glu Gln Cys Lys Pro Thr Cys Ser Gly Thr Arg Phe Arg Ser Gly Asn 580 585 590 Phe Ile Asp Gln Thr Arg Val Leu Asn Leu Gly Pro Ile Thr Arg Gln 595 600 605 Gly Val Gln Ala Ser Val Ser Lys Ala Ala Ser Ser Asn Leu Arg Leu 610 615 620 Leu Ser Ile Trp Leu Leu Leu Phe Pro Ser Ala Thr Leu Ile Phe Met 625 630 635 640 Val Gln 12644PRTRattus norvegicus 12Met Gly Gln Leu Leu Ser Leu Thr Trp Leu Leu Leu Val Met Val Val 1 5 10 15 Thr Pro Trp Phe Thr Val Ala Gly Ala Asn Asp Ser Pro Glu Ala Arg 20 25 30 Arg Cys Ser Glu Cys His Asp Asn Ala Thr Cys Val Leu Asp Gly Val 35 40 45 Val Thr Thr Cys Ser Cys Gln Ala Gly Phe Thr Gly Asp Gly Leu Val 50 55 60 Cys Glu Asp Ile Asp Glu Cys Ala Thr Pro Trp Thr His Asn Cys Ser 65 70 75 80 Asn Ser Ile Cys Met Asn Thr Leu Gly Ser Tyr Glu Cys Ser Cys Gln 85 90 95 Asp Gly Phe Arg Leu Thr Pro Gly Leu Gly Cys Ile Asp Val Asn Glu 100 105 110 Cys Thr Glu Gln Gly Leu Ser Asn Cys His Ser Leu Ala Thr Cys Val 115 120 125 Asn Thr Glu Gly Ser Tyr Ser Cys Val Cys Pro Lys Gly Tyr Arg Gly 130 135 140 Asp Gly Trp Tyr Cys Glu Cys Ser Pro Gly Phe Cys Glu Pro Gly Leu 145 150 155 160 Asp Cys Leu Pro Gln Gly Pro Ser Gly Lys Leu Val Cys Gln Asp Pro 165 170 175 Cys Asn Val Tyr Glu Thr Leu Thr Glu Tyr Trp Arg Ser Thr Asp Tyr 180 185 190 Gly Ala Gly Tyr Ser Cys Asp Ser Asp Met His Gly Trp Tyr Arg Phe 195 200 205 Thr Gly Gln Gly Gly Val Arg Met Ala Glu Thr Cys Val Pro Val Leu 210 215 220 Arg Cys Asn Thr Ala

Ala Pro Met Trp Leu Asn Gly Ser His Pro Ser 225 230 235 240 Ser Arg Glu Gly Ile Val Ser Arg Thr Ala Cys Ala His Trp Ser Asp 245 250 255 His Cys Cys Leu Trp Ser Thr Glu Ile Gln Val Lys Ala Cys Pro Gly 260 265 270 Gly Phe Tyr Val Tyr Asn Leu Thr Glu Pro Pro Glu Cys Asn Leu Ala 275 280 285 Tyr Cys Thr Asp Pro Ser Ser Val Glu Gly Thr Cys Glu Glu Cys Gly 290 295 300 Val Asp Glu Asp Cys Val Ser Asp Asn Gly Arg Trp Arg Cys Gln Cys 305 310 315 320 Lys Gln Asp Phe Asn Val Thr Asp Val Ser Leu Leu Glu His Arg Leu 325 330 335 Glu Cys Glu Ala Asn Glu Ile Lys Ile Ser Leu Ser Lys Cys Gln Leu 340 345 350 Gln Ser Leu Gly Phe Met Lys Val Phe Met Tyr Leu Asn Asp Arg Gln 355 360 365 Cys Ser Gly Phe Ser Glu Arg Gly Glu Arg Asp Trp Met Ser Ile Val 370 375 380 Thr Pro Ala Arg Asp Gly Pro Cys Gly Thr Val Leu Arg Arg Asn Glu 385 390 395 400 Thr His Ala Thr Tyr Ser Asn Thr Leu Tyr Leu Ala Ser Glu Ile Ile 405 410 415 Ile Arg Asp Ile Asn Ile Arg Ile Asn Phe Glu Cys Ser Tyr Pro Leu 420 425 430 Asp Met Lys Val Ser Leu Lys Thr Ser Leu Gln Pro Met Val Ser Ala 435 440 445 Leu Asn Ile Ser Leu Gly Gly Thr Gly Lys Phe Thr Val Gln Met Ala 450 455 460 Leu Phe Gln Asn Pro Thr Tyr Thr Gln Pro Tyr Gln Gly Pro Ser Val 465 470 475 480 Met Leu Ser Thr Glu Ala Phe Leu Tyr Val Gly Thr Met Leu Asp Gly 485 490 495 Gly Asp Leu Ser Arg Phe Val Leu Leu Met Thr Asn Cys Tyr Ala Thr 500 505 510 Pro Ser Ser Asn Ser Thr Asp Pro Val Lys Tyr Phe Ile Ile Gln Asp 515 520 525 Arg Cys Pro His Thr Glu Asp Thr Thr Ile Gln Val Thr Glu Asn Gly 530 535 540 Glu Ser Ser Gln Ala Arg Phe Ser Ile Gln Met Phe Arg Phe Ala Gly 545 550 555 560 Asn Ser Asp Leu Val Tyr Leu His Cys Glu Val Tyr Leu Cys Asp Thr 565 570 575 Met Ser Glu Gln Cys Lys Pro Thr Cys Ser Gly Thr Arg Tyr Arg Ser 580 585 590 Gly Asn Phe Ile Asp Gln Thr Arg Val Leu Asn Leu Gly Pro Ile Thr 595 600 605 Arg Gln Gly Val Gln Ala Ser Val Ser Lys Ala Ala Ser Ser Asn Leu 610 615 620 Gly Phe Leu Ser Ile Trp Leu Leu Leu Phe Leu Ser Ala Thr Leu Thr 625 630 635 640 Leu Met Val His 133199DNAHomo sapiens 13tcctgctcca aatgactgag ttcttcaaaa tgtgcaatgt gctgagaatt ggggagccaa 60gactgggatg ttggtgaggt aaggaggggg agtacaaggg gtaaagtccc agcaaaacaa 120gggctgcagt gttatgcaat tttttagtcc atataagtga cacctcctgg agttgtatac 180tatacaatca aagcactcct tccagctgtg gggaggagag ttagatcatg catttgtccc 240atccatctct gttcacagga caccagacat cagagacaga gagaaaaatt caaagggcca 300acccgtcttt cctttgggca ggtgctatct agacctgaag tagcgggaag agcagaaagg 360atggggcagc catctctgac ttggatgctg atggtggtgg tggcctcttg gttcatcaca 420actgcagcca ctgacacctc agaagcaagt aagtgaaaag tgtgtgtgcg ttgtatatgt 480gtgtatgcac gtgtatgtgt gaatgtgtgg gggaagcaat gtagcacctg tcagaggtga 540tctcaatcct cctatcgcac ttgagacttg cattgtcttc attctaagtc catttcttag 600actcaatatg cacaggactg acttagaaat tttgctaaag tgcatattct ggttcagcag 660atctgcagta ggacctgaga tgctgaattt ttaacaagct tccaggcgat gctcatactg 720gggtccctgg agtacacatt gaaaagcaag gggctagaac atctctaagg cctgcaggcc 780ctttattgga agtcagaaac atactctatc acataggaga tttgaaccca tgcaggagga 840tccaaacacc ttccctttca actttaagag gtcattccat tgggttgaga tttgctgtca 900ccccactttc attttctccc tggagtacgt tggggcacga tgaatactat tgcggtgtcc 960tggttaaaag cacatatttt gtggtcctgc catctgcgtt tttatcctgg ttctacttct 1020taccaaagga gtaaggggct taatccctct gaacctcagt ctcctcatct ttaaaataag 1080gatacataaa aaactgacct cacgaggccc ttgggaagta ttcaacaaga tagtgagtga 1140aaagtgcaca tcctattgcc tggcatatag taattgctta ataaacaaca gcttcttttt 1200ttttttaatg gttattttta ttacggagga acaaagtaca actgcccagc caggtggagt 1260tggaggactc cgcagagagg aggcgacact gagcagggtc ctgatgaaga tttcaccagc 1320cagggaagca gaaaacataa aatgtgcaaa gaaagggagg ggcaacaggt tcaccgtaaa 1380tcctaccaaa gtataggaat tctgcgcatt acttttctga atgtggctat tttaaaagaa 1440gacagcttga aagcaatgct taacacaaaa aatgaatggt ggagctgggc gcgattgcac 1500gtgcctgtgg tcccaacttt ttgggaagct gaggcagggt gcggtggtgg cttgaactca 1560gggagtagaa cgcttgaacc caggaattgg aggctatggt gagctatgat cgcactactg 1620cactccagcc tgggcgacag agcaagaccc ctctccaaaa aaataaataa agttaaaaaa 1680tacaatgaaa taaacacaga atgaacggtg gaggcttgac atcatcagag gagttttgtt 1740tctttgcttc tttccttgtt ttggagggag ccctctaggg aataagtctt aaaaataatg 1800agttccctgg agaatgaggg aaggatctct gggtggccat gggcccagct gcccaaaccc 1860tgaagctggg cttttctgtc cacaggatgg tgctctgaat gtcacagcaa tgccacctgc 1920acggaggatg aggccgttac gacgtgcacc tgtcaggagg gcttcaccgg cgatggcctg 1980acctgcgtgg acctggatga gtgcgccatt cctggagctc acaactgctc cgccaacagc 2040agctgcgtaa acacgccagg ctccttctcc tgcgtctgcc ccgaaggctt ccgcctgtcg 2100cccggtctcg gctgcacaga cgtggatgag tgcgctgagc ctgggcttag ccactgccac 2160gccctggcca catgtgtcaa tgtggtgggc agctacttgt gcgtatgccc cgcgggctac 2220cggggggatg gatggcactg tgagtgctcc ccgggctcct gcgggccggg gttggactgc 2280gtgcccgagg gcgacgcgct cgtgtgcgcg gatccgtgtc aggcgcaccg caccctggac 2340gagtactggc gcagcaccga gtacggggag ggctacgcct gcgacacgga cctgcgcggc 2400tggtaccgct tcgtgggcca gggcggtgcg cgcatggccg agacctgcgt gccagtcctg 2460cgctgcaaca cggccgcccc catgtggctc aatggcacgc atccgtccag cgacgagggc 2520atcgtgagcc gcaaggcctg cgcgcactgg agcggccact gctgcctgtg ggatgcgtcc 2580gtccaggtga aggcctgtgc cggcggctac tacgtctaca acctgacagc gccccccgag 2640tgtcacctgg cgtactgcac aggtcagccg gagtctcccc acagtcctca tcccaggcct 2700ggaaaggcac tgcagaggac gggggtgcgt ccttattgat tgtctgtctg tccctgtgac 2760cctgcagacc ccagctccgt ggaggggacg tgtgaggagt gcagtataga cgaggactgc 2820aaatcgaata atggcagatg gcactgccag tgcaaacagg acttcaacat cactggtgag 2880gccagtgggg aggaagcggg ttgttgagaa acctgtcact gcctggggga gggacacatt 2940cctcccctgt