BORIS Isoforms Patent 8440415 May 14th 2013 || Inventors: Lobanenkov; Victor V. (Rockville, MD),...

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United States Patent 8,440,415Lobanenkov , et al. May 14, 2013

BORIS isoforms and methods of detecting and treating disease

Abstract

A method of detecting a proliferative disease, such as a disease associated with the abnormalexpression of BORIS, in a mammal comprising testing for the expression of a BORIS isoform in thetissue of a mammal that does not express BORIS in the absence of disease, as well as a method oftreating or preventing such a disease, isolated or purified BORIS isoform polypeptides and nucleicacids, and kits and arrays comprising same.

Inventors: Lobanenkov; Victor V. (Rockville, MD), Pugacheva; Elena (Germantown, MD),Loukinov; Dmitri (Germantown, MD)

Applicant: Name City State Country Type

Lobanenkov; Victor V.Pugacheva; ElenaLoukinov; Dmitri

RockvilleGermantownGermantown

MDMDMD

USUSUS

Assignee: The United States of America, as represented by the Secretary, Department ofHealth and Human Services (Washington, DC)N/A (

Family ID: 38846916Appl. No.: 13/478,779Filed: May 23, 2012

Related U.S. Patent Documents

Application Number Filing Date Patent Number Issue Date

United States Patent: 8440415 http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=...

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12439063 8206933PCT/US2007/077281 Aug., 2007

60841342 Aug., 2006

Current U.S. Class: 435/7.1 ; 436/518Current International Class: G01N 33/53 (20060101)Current CPC Class: G01N 33/574 (20130101)

References Cited [Referenced By]

U.S. Patent Documents2005/0182249 August 2005 Lobanenkov et al.

Foreign Patent DocumentsWO 03/072799 Sep., 2003 WOWO 2006/034335 Mar., 2006 WO

Other References

D'Arcy et al. (Clin. Cancer Res 2006 vol. 12, p. 5978-5986). cited by examiner .Klenova et al., "The novel Boris + CTCF gene family is uniquely involved in theepigenetics of normal biology and cancer," seminars in Cancer Biology, 12, 399-414(2002). cited by applicant .Loukinov et al., "BORIS, a novel male germ-line-specific protein associated withepigenetic reprogramming events, shares, the same 11-zinc-finger domain with CTCF, theinsulator protein involved in reading imprinting marks in the soma," PNAS, 99 (10),6806-6811 (2002). cited by applicant .Renaud et al., "Characterization of alternative promoters for alternative forms ofBORIS-like transcripts," Proceedings of the American Association for Cancer ResearchAnnual Meetings, 46 (#1947), 456 (2005). cited by applicant .Renaud et al., "Expression of the CTCF-paralogous cancer testis gene, brother of theregulator of imprinted sites (Boris), is regulated by three alternative promoters modulatedby CpG methylation and by CTCF and p53 transcription factors," Nucleic Acids Research,35 (21), 7372-7388 (2007). cited by applicant .UniProt Consortium, Accession No. A6XGM0, 2007. cited by applicant .International Search Report and Written Opinion of PCT/US2007/077281, EuropeanPatent Office, dated Mar. 28, 2008. cited by applicant .Pugacheva, et al., The Structural Complexity of the Human BORIS Gene inGametogenesis and Cancer, PLOS ONE, Nov. 2010, vol. 5, Issue 1, e13872. cited byapplicant .Japanese Patent Office, First Examination Report in Japanese Patent Application No.526917/2009 (Oct. 9, 2012). cited by applicant .


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Konishi et al., "Expression of Boris (CTCFL) mRNA in breast cancer cell line andknockdown thereof by siRNA," Journal of Japan Surgical Society, 107, Extra Edition (2),669, Ps-149-2 (Mar. 5, 2006) Abstract. cited by applicant .Loukinov et al., "Antitumor Efficacy of DNA Vaccination to the Epigenetically ActingTumor Promoting Transcription Factors Boris and CD80 Molecular Adjuvant," Journal ofCellular Biochemistry, 98, 1037-1043 (2006). cited by applicant .Renaud et al., "Implication of DNA methylation, CTCF and BORIS factors in