gagattgggg ccatatgggt atgacgcagg ggatatatat ccaacctgag 3000tgaaaacaga agatccacta atacccatta aagccggcaa gaggctctct gaggctccct 3060gagtctccct ttagttgact tcaaagctgc caaagatttg gggacctcct cgcacccagc 3120cttctttctg aggcccacac cacagtgggc acccacgttg ctgccatctg ggagccaaag 3180accatctgag ccctattcc 319914940DNAHomo sapiens 14acctctggac ctcaagtaat ctgtctgcct tggcctccca aagtgctagg attataggca 60tgagccaccg catctagcct ttttattttt ttaaacgagt attcattgtt atttaatgct 120gggacatcaa aaccccccaa aaccgtcctg catttggtat ataacccaca tttaggggaa 180cccaagactg agtggttggt cagtggatgt atccattgat gtcagaggtc caatcttgag 240tccccatcac attgggaggg gacagatcag ctcaaggcta tgctgagcac ttccagatgg 300tggtcagccc agccagctgg acctggcccc tggggatgtg ctgggccccc aagctataga 360cacacgtcct caatcccacc taacctgttt cagatatctc cctcctggag cacaggctgg 420aatgtggggc caatgacatg aaggtgtcgc tgggcaagtg ccagctgaag agtctgggct 480tcgacaaggt cttcatgtac ctgagtgaca gccggtgctc gggcttcaat gacagagaca 540accgggactg ggtgtctgta gtgaccccag cccgggatgg cccctgtggg acagtgttga 600cggtacgtcc tggccagtgg gggacagaac cagagcactg cctggttcaa gtttcagctc 660tatcacttcc tagttataga agctttgggg agttatttag cctggctgtg cctcagtttc 720atcaactgta aagtggagaa ataatagtac ctactccaca ggtgtattga gaggattgaa 780tgagttaatg tgttgaagtg attaggacag tgactgcaca cagtaagtgc tcaataaaca 840tcagcttcaa ataaagaaag caattcatgg tgatagttct ccattttaca gatgggaaaa 900gtagggccat agtagggatt gtctcagcca gtaggcatca 94015475DNAHomo sapiens 15accagcagat ttagctttga agtcctactc agattctcat gcccctttct ctcatcccca 60ccccccctcc acccccattc cctgcaacag aggaatgaaa cccatgccac ttacagcaac 120accctctacc tggcagatga gatcatcatc cgtgacctca acatcaaaat caactttgca 180tgctcctacc ccctggacat gaaagtcagc ctgaagaccg ccctacagcc aatggtcagg 240tgtggccaga gagggtccct agggccccta gatggttcta accccaaacc ccttaaccat 300gagcttccct gtcaactgcc acccacaggg agctgggagt gagggctggg aatcagggtt 360gcccaatgga agagccagga attctggagc ccaggttcaa atctagactt tgtcataaat 420gatggttatg ccctggccag tgggggacag agtcaaagca ctgcctggtt caagc 47516711DNAHomo sapiens 16agcagcatcc aggcacttgt cagaaatgca ggaccttgag ccccacccca atactcacca 60aatcagagcc tgcattttat ctagatccca agttgacctg cgtgtactta ttgcggtttg 120caaagcaaca gttggtgggt tccactctta ttgctggata aaaatgcaaa caactgcaag 180ggactgccta ggaatgcaaa tcagagaagg tggcctatct gcagatgttc tcagcccggt 240cctctcacca acccttctcc cctggcagtg ctctaaacat cagagtgggc gggaccggca 300tgttcaccgt gcggatggcg ctcttccaga ccccttccta cacgcagccc taccaaggct 360cctccgtgac actgtccact gaggcttttc tctacgtggg caccatgttg gatgggggcg 420acctgtcccg atttgcactg ctcatgacca actgctatgc cacacccagt agcaatgcca 480cggaccccct gaagtacttc atcatccagg acaggtaagg caaaggttcc tacatgggaa 540ctcatgggta gaattcagag ggggtctttg gacttggatg gaggaaaatt gcatcttttt 600tttttttttt tttgacagag tcttgctctg tcgccaaggt tggagtgcaa tggtgtgacc 660tcggctcact gcaacctccg cctcctgggt tcaagtgatt cttctgcctc a 711171111DNAHomo sapiens 17atttgaatcc aggaagtctg actccagaat ctttatttaa ccaaccacat taaatgatgt 60gtaaccctcc cagatgccca cacactagag actcaactat ccaagtggtg gagaatgggg 120agtcctccca gggccgattt tccgtccaga tgttccggtt tgctggaaac tatgacctag 180tctacctgca ctgtgaagtc tatctctgtg acaccatgaa tgaaaagtgc aagcctgtga 240gttgactccc ctcccccagc ccatctcttg taaccaaaga catttggcca caaagaaaac 300aaatcaatat ttcttccctg tttccctctt ttaccagagg gatagaatga gcaataagat 360gaggtgggcg tggctaggca ggaaacctaa gctgcagggg aaatcaggtg ggatcagtaa 420agtgcggcag gctggtaaga gctctggctt atctgcaagc ttgtgttcaa ataacaggag 480ctgacatttt taagcactgt gcccacttta tttgtgttag cttttaatgc ttcacagcaa 540ctctataagg gaggtattac tggttccctt tcctcatgag gagaggggct cagagaactt 600cagtggcttg cctgagatca tgcatctatc taacaaatgg cagagctggg acctgcacga 660gccccggtat acaggtctcc taacaacttc tgcctggggc aagggaaggc acctgtgagg 720tgggcagtcc actccacgtg gcagaaccac attcaggctc cttcatggag ggtgtttttc 780tattgccctc tccctgtaga cctgctctgg gaccagattc cgaagtggga gtgtcataga 840tcaatcccgt gtcctgaact tgggtcccat cacacggaaa ggtaagagag ccactcgctc 900ctcaacattc ctggctggga aagatttctg gagaggaaga gggataacag agcctggcac 960cttggcacct tactgagctc tgaagaactg ggagcaagtg gatcctctgg ggcaaggtgg 1020aatacagact gccttccttt cactattccc attcatacac ccattcattg gacaaatatg 1080atttgtagat gaatgtaaca caggacacgg g 111118345DNAHomo sapiens 18gagcccctga tgggtctgaa gtaggggagt aacatgatca gatttgggtt ttgaagagat 60cagtctggct gcgaagtgaa aagtagattg aaggggtttc tgtcaggatg cttgccaaat 120ctcatgcatt ctttattcac tgatccttct gttttcctcc aaaggtgtcc aggccacagt 180ctcaagggct tttagcagct tgggtaagtt caggtccttt ctgcagtggg acctgttcca 240gaactctcct ggggggcttc tatctgttaa cttgtaatgc ttcatagcaa ctctataagg 300gaggtgttac tagttccgtt ttctaaataa ggagagtggc tcaga 34519733DNAHomo sapiens 19tagattgggc acttcacaag aatgcccttt gcccttttga ggaggtacca agcctagtgc 60cggaggaaag attatctttt tcaaatcggt ccaccttttt cagggcagat aaggaggaag 120cttccttttt ctaggagagc agcccagaga gggtgtcctc ttctgattgg tcagcctaga 180cgaggcagct tatgttaatt tgcacaaaag tacagcagta ctagcagttg ccctgtcact 240gttttctttt cagggctcct gaaagtctgg ctgcctctgc ttctctcggc caccttgacc 300ctgacttttc agtgactgac agcggaaagc cctgtgctcc atggctgcca tctcacctcc 360tgctgggcag ggggcatgat gcgggccagt gctccagcca cagaaaagaa agttcatgct 420ttgttcagcc tgccttcttt tctccctttt aatcctggct gtcgagaaac agcctgtgtc 480tttaaatgct gctttttctc aaaatgggac ttgtgacggt gtacctgagg cccccatctc 540cttaaagagt gtggcaaaat aatgattttt aaatctcagt ctttgaagtc atccattcat 600tcaacaagta tttactgaac tctaccatgt aggcactatg tatggtgcta aggatcctac 660ggtgggaaaa aataaccccc cacactgtcc tcatggagtt cacagtctgc tcagtgagac 720tgggttctgc tgt 733204178DNAHomo sapiens 20gcggccgcgg gagctgcggg gagcgcgggg gcggcccgga gcgtgccggg gtccccgcgc 60ctcgctcgcc ggccgcgctc cgaagatggt ggcggcgccg tgcgcccgga ggctggcccg 120gcgctcgcac tcggcgctgc tcgcggcgct cacggtgctg ctgctgcaga cgctggtcgt 180gtggaatttc agcagcctcg actccggggc cggggagcgc cgcgggggcg cagcggtcgg 240cggcggggag cagccgcccc cggccccggc cccgcgccgg gagcgccggg acctgcccgc 300cgagccggct gcagcccgag gaggaggagg aggcggcggc ggaggaggag gaggacgggg 360gccccaggcg cgggcgcggg gaggcggccc cggagaaccg cggggacagc agccggccag 420ccggggggca ctgcccgccc gggctctgga tccacaccca agtccgctca tcaccctgga 480gactcaggat ggctactttt ctcatcggcc gaaagagaaa gtgcgaacag acagcaacaa 540cgagaactct gtccccaaag actttgagaa tgtggacaac agcaacttcg cacccaggac 600tcaaaagcag aagcaccagc ctgagttggc gaagaagcca ccgagtagac agaaggagct 660tttgaaaagg aagctggaac agcaggagaa aggaaaagga catacattcc ctgggaaagg 720ccccggtgag gtgctgcctc ccggggacag agccgcagcc aacagcagcc acgggaagga 780tgtgtccaga ccgcctcatg ccaggaaaac tgggggcagc tcccccgaga ccaagtatga 840ccagccccct aagtgtgaca tctcaggcaa ggaggccatc tctgccctgt cccgtgctaa 900gtccaagcac tgccgccagg agattgggga gacttactgc cgccacaagt tagggctgct 960gatgcctgag aaggtgactc ggttctgccc cctcgagggt aaagccaaca agaacgtgca 1020gtgggacgag gactccgtgg agtacatgcc agccaacccg gtcagaatcg cctttgtcct 1080ggtggtccac ggccgtgcct ctcggcagtt gcagcgcatg ttcaaggcca tctaccacaa 1140agaccacttc tactacatcc acgtggacaa gcgctctaat tacctgcatc ggcaagtgct 1200ccaggtctcc aggcagtaca gcaatgtccg cgtcaccccc tggagaatgg ccaccatctg 1260gggaggagcc agcctcctgt ccacctacct gcagagcatg cgggacctcc tggagatgac 1320cgactggccc tgggacttct tcatcaacct gagtgcggcc gactacccca tcaggacaaa 1380tgaccagttg gtggcgtttc tctcccgata ccgagatatg aatttcttga agtcacacgg 1440ccgggacaat gcaaggttca ttcggaagca gggcctggat cggctcttcc tggagtgcga 1500cgctcacatg tggcgcctgg gagatcggcg gatcccagag ggcattgccg tggatggcgg 1560ttcggactgg ttcctgctga accggaggtt tgtagaatat gtgaccttct ccacagacga 1620tctggtgacc aagatgaaac agttctactc ctacaccctg cttcctgctg agtccttctt 1680ccatacggtc ctggagaaca gcccccactg cgacaccatg gtggacaaca acctgcgcat 1740caccaactgg aatcgcaagc tgggctgcaa gtgccagtac aagcacatcg tggactggtg 1800cggctgctcc cccaatgact tcaagccgca ggacttccac cgcttccagc agacagcccg 1860gcctaccttc tttgcccgca agtttgaagc cgtggtgaat caggaaatca ttgggcagct 1920ggactattac ctgtacggga actaccctgc aggtaccccg ggcctgcgct cctactggga 1980gaatgtctac gatgagcctg acggcatcca cagcctgagc gacgtgacac tcaccttgta 2040ccactccttt gcccgcctgg gtcttcgacg ggccgagacg tccctgcaca cggatgggga 2100gaacagctgc cgatactacc caatgggcca cccagcatct gtgcacctct acttccttgc 2160tgaccgcttc cagggctttc tgatcaagca tcatgctacc aatctggctg tgagcaaact 2220agagactctg gagacctggg tgatgccgaa aaaagtcttc aagatcgcaa gcccacccag 2280tgactttggg aggcttcagt tttccgaggt cggcactgac tgggatgcca aggagaggct 2340attccgcaac tttgggggtc ttctggggcc catggatgag ccggtgggta tgcagaagtg 2400ggggaaggga cctaatgtga ccgtgaccgt catttgggtg gatcccgtca atgtcatcgc 2460agccacctac gacatcctca ttgagtccac tgccgaattc acacactaca agcccccttt 2520gaacttgccc ctgaggcctg gggtctggac agtgaaaatt ctccaccact gggtgccagt 2580tgcagagacc aaattcctcg ttgcgcctct gaccttctcg aacaggcagc ccatcaaacc 2640tgaggaggca ctgaagctgc acaatgggcc cctccgcaat gcctacatgg agcagagctt 2700ccagagccta aaccccgtcc tcagcctgcc catcaacccc gcccaggtgg aacaggcacg 2760gaggaacgca gcctccacgg gcacagcgct ggagggatgg ctggactcgt tggtgggcgg 2820gatgtggact gccatggaca tctgtgccac gggccccaca gcctgcccgg tcatgcagac 2880ctgcagccag acggcctgga gctccttcag ccctgacccc aagtcggagc tgggggcagt 2940caaacctgat ggccggctca ggtagcactg ggcacgagga gtgggccaca gcaggatctc 3000aacgggaaag cagccagagg ggttgtgggg cctgaacccc ggcctcccac cctgggggag 3060gccctctgtg aatgggtctc tcctggccat agaatgatgg aaagggaagg tcagcaggtc 3120aaagcaggat cagccaacaa cctgcctttg gcaagctgcg ggtgggatgg ctcagtccct 3180gcactgtgac tgtctcacct cttctggttg atcctcaagt cctacaggtt ccttgtcttc 3240cccttccagt gacccacccc tgaccccaga cgtgtgattt tcagactttt ctttcgagca 3300gcagaacttc gtttacggag cacagtcata agtggaggtt cagggtgctg acgaaatcca 3360agctgctctg gttgaagctg acaagtgcga ggttccctcc caaagctcag ccctctgggc 3420ggtccccttg cccagggtat ctcctacggt acctcttcag aacccaaggg ctctgcaaat 3480gccagtttga caagcactgc ccagaccaac catgggttca aactccagcc ctgccctttg 3540gttcattttt ctgcttctct tggctggggg actctggtgc cagccttgaa agtcatggtc 3600gtgggccctt tcccatggag gctgcagcct taggagagct ctgagcctct cagcagccct 3660ccttgggttg aactattctc cttagtaact aggtaagtgg gaaagccttt tgatgtggca 3720tggccaaggt ccagccacaa gtgcaactgc cacctgtcca ggggtctggg cctccttccc 3780tcaaggctgc cacacaaagt agcagaaata ggatgatgtt tgtgagcacc agactcaaga 3840ccatgacctt ctttgatcct tgaaaatggg aactttgaca gccatgacca tgaaactcac 3900aaggcaacgc gatgaaactc acaaagcaat gcttggagca aaactcctga gctagacagc 3960acagcagcac ccatcccctg ccagagccct tccgttctga ggtcagacac acaaaacctt 4020cgtcaattgc acaccggtgc tgttgggagt gaccaaacca catgaaccag acttttcccg 4080tccaggaaat agcatttcag atttggtttt taatttcatg cccttcggcc acaggctcaa 4140cgggacatgc aacataaaaa tgggaaggtt atttaaac 4178212591DNAHomo sapiens 21gccaagggca ctattggcca gttccgttca acgaagtggt tgcttttttt agttccggca 60atgagttgcg ccggggcggc ggcggctccc cgcctttggc ggctgcgccc gggggcccgg 120cggtccctct cagcttatgg aagaagaacc agtgtcagat ttcgcagttc aggaatgact 180ttagacaata tcagtcgggc agctgtggat cgaataatcc gggtggatca tgcaggcgaa 240tatggagcaa accgcatcta tgccgggcag atggctgtcc

tgggtcggac cagcgtcggg 300ccagtcattc agaaaatgtg ggatcaagaa aaggaccatt tgaaaaagtt caatgagttg 360atggttacgt tcagggtccg gccaacagtt ctgatgccct tgtggaacgt gctggggttt 420gcactggggg cggggaccgc cttgctcggg aaggaaggtg ccatggcctg caccgtggcg 480gtggaagaga gcatagcaca tcactacaac aaccagatca ggacgctgat ggaggaggac 540cctgaaaaat acgaggaact tcttcagctg ataaagaaat ttcgggatga agagcttgag 600caccatgaca taggcctcga ccatgatgca gaattggctc cagcctatgc cgtcctgaag 660agcattatcc aggccggatg cagagtggcg atatatttat cagaaagatt ataaagtgtg 720tccagttttg cctgtctata aaagatgata gtaatttacc aagtgacatt tgcagagaaa 780caggtgtaca gttatcgttg tacttttgta caatgtgaat tttgttaata aattataagg 840tttgtttttt tttttttaaa ctctgcagtg ttgatttttc tctgggttgt tttttctgcc 900atgagaccaa caggtcacca gccttgttca agttacagca aacgaagctg ggccttgttt 960ggtctcatac ttaattttct tttatataca tgtttttctt ttacatgcat atatatatat 1020tttattttat tttatgtttt ttggagacag ggcctcgctc ttttgtccag gccgggtcac 1080aactcactgc agcctggacc tcctagcctc aagcaatcca cccacctcag ccttccaagt 1140agctgggact acaggtgtgc accaccacag ctggctaatt ctattttttt atagaggcga 1200agtctcacta tgtcgccagg ctggtctcta actcctgggc tcagtgatcc tcccgtttcg 1260acttcccaaa gtgctgggat tacaggtgtg agccacttca ccaggcccat tttctcctaa 1320aacttcaagg acaaatcatt aataatgtaa caggaatctt taggagaaaa aacaatttgg 1380tttactgata acaaaagata attggaaaca tgagagtatt tgagattggc caagcagaac 1440tatgaagtcc atcaagtaag tcaaagatca tcgtttctgt tttgaattgt gggtgataat 1500gggtgggaga gtgctacagt ctgtatgtct gtgtctccct agaattcata cgatgaaatc 1560ttcactctca agttgataga aggtggggcc cttgggaagt gtgaggtcat gagagtggag 1620ccctcatgaa tgggatcagt gccttatgaa aggccctaga gagatacctc atcctctcca 1680cagtgtgaga cttcaagggg aagtatgaga cttctctgag gaagcagacc cttcacaagc 1740aaaatcagcc agcactttga tcacggactt cccagcctct aggactgtga gcaataaatg 1800tttgatgttt ataagccacc cagactgtgg tattttgtta tagcagcctg aacagactaa 1860gacgggggtg ttgcttccat caaaggatgt actaagttgt ggattatttg tgaaattgaa 1920ttacaacctt ttccttaagg tcttttacca cctccccccc aaaaaaatcc cccaaaactg 1980attcagattt tcatacttta atgaaatatt ttataatttg caaattttta agtaatttat 2040gaaaaaccta gatcagtgga tctcctctct ggctgcccat tagaatgtcc tgtggagatt 2100aaactttttt ttttcagttt atggaccaag agttttgatt tatttagggt ggagttcagg 2160atcagaatgg tttcagaagc tcccaggtga ttccggagtg agttggagct gcaagcccct 2220gagctagatt ataagatgct tctgggaaag aaccacattt taggaatttg cttcccaccc 2280agtgccctgc atttaatcag cacctgatga cttggcagga cttgccccac cagggtctgg 2340ctttgaaggg tagtggacac caggatcctt tggattaatc ctctgccacc tctctctttt 2400cctcaaccga gagtgaattt atgtaattga gtgaaagtct acgaatcata attgtaataa 2460attaaggctg ggcatttgtt tgaaattaga taggataaag ccaaaggttt gaacaagttg 2520tggatggttt gtaaaaatta atcttacaaa ataaatgctg tgtgtgaaca cgttgattaa 2580attcaaaaaa a 2591221141DNAHomo sapiens 22gttaagggct ccgtggacat ctcaggtctt cagggtcttc catctggaac tatataaagt 60tcagaaaaca tgtctcgaag atatgactcc aggaccacta tattttctcc agaaggtcgc 120ttataccaag ttgaatatgc catggaagct attggacatg caggcacctg tttgggaatt 180ttagcaaatg atggtgtttt gcttgcagca gagagacgca acatccacaa gcttcttgat 240gaagtctttt tttctgaaaa aatttataaa ctcaatgagg acatggcttg cagtgtggca 300ggcataactt ctgatgctaa tgttctgact aatgaactaa ggctcattgc tcaaaggtat 360ttattacagt atcaggagcc aataccttgt gagcagttgg ttacagcgct gtgtgatatc 420aaacaagctt atacacaatt tggaggaaaa cgtccctttg gtgtttcatt gctgtacatt 480ggctgggata agcactatgg ctttcagctc tatcagagtg accctagtgg aaattacggg 540ggatggaagg ccacatgcat tggaaataat agcgctgcag ctgtgtcaat gttgaaacaa 600gactataaag aaggagaaat gaccttgaag tcagcacttg ctttagctat caaagtacta 660aataagacca tggatgttag taaactctct gctgaaaaag tggaaattgc aacactaaca 720agagagaatg gaaagacagt aatcagagtt ctcaaacaaa aagaagtgga gcagttgatc 780aaaaaacacg aggaagaaga agccaaagct gagcgtgaga agaaagaaaa agaacagaaa 840gaaaaggata aatagaatca gagattttat tactcatttg gggcaccatt tcagtgtaaa 900agcagtccta ctcttccaca ctaggaaggc tttacttttt ttaactggtg cagtgggaaa 960ataggacatt acatactgaa ttgggtcctt gtcatttctg tccaattgaa tactttattg 1020taacgatgat ggttaccctt catggacgtc ttaatcttcc acacacatcc cctttttttg 1080gaataaaatt tggaaaatgg aaatgaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1140a 1141232870DNAHomo sapiens 23aggtcgcagg cgggcgtgcg tggagcgggg gccgcggccg cgccgcagag atgtgactcg 60ggccgaaggc cagctggagc gtcggcgctg cggggccgcg ggggtcgaat gttcgtggca 120tcagagagaa agatgagagc tcaccaggtg ctcaccttcc tcctgctctt cgtgatcacc 180tcggtggcct ctgaaaacgc cagcacatcc cgaggctgtg ggctggacct cctccctcag 240tacgtgtccc tgtgcgacct ggacgccatc tggggcattg tggtggaggc ggtggccggg 300gcgggcgccc tgatcacact gctcctgatg ctcatcctcc tggtgcggct gcccttcatc 360aaggagaagg agaagaagag ccctgtgggc ctccactttc tgttcctcct ggggaccctg 420ggcctctttg ggctgacgtt tgccttcatc atccaggagg acgagaccat ctgctctgtc 480cgccgcttcc tctggggcgt cctctttgcg ctctgcttct cctgcctgct gagccaggca 540tggcgcgtgc ggaggctggt gcggcatggc acgggccccg cgggctggca gctggtgggc 600ctggcgctgt gcctgatgct ggtgcaagtc atcatcgctg tggagtggct ggtgctcacc 660gtgctgcgtg acacaaggcc agcctgcgcc tacgagccca tggactttgt gatggccctc 720atctacgaca tggtactgct tgtggtcacc ctggggctgg ccctcttcac tctgtgcggc 780aagttcaaga ggtggaagct gaacggggcc ttcctcctca tcacagcctt cctctctgtg 840ctcatctggg tggcctggat gaccatgtac ctcttcggca atgtcaagct gcagcagggg 900gatgcctgga acgaccccac cttggccatc acgctggcgg ccagcggctg ggtcttcgtc 960atcttccacg ccatccctga gatccactgc acccttctgc cagccctgca ggagaacacg 1020cccaactact tcgacacgtc gcagcccagg atgcgggaga cggccttcga ggaggacgtg 1080cagctgccgc gggcctatat ggagaacaag gccttctcca tggatgaaca caatgcagct 1140ctccgaacag caggatttcc caacggcagc ttgggaaaaa gacccagtgg cagcttgggg 1200aaaagaccca gcgctccgtt tagaagcaac gtgtatcagc caactgagat ggccgtcgtg 1260ctcaacggtg ggaccatccc aactgctccg ccaagtcaca caggaagaca cctttggtga 1320aagactttaa gttccagaga atcagaattt ctcttaccga tttgcctccc tggctgtgtc 1380tttcttgagg gagaaatcgg taacagttgc cgaaccaggc cgcctcacag ccaggaaatt 1440tggaaatcct agccaagggg atttcgtgta aatgtgaaca ctgacgaact gaaaagctaa 1500caccgactgc ccgcccctcc cctgccacac acacagacac gtaataccag accaacctca 1560atccccgcaa actaaagcaa agctaattgc aaatagtatt aggctcactg gaaaatgtgg 1620ctgggaagac tgtttcatcc tctgggggta gaacagaacc aaattcacag ctggtgggcc 1680agactggtgt tggttggagg tggggggctc ccactcttat cacctctccc cagcaagtgc 1740tggaccccag gtagcctctt ggagatgacc gttgcgttga ggacaaatgg ggactttgcc 1800accggcttgc ctggtggttt gcacatttca ggggggtcag gagagttaag gaggttgtgg 1860gtgggattcc aaggtgaggc ccaactgaat cgtggggtga gctttatagc cagtagaggt 1920ggagggaccc tggcatgtgc caaagaagag gccctctggg tgatgaagtg accatcacat 1980ttggaaagtg atcaaccact gttccttcta tggggctctt gctctaatgt ctatggtgag 2040aacacaggcc ccgccccttc ccttgtagag ccatagaaat attctggctt ggggcagcag 2100tcccttcttc ccttgatcat ctcgccctgt tcctacactt acgggtgtat ctccaaatcc 2160tctcccaatt ttattccctt attcatttca agagctccaa tggggtctcc agctgaaagc 2220ccctccggga ggcaggttgg aaggcaggca ccacggcagg ttttccgcga tgatgtcacc 2280tagcagggct tcaggggttc ccactaggat gcagagatga cctctcgctg cctcacaagc 2340agtgacacct cgggtccttt ccgttgctat ggtgaaaatt cctggatgga atggatcaca 2400tgagggtttc ttgttgcttt tggagggtgt gggggatatt ttgttttggt ttttctgcag 2460gttccatgaa aacagccctt ttccaagccc attgtttctg tcatggtttc catctgtcct 2520gagcaagtca ttcctttgtt atttagcatt tcgaacatct cggccattca aagcccccat 2580gttctctgca ctgtttggcc agcataacct ctagcatcga ttcaaagcag agttttaacc 2640tgacggcatg gaatgtataa atgagggtgg gtccttctgc agatactcta atcactacat 2700tgctttttct ataaaactac ccataagcct ttaaccttta aagaaaaatg aaaaaggtta 2760gtgtttgggg gccgggggag gactgaccgc ttcataagcc agtacgtctg agctgagtat 2820gtttcaataa accttttgat atttctcaaa aaaaaaaaaa aaaaaaaaaa 2870242448DNAHomo sapiens 24attcccatgg ctggccagag gaggaacgct ttgtgttctc atcggagctg catgggaagt 60ctgcatacag caaagtgacc tgcatgcctc accttatgga aaggatggtg ggctctggcc 120tcctgtggct ggccttggtc tcctgcattc tgacccaggc atctgcagtg cagcgaggtt 180atggaaaccc cattgaagcc agttcgtatg ggctggacct ggactgcgga gctcctggca 240ccccagaggc tcatgtctgt tttgacccct gtcagaatta caccctcctg gatgaaccct 300tccgaagcac agagaactca gcagggtccc aggggtgcga taaaaacatg agcggctggt 360accgctttgt aggggaagga ggagtaagga tgtcggagac ctgtgtccag gtgcaccgat 420gccagacaga cgctcccatg tggctgaatg ggacccaccc tgcccttggg gatggcatca 480ccaaccacac tgcctgtgcc cattggagtg gcaactgctg tttctggaaa acagaggtgc 540tggtgaaggc ctgcccaggc gggtaccatg tgtaccggtt ggaaggcact ccctggtgta 600atctgagata ctgcacagtt ccacgagacc catccactgt ggaggacaag tgtgagaagg 660cctgccgccc cgaggaggag tgccttgccc tcaacagcac ctggggctgt ttctgcagac 720aggacctcaa tagttctgat gtccacagtt tgcagcctca gctagactgt gggcccaggg 780agatcaaggt gaaggtggac aaatgtttgc tgggaggcct gggtttgggg gaggaggtca 840ttgcctacct gcgagaccca aactgcagca gcatcttgca gacagaggag aggaactggg 900tatctgtgac cagccccgtc caggctagtg cctgcaggaa cattctggag agaaatcaaa 960cccatgccat ctacaaaaac accctctcct tggtcaatga tttcatcatc agagacacca 1020tcctcaacat caacttccaa tgtgcctacc cactggacat gaaagtcagc ctccaagctg 1080ccttgcagcc cattgtaagt tccctgaacg tcagtgtgga cgggaatgga gagttcattg 1140tcaggatggc cctcttccaa gaccagaact acacgaatcc ttacgaaggg gatgcagttg 1200aactgtctgt tgagtccgtg ctgtatgtgg gtgccatctt ggaacaaggg gacacctccc 1260ggtttaacct ggtgttgagg aactgctatg ccacccccac tgaagacaag gctgaccttg 1320tgaagtattt catcatcaga aacagctgct caaatcaacg tgattccacc atccacgtgg 1380aggagaatgg gcagtcctcg gaaagccggt tctcagttca gatgttcatg tttgctggac 1440attatgacct agttttcctg cattgtgaga ttcatctctg tgattctctt aatgaacagt 1500gccagccttc ttgctcaaga agtcaagtcc gcagtgaagt accggccatc gacctagccc 1560gggttctaga tttggggccc atcactcgga gaggtgcaca gtctcccggt gtcatgaatg 1620gaacccctag cactgcaggg ttcctggtgg cctggcctat ggtcctcctg actgtcctcc 1680tggcttggct gttctgagag ctccgctgag catctggcct tgaagtttgt gttcttccct 1740ctggcaatgg ctcccttcag cacttctgct ttccactcca attcacacag gcttggtatt 1800aacagaatca aggccaggct aggttaggaa aagggaagag ctttcacctt ctttaaaact 1860ctcggctggg cgcagtggct catgcctgta atcccagcat tttgggaggc tgaggcaggt 1920ggatcacctg aggtcagcag ttcaaaatca gcctggccaa aatgctgaaa ctccgtctct 1980actaaaaata caaaaattag ccaggcatgg tggcaggcgc ctgtaatccc agctactcgg 2040gaggccaagg caggagaatt gctcgaactc agggggtgga ggttgcagtg agttgagatt 2100gtgccattgc actccagcct gggcaacaga gcaagactct gtctcaggaa aaaaaaaaaa 2160aaaaaagaaa agcaacatag tggggtttct gtcaatctgt cctcggctgc ccttctcatt 2220tgttgatggg accttgaaag caagcttgct aggtgccctc tgtggctcca gcctttaccg 2280gaagtgtggt gcatgttttt aacttcaggg aagcggtatc ctgtcactgg ggtatgggat 2340gagcatggag aagaggcacc agccacgatt ccttcctaag catctcctgt tctgactgct 2400catgaattga agaaactgac ccttgtgttc aaaaaaaaaa aaaaaaaa 2448252264DNAHomo sapiens 25agactaactc tacctttctg gcttcaggtg ctatctagac ctgaagtagc gggaagagca 60gaaaggatgg ggcagccatc tctgacttgg atgctgatgg tggtggtggc ctcttggttc 120atcacaactg cagccactga cacctcagaa gcaagatggt gctctgaatg tcacagcaat 180gccacctgca cggaggatga ggccgttacg acgtgcacct gtcaggaggg cttcaccggc 240gatggcctga cctgcgtgga cctggatgag tgcgccattc ctggagctca caactgctcc 300gccaacagca gctgcgtaaa cacgccaggc tccttctcct gcgtctgccc cgaaggcttc 360cgcctgtcgc ccggtctcgg ctgcacagac gtggatgagt gcgctgagcc tgggcttagc 420cactgccacg ccctggccac atgtgtcaat gtggtgggca gctacttgtg cgtatgcccc 480gcgggctacc ggggggatgg atggcactgt gagtgctccc cgggctcctg cgggccgggg 540ttggactgcg tgcccgaggg cgacgcgctc gtgtgcgcgg atccgtgcca ggcgcaccgc 600accctggacg agtactggcg cagcaccgag tacggggagg gctacgcctg cgacacggac 660ctgcgcggct ggtaccgctt cgtgggccag ggcggtgcgc gcatggccga gacctgcgtg 720ccagtcctgc gctgcaacac ggccgccccc atgtggctca atggcacgca tccgtccagc 780gacgagggca tcgtgagccg caaggcctgc gcgcactgga gcggccactg ctgcctgtgg 840gatgcgtccg tccaggtgaa ggcctgtgcc ggcggctact acgtctacaa cctgacagcg 900ccccccgagt gtcacctggc gtactgcaca gaccccagct ccgtggaggg gacgtgtgag 960gagtgcagta tagacgagga ctgcaaatcg aataatggca gatggcactg ccagtgcaaa 1020caggacttca acatcactga tatctccctc ctggagcaca ggctggaatg tggggccaat 1080gacatgaagg tgtcgctggg caagtgccag ctgaagagtc tgggcttcga caaggtcttc 1140atgtacctga gtgacagccg gtgctcgggc ttcaatgaca gagacaaccg ggactgggtg 1200tctgtagtga ccccagcccg ggatggcccc tgtgggacag tgttgacgag gaatgaaacc 1260catgccactt acagcaacac cctctacctg gcagatgaga tcatcatccg tgacctcaac 1320atcaaaatca actttgcatg ctcctacccc ctggacatga aagtcagcct gaagaccgcc 1380ctacagccaa tggtcagtgc tctaaacatc agagtgggcg ggaccggcat gttcaccgtg 1440cggatggcgc tcttccagac cccttcctac acgcagccct accaaggctc ctccgtgaca 1500ctgtccactg aggcttttct ctacgtgggc accatgttgg atgggggcga cctgtcccga 1560tttgcactgc tcatgaccaa ctgctatgcc acacccagta gcaatgccac ggaccccctg 1620aagtacttca tcatccagga cagatgccca cacactagag actcaactat ccaagtggtg 1680gagaatgggg agtcctccca gggccgattt tccgtccaga tgttccggtt tgctggaaac 1740tatgacctag tctacctgca ctgtgaagtc tatctctgtg acaccatgaa tgaaaagtgc 1800aagcctacct gctctgggac cagattccga agtgggagtg tcatagatca atcccgtgtc 1860ctgaacttgg gtcccatcac acggaaaggt gtccaggcca cagtctcaag ggcttttagc 1920agcttggggc tcctgaaagt ctggctgcct ctgcttctct cggccacctt gaccctgact 1980tttcagtgac tgacagcgga aagccctgtg ctccatggct gccatctcac ctcctgctgg 2040gcagggggca tgatgcgggc cagtgctcca gccacagaaa agaaagttca tgctttgttc 2100agcctgcctt cttttctccc ttttaatcct ggctgtcgag aaacagcctg tgtctttaaa 2160tgctgctttt tctcaaaatg ggacttgtga cggtgtacct gaggccccca tctccttaaa 2220gagtgtggca aaataatgat ttttaaatct caaaaaaaaa aaaa 2264261945DNAHomo sapiens 26agccatctct tcccaaggca ggtggtgact tgagaactct gtgcctggtt tctgaggact 60gtttcaccat gcagtggcta atgaggttcc ggaccctctg gggcatccac aaatccttcc 120acaacatcca ccctgcccct tcacagctgc gctgccggtc tttatcagaa tttggagccc 180caagatggaa tgactatgaa gtaccggagg aatttaactt tgcaagttat gtactggact 240actgggctca aaaggagaag gagggcaaga gaggtccaaa tccagctttt tggtgggtga 300atggccaagg ggatgaagta aagtggagct tcagagagat gggagaccta acccgccgtg 360tagccaacgt cttcacacag acctgtggcc tacaacaggg agaccatctg gccttgatgc 420tgcctcgagt tcctgagtgg tggctggtgg ctgtgggctg catgcgaaca gggatcatct 480tcattcctgc gaccatcctg ttgaaggcca aagacattct ctatcgacta cagttgtcta 540aagccaaggg cattgtgacc atagatgccc ttgcctcaga ggtggactcc atagcttctc 600agtgcccctc tctgaaaacc aagctcctgg tgtctgatca cagccgtgaa gggtggctgg 660acttccgatc gctggttaaa tcagcatccc cagaacacac ctgtgttaag tcaaagacct 720tggacccaat ggtcatcttc ttcaccagtg ggaccacagg cttccccaag atggcaaaac 780actcccatgg gttggcctta caaccctcct tcccaggaag taggaaatta cggagcctga 840agacatctga tgtctcctgg tgcctgtcgg actcaggatg gattgtggct accatttgga 900ccctggtaga accatggaca gcgggttgta cagtctttat ccaccatctg ccacagtttg 960acaccaaggt catcatacag acattgttga aataccccat taaccacttt tggggggtat 1020catctatata tcgaatgatt ctgcagcagg atttcaccag catcaggttc cctgccctgg 1080agcactgcta tactggcggg gaggtcgtgt tgcccaagga tcaggaggag tggaaaagac 1140ggacgggcct tctgctctac gagaactatg ggcagtcgga aacgggacta atttgtgcca 1200cctactgggg aatgaagatc aagccgggtt tcatggggaa ggccactcca ccctatgacg 1260tccaggtcat tgatgacaag ggcagcatcc tgccacctaa cacagaagga aacattggca 1320tcagaatcaa acctgtcagg cctgtgagcc tcttcatgtg ctatgagggt gacccagaga 1380agacagctaa agtggaatgt ggggacttct acaacactgg ggacagagga aagatggatg 1440aagagggcta catttgtttc ctggggagga gtgatgacat cattaatgcc tctgggtatc 1500gcatcgggcc tgcagaggtt gaaagcgctt tggtggagca cccagcggtg gcggagtcag 1560ccgtggtggg cagcccagac ccgattcgag gggaggtggt gaaggccttt attgtcctga 1620ccccacagtt cctgtcccat gacaaggatc agctgaccaa ggaactgcag cagcatgtca 1680agtcagtgac agccccatac aagtacccaa ggaacgtgga gtttgtctca gagctgccaa 1740aaaccatcac tggcaagatt gaacggaagg aacttcggaa aaaggagact ggtcagatgt 1800aatcggcagt gaactcagaa cgcactgcac acctaaggca aatccctggc cactttagtc 1860tccccactat ggtgaggacg agggtggggc attgagagtg ttgatttggg aaagtatcag 1920gagtgccata atcactagtg aattc 194527930DNAMus musculus 27atggagaacc aaaacaatgt gacagaattt atccttctgg gactcacaga gaacccaaag 60atgcaaaaaa ttgtattcat tatgtttttt cttatctaca tcatttctat aacaggaaat 120gtgctcattg tggtcaccat aacttctacg tcattattag agtcccccat gtactttttc 180ctggcttatc tatcctttat tgatgcttgc tattcctctg ttagcacccc taaactgata 240gcagattcac tctgtgaaaa gaagaccatc ccatttaatg gatgcatgac tcagatcttt 300ggggagcatt tgtttggagg tgctgaaatc atcctgctga cagtaatggc ctatgaccgc 360tatgtggcca tctgcaaacc ccttcattat gcaacgatca tgagtcgaag actatgtagc 420ctgctagtgg gagtgtcatg gctaggaggt tttcttcatg ccaccataca gatcctgttc 480attttccaat tacccttctg tggccctaac atcatagatc attttatgtg tgatcttaat 540cctttgctca accttgtatg caccgatact cacactcttg gaatctttgt tgcagccaac 600agtggtttta tttgtctgct aaacttcctt cttctattgg tctcctatgt tgccatcctg 660cgctccctaa agaaccacag tgcagaggga aggcgcaaag ccctctctac ctgtatttca 720cacataacag tggttgtctt attctttgtg ccttgcatat ttgtatacat gagacctgta 780gctaccttac ccattgataa agcagttgct atgttctata ctatgataac tcccatgttg 840aaccccttaa tctatacctt aagaaatgct cagatgaaag atgccattaa gaaattgggt 900agcactaaaa ttctttcaag taataaatga 930282591DNAHomo sapiens 28gccaagggca ctattggcca gttccgttca acgaagtggt tgcttttttt agttccggca 60atgagttgcg ccggggcggc ggcggctccc cgcctttggc ggctgcgccc gggggcccgg 120cggtccctct cagcttatgg aagaagaacc agtgtcagat ttcgcagttc aggaatgact 180ttagacaata tcagtcgggc agctgtggat cgaataatcc gggtggatca tgcaggcgaa 240tatggagcaa accgcatcta tgccgggcag atggctgtcc tgggtcggac cagcgtcggg 300ccagtcattc agaaaatgtg ggatcaagaa aaggaccatt tgaaaaagtt caatgagttg 360atggttacgt tcagggtccg gccaacagtt ctgatgccct tgtggaacgt gctggggttt 420gcactggggg cggggaccgc cttgctcggg aaggaaggtg ccatggcctg caccgtggcg 480gtggaagaga gcatagcaca tcactacaac aaccagatca ggacgctgat ggaggaggac 540cctgaaaaat acgaggaact tcttcagctg ataaagaaat ttcgggatga agagcttgag 600caccatgaca taggcctcga ccatgatgca gaattggctc cagcctatgc cgtcctgaag 660agcattatcc aggccggatg cagagtggcg atatatttat cagaaagatt ataaagtgtg 720tccagttttg cctgtctata aaagatgata gtaatttacc aagtgacatt tgcagagaaa 780caggtgtaca gttatcgttg

tacttttgta caatgtgaat tttgttaata aattataagg 840tttgtttttt tttttttaaa ctctgcagtg ttgatttttc tctgggttgt tttttctgcc 900atgagaccaa caggtcacca gccttgttca agttacagca aacgaagctg ggccttgttt 960ggtctcatac ttaattttct tttatataca tgtttttctt ttacatgcat atatatatat 1020tttattttat tttatgtttt ttggagacag ggcctcgctc ttttgtccag gccgggtcac 1080aactcactgc agcctggacc tcctagcctc aagcaatcca cccacctcag ccttccaagt 1140agctgggact acaggtgtgc accaccacag ctggctaatt ctattttttt atagaggcga 1200agtctcacta tgtcgccagg ctggtctcta actcctgggc tcagtgatcc tcccgtttcg 1260acttcccaaa gtgctgggat tacaggtgtg agccacttca ccaggcccat tttctcctaa 1320aacttcaagg acaaatcatt aataatgtaa caggaatctt taggagaaaa aacaatttgg 1380tttactgata acaaaagata attggaaaca tgagagtatt tgagattggc caagcagaac 1440tatgaagtcc atcaagtaag tcaaagatca tcgtttctgt tttgaattgt gggtgataat 1500gggtgggaga gtgctacagt ctgtatgtct gtgtctccct agaattcata cgatgaaatc 1560ttcactctca agttgataga aggtggggcc cttgggaagt gtgaggtcat gagagtggag 1620ccctcatgaa tgggatcagt gccttatgaa aggccctaga gagatacctc atcctctcca 1680cagtgtgaga cttcaagggg aagtatgaga cttctctgag gaagcagacc cttcacaagc 1740aaaatcagcc agcactttga tcacggactt cccagcctct aggactgtga gcaataaatg 1800tttgatgttt ataagccacc cagactgtgg tattttgtta tagcagcctg aacagactaa 1860gacgggggtg ttgcttccat caaaggatgt actaagttgt ggattatttg tgaaattgaa 1920ttacaacctt ttccttaagg tcttttacca cctccccccc aaaaaaatcc cccaaaactg 1980attcagattt tcatacttta atgaaatatt ttataatttg caaattttta agtaatttat 2040gaaaaaccta gatcagtgga tctcctctct ggctgcccat tagaatgtcc tgtggagatt 2100aaactttttt ttttcagttt atggaccaag agttttgatt tatttagggt ggagttcagg 2160atcagaatgg tttcagaagc tcccaggtga ttccggagtg agttggagct gcaagcccct 2220gagctagatt ataagatgct tctgggaaag aaccacattt taggaatttg cttcccaccc 2280agtgccctgc atttaatcag cacctgatga cttggcagga cttgccccac cagggtctgg 2340ctttgaaggg tagtggacac caggatcctt tggattaatc ctctgccacc tctctctttt 2400cctcaaccga gagtgaattt atgtaattga gtgaaagtct acgaatcata attgtaataa 2460attaaggctg ggcatttgtt tgaaattaga taggataaag ccaaaggttt gaacaagttg 2520tggatggttt gtaaaaatta atcttacaaa ataaatgctg tgtgtgaaca cgttgattaa 2580attcaaaaaa a 2591291912DNAHomo sapiens 29cccaggcgcc ccggccttat tccagcctgg ggagcgcctc ggtggggagc acgggacagc 60gagggaggcc gaggcggggg ccctgggcgc ccgatatctc cgaaccgggg aggcggcccc 120gattccgaga gccggaacgc agggaaaggc aaggacgggg cggccggcgg aggggcgggc 180gccgctcatc agccacgcca gtcacgtctg gggccaccgg ctgccttttt cttcctttcc 240ccctttgctt tcttccccct ccgctgttgg cgagggcaaa gtggccgtgg cggcgccatg 300cccgggccgg agtgagtgcg cgcgggcgaa aatggcgtac atccagttgg aaccattaaa 360cgagggtttt ctttctagaa tctctggtct gctgctgtgc agatggacct gccggcactg 420ctgtcagaag tgctacgagt ccagctgttg ccagtcaagt gaggatgaag ttgaaattct 480gggacctttc cctgctcaga cccctccctg gctgatggcc agccggagca gtgacaagga 540tggtgactct gtccacacgg ccagcgaagt cccgctgacc ccacggacca attccccgga 600tggaagacgc tcgtcctcag acacatccaa gtctacatac agcctgacgc ggaggatttc 660gagtcttgag tcaagacgtc ccagctctcc actcatcgat attaaaccca tcgagtttgg 720cgttctcagc gccaagaagg agcccatcca accttcggtg ctcagacgga cctataaccc 780cgacgactat ttcaggaagt tcgaacccca cctgtactcc ctcgactcca acagcgacga 840tgtggactct ctgacagacg aggagatcct gtccaagtac cagctgggca tgctgcactt 900cagcactcag tacgacctgc tgcacaacca cctcaccgtg cgcgtgatcg aggccaggga 960cctgccacct cccatctccc acgatggctc gcgccaggac atggcgcact ccaaccccta 1020cgtcaagatc tgtctcctgc cagaccagaa gaactcaaag cagaccgggg tcaaacgcaa 1080gacccagaag cccgtgtttg aggagcgcta caccttcgag atccccttcc tggaggccca 1140gaggaggacc ctgctcctga ccgtggtgga ttttgataag ttctcccgcc actgtgtcat 1200tgggaaagtt tctgtgcctt tgtgtgaagt tgacctggtc aagggcgggc actggtggaa 1260ggcgctgatt cccagttctc agaatgaagt ggagctgggg gagctgcttc tgtcactgaa 1320ttatctccca agtgctggca gactgaatgt tgatgtcatt cgagccaagc aacttcttca 1380gacagatgtg agccaaggtt cagacccctt tgtgaaaatc cagctggtgc atggactcaa 1440acttgtgaaa accaagaaga cgtccttctt aaggggcaca attgatcctt tctacaatga 1500atccttcagc ttcaaagttc cccaagaaga actggaaaat gccagcctag tgtttacagt 1560tttcggccac aacatgaaga gcagcaatga cttcatcggg aggatcgtca ttggccagta 1620ctcttcaggc ccctctgaga ccaaccactg gaggcgcatg ctcaacacgc accgcacagc 1680cgtggagcag tggcatagcc tgaggtcccg agctgagtgt gaccgcgtgt ctcctgcctc 1740cctggaggtg acctgagggc tgcagggaag gcagctttca tttgtttaaa aaaaaaaaaa 1800aaagacggaa aaaaatgtgt cacatactat tacatccaca cctgcataca cactcgcaac 1860atgtctacac acgtccacac acacagacac acagataccc caaatcctct ca 1912301401DNAHomo sapiens 30atgcaaaggt ggacactgtg ggctgcagcc ttcctgaccc tccactctgc acaggccttt 60ccacaaacag acatcagtat cagtccagcc ctgccagagc tgcccctgcc ttccctgtgc 120cccctgttct ggatggagtt caaaggccac tgctatcgat tcttccctct caataagacc 180tgggctgagg ccgacctcta ctgttctgag ttctctgtgg gcaggaagtc cgccaagctg 240gcctccatcc acagctggga ggagaatgtc tttgtatatg acctcgtgaa cagctgtgtt 300cccggcatcc cagctgacgt ctggacaggc cttcatgatc acagacagga agggcagttt 360gaatggactg atggctcatc ctatgactac agctactggg atggcagcca gccagatgat 420ggcgtccacg cggacccaga agaagaggac tgcgtgcaga tatggtacag gcctaccagt 480gagcagctac aggccccaga gccccagtta cccttatcaa tctcagaggc cacagatgtc 540tatctccctg aggatttccc agctgagccc aagctcatgg accagtcctg ggtgtccagg 600aagagcctga aaccatccaa gagtcatctt atggagccac ccactccagt ggccaagcac 660caaaaggcaa agacccgaca taggagcctg cgcggcgtct ggtggccatc aggtaaggct 720gggtcatgga aagaaagaat gaatgcagac tacgggcgaa gaaagcgatc ggccccgagg 780caggaaggcc ggctccggtg cagggagcgc cgcctgcggg ctgcttcggg ccagggtcga 840cccgagggcc agcgcaagca gcggcaacag gagcgccagg agagaggctg ggaagaactg 900ggaggggtgt ccccaatgcg gggcgcccaa gcgtggcagc acgggctggg agcggggagc 960cagcggggtg cggcgccgga gtgcggggag aaccaccagg cgccggaatt ggggagcacg 1020tggagggggc agcggctcca gccccagacc gccgcgctct gtcactttgc attaagaaag 1080cttccgggga atgcacacgg cctggccgcc gccttcgtgc agcccgccct gcaggtgcag 1140gaagaaaaga ataatcgcac ccgtttctca ggtgcttact tcaccatgtc cgatccgacg 1200tgtgaccaag atagcaagga gcagtcttta aggcgacacg gcagagaggc agaaaaagat 1260gggccttacc ggttagttaa gaaaaaaaga ggacctgttg cctgtccctc tagctttgaa 1320ctacaaagtg gaggggaagt ttgtctggat tttcctgtag aactgagggc agggacctgg 1380attgctcgag aacctccata a 1401312870DNAHomo sapiens 31aggtcgcagg cgggcgtgcg tggagcgggg gccgcggccg cgccgcagag atgtgactcg 60ggccgaaggc cagctggagc gtcggcgctg cggggccgcg ggggtcgaat gttcgtggca 120tcagagagaa agatgagagc tcaccaggtg ctcaccttcc tcctgctctt cgtgatcacc 180tcggtggcct ctgaaaacgc cagcacatcc cgaggctgtg ggctggacct cctccctcag 240tacgtgtccc tgtgcgacct ggacgccatc tggggcattg tggtggaggc ggtggccggg 300gcgggcgccc tgatcacact gctcctgatg ctcatcctcc tggtgcggct gcccttcatc 360aaggagaagg agaagaagag ccctgtgggc ctccactttc tgttcctcct ggggaccctg 420ggcctctttg ggctgacgtt tgccttcatc atccaggagg acgagaccat ctgctctgtc 480cgccgcttcc tctggggcgt cctctttgcg ctctgcttct cctgcctgct gagccaggca 540tggcgcgtgc ggaggctggt gcggcatggc acgggccccg cgggctggca gctggtgggc 600ctggcgctgt gcctgatgct ggtgcaagtc atcatcgctg tggagtggct ggtgctcacc 660gtgctgcgtg acacaaggcc agcctgcgcc tacgagccca tggactttgt gatggccctc 720atctacgaca tggtactgct tgtggtcacc ctggggctgg ccctcttcac tctgtgcggc 780aagttcaaga ggtggaagct gaacggggcc ttcctcctca tcacagcctt cctctctgtg 840ctcatctggg tggcctggat gaccatgtac ctcttcggca atgtcaagct gcagcagggg 900gatgcctgga acgaccccac cttggccatc acgctggcgg ccagcggctg ggtcttcgtc 960atcttccacg ccatccctga gatccactgc acccttctgc cagccctgca ggagaacacg 1020cccaactact tcgacacgtc gcagcccagg atgcgggaga cggccttcga ggaggacgtg 1080cagctgccgc gggcctatat ggagaacaag gccttctcca tggatgaaca caatgcagct 1140ctccgaacag caggatttcc caacggcagc ttgggaaaaa gacccagtgg cagcttgggg 1200aaaagaccca gcgctccgtt tagaagcaac gtgtatcagc caactgagat ggccgtcgtg 1260ctcaacggtg ggaccatccc aactgctccg ccaagtcaca caggaagaca cctttggtga 1320aagactttaa gttccagaga atcagaattt ctcttaccga tttgcctccc tggctgtgtc 1380tttcttgagg gagaaatcgg taacagttgc cgaaccaggc cgcctcacag ccaggaaatt 1440tggaaatcct agccaagggg atttcgtgta aatgtgaaca ctgacgaact gaaaagctaa 1500caccgactgc ccgcccctcc cctgccacac acacagacac gtaataccag accaacctca 1560atccccgcaa actaaagcaa agctaattgc aaatagtatt aggctcactg gaaaatgtgg 1620ctgggaagac tgtttcatcc tctgggggta gaacagaacc aaattcacag ctggtgggcc 1680agactggtgt tggttggagg tggggggctc ccactcttat cacctctccc cagcaagtgc 1740tggaccccag gtagcctctt ggagatgacc gttgcgttga ggacaaatgg ggactttgcc 1800accggcttgc ctggtggttt gcacatttca ggggggtcag gagagttaag gaggttgtgg 1860gtgggattcc aaggtgaggc ccaactgaat cgtggggtga gctttatagc cagtagaggt 1920ggagggaccc tggcatgtgc caaagaagag gccctctggg tgatgaagtg accatcacat 1980ttggaaagtg atcaaccact gttccttcta tggggctctt gctctaatgt ctatggtgag 2040aacacaggcc ccgccccttc ccttgtagag ccatagaaat attctggctt ggggcagcag 2100tcccttcttc ccttgatcat ctcgccctgt tcctacactt acgggtgtat ctccaaatcc 2160tctcccaatt ttattccctt attcatttca agagctccaa tggggtctcc agctgaaagc 2220ccctccggga ggcaggttgg aaggcaggca ccacggcagg ttttccgcga tgatgtcacc 2280tagcagggct tcaggggttc ccactaggat gcagagatga cctctcgctg cctcacaagc 2340agtgacacct cgggtccttt ccgttgctat ggtgaaaatt cctggatgga atggatcaca 2400tgagggtttc ttgttgcttt tggagggtgt gggggatatt ttgttttggt ttttctgcag 2460gttccatgaa aacagccctt ttccaagccc attgtttctg tcatggtttc catctgtcct 2520gagcaagtca ttcctttgtt atttagcatt tcgaacatct cggccattca aagcccccat 2580gttctctgca ctgtttggcc agcataacct ctagcatcga ttcaaagcag agttttaacc 2640tgacggcatg gaatgtataa atgagggtgg gtccttctgc agatactcta atcactacat 2700tgctttttct ataaaactac ccataagcct ttaaccttta aagaaaaatg aaaaaggtta 2760gtgtttgggg gccgggggag gactgaccgc ttcataagcc agtacgtctg agctgagtat 2820gtttcaataa accttttgat atttctcaaa aaaaaaaaaa aaaaaaaaaa 2870322439DNAHomo sapiens 32attcccatgg ctggccagag gaggaacgct ttgtgttctc atcggagctg catgggaagt 60ctgcatacag caaagtgacc tgcatgcctc accttatgga aaggatggtg ggctctggcc 120tcctgtggct ggccttggtc tcctgcattc tgacccaggc atctgcagtg cagcgaggtt 180atggaaaccc cattgaagcc agttcgtatg ggctggacct ggactgcgga gctcctggca 240ccccagaggc tcatgtctgt tttgacccct gtcagaatta caccctcctg gatgaaccct 300tccgaagcac agagaactca gcagggtccc aggggtgcga taaaaacatg agcggctggt 360accgctttgt aggggaagga ggagtaagga tgtcggagac ctgtgtccag gtgcaccgat 420gccagacaga cgctcccatg tggctgaatg ggacccaccc tgcccttggg gatggcatca 480ccaaccacac tgcctgtgcc cattggagtg gcaactgctg tttctggaaa acagaggtgc 540tggtgaaggc ctgcccaggc gggtaccatg tgtaccggtt ggaaggcact ccctggtgta 600atctgagata ctgcacagac ccatccactg tggaggacaa gtgtgagaag gcctgccgcc 660ccgaggagga gtgccttgcc ctcaacagca cctggggctg tttctgcaga caggacctca 720atagttctga tgtccacagt ttgcagcctc agctagactg tgggcccagg gagatcaagg 780tgaaggtgga caaatgtttg ctgggaggcc tgggtttggg ggaggaggtc attgcctacc 840tgcgagaccc aaactgcagc agcatcttgc agacagagga gaggaactgg gtatctgtga 900ccagccccgt ccaggctagt gcctgcagga acattctgga gagaaatcaa acccatgcca 960tctacaaaaa caccctctcc ttggtcaatg atttcatcat cagagacacc atcctcaaca 1020tcaacttcca atgtgcctac ccactggaca tgaaagtcag cctccaagct gccttgcagc 1080ccattgtaag ttccctgaac gtcagtgtgg acgggaatgg agagttcatt gtcaggatgg 1140ccctcttcca agaccagaac tacacgaatc cttacgaagg ggatgcagtt gaactgtctg 1200ttgagtccgt gctgtatgtg ggtgccatct tggaacaagg ggacacctcc cggtttaacc 1260tggtgttgag gaactgctat gccaccccca ctgaagacaa ggctgacctt gtgaagtatt 1320tcatcatcag aaacagctgc tcaaatcaac gtgattccac catccacgtg gaggagaatg 1380ggcagtcctc ggaaagccgg ttctcagttc agatgttcat gtttgctgga cattatgacc 1440tagttttcct gcattgtgag attcatctct gtgattctct taatgaacag tgccagcctt 1500cttgctcaag aagtcaagtc cgcagtgaag taccggccat cgacctagcc cgggttctag 1560atttggggcc catcactcgg agaggtgcac agtctcccgg tgtcatgaat ggaaccccta 1620gcactgcagg gttcctggtg gcctggccta tggtcctcct gactgtcctc ctggcttggc 1680tgttctgaga gctccgctga gcatctggcc ttgaagtttg tgttcttccc tctggcaatg 1740gctcccttca gcacttctgc tttccactcc aattcacaca ggcttggtat taacagaatc 1800aaggccaggc taggttagga aaagggaaga gctttcacct tctttaaaac tctcggctgg 1860gcgcagtggc tcatgcctgt aatcccagca ttttgggagg ctgaggcagg tggatcacct 1920gaggtcagca gttcaaaatc agcctggcca aaatgctgaa actccgtctc tactaaaaat 1980acaaaaatta gccaggcatg gtggcaggcg cctgtaatcc cagctactcg ggaggccaag 2040gcaggagaat tgctcgaact cagggggtgg aggttgcagt gagttgagat tgtgccattg 2100cactccagcc tgggcaacag agcaagactc tgtctcagga aaaaaaaaaa aaaaaaagaa 2160aagcaacata gtggggtttc tgtcaatctg tcctcggctg cccttctcat ttgttgatgg 2220gaccttgaaa gcaagcttgc taggtgccct ctgtggctcc agcctttacc ggaagtgtgg 2280tgcatgtttt taacttcagg gaagcggtat cctgtcactg gggtatggga tgagcatgga 2340gaagaggcac cagccacgat tccttcctaa gcatctcctg ttctgactgc tcatgaattg 2400aagaaactga cccttgtgtt caaaaaaaaa aaaaaaaaa 2439332327DNAHomo sapiens 33agactaactc tacctttctg gcttcaggac accagacatc agagacagag agaaaaattc 60aaagggccaa cccgtctttc ctttgggcag gtgctatcta gacctgaagt agcgggaaga 120gcagaaagga tggggcagcc atctctgact tggatgctga tggtggtggt ggcctcttgg 180ttcatcacaa ctgcagccac tgacacctca gaagcaagat ggtgctctga atgtcacagc 240aatgccacct gcacggagga tgaggccgtt acgacgtgca cctgtcagga gggcttcacc 300ggcgatggcc tgacctgcgt ggacctggat gagtgcgcca ttcctggagc tcacaactgc 360tccgccaaca gcagctgcgt aaacacgcca ggctccttct cctgcgtctg ccccgaaggc 420ttccgcctgt cgcccggtct cggctgcaca gacgtggatg agtgcgctga gcctgggctt 480agccactgcc acgccctggc cacatgtgtc aatgtggtgg gcagctactt gtgcgtatgc 540cccgcgggct accgggggga tggatggcac tgtgagtgct ccccgggctc ctgcgggccg 600gggttggact gcgtgcccga gggcgacgcg ctcgtgtgcg cggatccgtg ccaggcgcac 660cgcaccctgg acgagtactg gcgcagcacc gagtacgggg agggctacgc ctgcgacacg 720gacctgcgcg gctggtaccg cttcgtgggc cagggcggtg cgcgcatggc cgagacctgc 780gtgccagtcc tgcgctgcaa cacggccgcc cccatgtggc tcaatggcac gcatccgtcc 840agcgacgagg gcatcgtgag ccgcaaggcc tgcgcgcact ggagcggcca ctgctgcctg 900tgggatgcgt ccgtccaggt gaaggcctgt gccggcggct actacgtcta caacctgaca 960gcgccccccg agtgtcacct ggcgtactgc acagacccca gctccgtgga ggggacgtgt 1020gaggagtgca gtatagacga ggactgcaaa tcgaataatg gcagatggca ctgccagtgc 1080aaacaggact tcaacatcac tgatatctcc ctcctggagc acaggctgga atgtggggcc 1140aatgacatga aggtgtcgct gggcaagtgc cagctgaaga gtctgggctt cgacaaggtc 1200ttcatgtacc tgagtgacag ccggtgctcg ggcttcaatg acagagacaa ccgggactgg 1260gtgtctgtag tgaccccagc ccgggatggc ccctgtggga cagtgttgac gaggaatgaa 1320acccatgcca cttacagcaa caccctctac ctggcagatg agatcatcat ccgtgacctc 1380aacatcaaaa tcaactttgc atgctcctac cccctggaca tgaaagtcag cctgaagacc 1440gccctacagc caatggtcag tgctctaaac atcagagtgg gcgggaccgg catgttcacc 1500gtgcggatgg cgctcttcca gaccccttcc tacacgcagc cctaccaagg ctcctccgtg 1560acactgtcca ctgaggcttt tctctacgtg ggcaccatgt tggatggggg cgacctgtcc 1620cgatttgcac tgctcatgac caactgctat gccacaccca gtagcaatgc cacggacccc 1680ctgaagtact tcatcatcca ggacagatgc ccacacacta gagactcaac tatccaagtg 1740gtggagaatg gggagtcctc ccagggccga ttttccgtcc agatgttccg gtttgctgga 1800aactatgacc tagtctacct gcactgtgaa gtctatctct gtgacaccat gaatgaaaag 1860tgcaagccta cctgctctgg gaccagattc cgaagtggga gtgtcataga tcaatcccgt 1920gtcctgaact tgggtcccat cacacggaaa ggtgtccagg ccacagtctc aagggctttt 1980agcagcttgg ggctcctgaa agtctggctg cctctgcttc tctcggccac cttgaccctg 2040acttttcagt gactgacagc ggaaagccct gtgctccatg gctgccatct cacctcctgc 2100tgggcagggg gcatgatgcg ggccagtgct ccagccacag aaaagaaagt tcatgctttg 2160ttcagcctgc cttcttttct cccttttaat cctggctgtc gagaaacagc ctgtgtcttt 2220aaatgctgct ttttctcaaa atgggacttg tgacggtgta cctgaggccc ccatctcctt 2280aaagagtgtg gcaaaataat gatttttaaa tctcaaaaaa aaaaaaa 2327341945DNAHomo sapiens 34agccatctct tcccaaggca ggtggtgact tgagaactct gtgcctggtt tctgaggact 60gtttcaccat gcagtggcta atgaggttcc ggaccctctg gggcatccac aaatccttcc 120acaacatcca ccctgcccct tcacagctgc gctgccggtc tttatcagaa tttggagccc 180caagatggaa tgactatgaa gtaccggagg aatttaactt tgcaagttat gtactggact 240actgggctca aaaggagaag gagggcaaga gaggtccaaa tccagctttt tggtgggtga 300atggccaagg ggatgaagta aagtggagct tcagagagat gggagaccta acccgccgtg 360tagccaacgt cttcacacag acctgtggcc tacaacaggg agaccatctg gccttgatgc 420tgcctcgagt tcctgagtgg tggctggtgg ctgtgggctg catgcgaaca gggatcatct 480tcattcctgc gaccatcctg ttgaaggcca aagacattct ctatcgacta cagttgtcta 540aagccaaggg cattgtgacc atagatgccc ttgcctcaga ggtggactcc atagcttctc 600agtgcccctc tctgaaaacc aagctcctgg tgtctgatca cagccgtgaa gggtggctgg 660acttccgatc gctggttaaa tcagcatccc cagaacacac ctgtgttaag tcaaagacct 720tggacccaat ggtcatcttc ttcaccagtg ggaccacagg cttccccaag atggcaaaac 780actcccatgg gttggcctta caaccctcct tcccaggaag taggaaatta cggagcctga 840agacatctga tgtctcctgg tgcctgtcgg actcaggatg gattgtggct accatttgga 900ccctggtaga accatggaca gcgggttgta cagtctttat ccaccatctg ccacagtttg 960acaccaaggt catcatacag acattgttga aataccccat taaccacttt tggggggtat 1020catctatata tcgaatgatt ctgcagcagg atttcaccag catcaggttc cctgccctgg 1080agcactgcta tactggcggg gaggtcgtgt tgcccaagga tcaggaggag tggaaaagac 1140ggacgggcct tctgctctac gagaactatg ggcagtcgga aacgggacta atttgtgcca 1200cctactgggg aatgaagatc aagccgggtt tcatggggaa ggccactcca ccctatgacg 1260tccaggtcat tgatgacaag ggcagcatcc tgccacctaa cacagaagga aacattggca 1320tcagaatcaa acctgtcagg cctgtgagcc tcttcatgtg ctatgagggt gacccagaga 1380agacagctaa agtggaatgt ggggacttct acaacactgg ggacagagga aagatggatg 1440aagagggcta catttgtttc ctggggagga gtgatgacat cattaatgcc tctgggtatc 1500gcatcgggcc tgcagaggtt gaaagcgctt tggtggagca cccagcggtg gcggagtcag 1560ccgtggtggg cagcccagac ccgattcgag gggaggtggt gaaggccttt attgtcctga 1620ccccacagtt cctgtcccat gacaaggatc agctgaccaa ggaactgcag cagcatgtca 1680agtcagtgac agccccatac aagtacccaa ggaacgtgga gtttgtctca gagctgccaa 1740aaaccatcac tggcaagatt gaacggaagg aacttcggaa aaaggagact ggtcagatgt 1800aatcggcagt gaactcagaa cgcactgcac acctaaggca aatccctggc cactttagtc 1860tccccactat ggtgaggacg agggtggggc attgagagtg ttgatttggg aaagtatcag 1920gagtgccata atcactagtg aattc 19453524DNAArtificialPrimer 35tcctgctcca aatgactgag ttct

243624DNAArtificialPrimer 36tcaacccaat ggaatgacct ctta 243724DNAArtificialPrimer 37ggtggaggct tgacatcatc agag 243824DNAArtificialPrimer 38ggaatagggc tcagatggtc tttg 243924DNAArtificialPrimer 39gccctggcct catgtgtcaa tgtg 244024DNAArtificialPrimer 40gggtcacagg gacagacaga caat 244124DNAArtificialPrimer 41cggcggctac tacgtctaca acct 244224DNAArtificialPrimer 42gtagctgccc accacattga caca 244324DNAArtificialPrimer 43acctctggac ctcaagtaat ctgt 244424DNAArtificialPrimer 44tgatgcctac tggctgagac aatc 244524DNAArtificialPrimer 45accagcagat ttagctttga agtc 244625DNAArtificialPrimer 46gcttgaacca ggcagtgctt tgacc 254724DNAArtificialPrimer 47agcagcatcc aggcacttgt caga 244824DNAArtificialPrimer 48tgaggcagaa gaatcacttg aacc 244924DNAArtificialPrimer 49tccaaagacc ccctctgaat tcta 245024DNAArtificialPrimer 50atttgaatcc aggaagtctg actc 245124DNAArtificialPrimer 51ggcaagccac tgaagttctc tgag 245224DNAArtificialPrimer 52gagcggctca gagaacttca gtgg 245324DNAArtificialPrimer 53cccgtgtcct gtgttacatt catc 245424DNAArtificialPrimer 54gagcccctga tgggtctgaa gtag 245524DNAArtificialPrimer 55tctgagccac tctccttatt taga 245624DNAArtificialPrimer 56tagattgggc acttcacaag aatg 245724DNAArtificialPrimer 57acagcagaac ccagtctcac tgag 245824DNAArtificialPrimer 58tctcacagtt ctggaggctg gaag 245925DNAArtificialPrimer 59ggtggaccct aattgcatag gattg 256024DNAArtificialPrimer 60tgtcctctag gggaagagat gtct 246124DNAArtificialPrimer 61aggtcaggga cctagtaact actc 246224DNAArtificialPrimer 62ccagagccct acaggagtgt actg 246324DNAArtificialPrimer 63caagaccagg ggatcacagt aact 246421DNAArtificialPrimer 64cagcctgggc aacagagact c 216524DNAArtificialPrimer 65aggcgctaaa ttcagagcaa atag 246624DNAArtificialPrimer 66gctgtaatgg tgctgtgtaa atct 246724DNAArtificialPrimer 67aagaatcctc cagacttcat acac 246824DNAArtificialPrimer 68atcagcttag cagacatctc ttcc 246924DNAArtificialPrimer 69cttgtagtcc cagctactca gtgg 247021DNAArtificialPrimer 70cacgagaatc ccttgaacct g 217121DNAArtificialPrimer 71tggctctcca ctcagagatt c 217224DNAArtificialPrimer 72ctgtggctgg cttgtttcac tcag 247324DNAArtificialPrimer 73ttgggtggag gcaatccaag tgtc 247424DNAArtificialPrimer 74tgtgttattg gtgaaatgca cata 247524DNAArtificialPrimer 75ggtggctcat gcctgtaatt tgag 247624DNAArtificialPrimer 76tgacaggcac atagattatt atgc 247724DNAArtificialPrimer 77cgtacccggc tgattatttt agat 247824DNAArtificialPrimer 78agataggggt ctagtttcat tatc 247924DNAArtificialPrimer 79acaaagctgg acatatcaca ctac 248024DNAArtificialPrimer 80aggctggtct cgaactcctg acct 248124DNAArtificialPrimer 81gggactacag gtgtgtgaat ttga 248224DNAArtificialPrimer 82aggacggctg aatgtctgtc atca 248324DNAArtificialPrimer 83ttggggagtc cctaaatgac ttta 248424DNAArtificialPrimer 84ggcagaaatg gcacatctta acta 248524DNAArtificialPrimer 85cagcctgggt gacagagtga gact 248624DNAArtificialPrimer 86acccagtaga gacccatctt actc 248724DNAArtificialPrimer 87acccagtaga gacccatctt actc 24

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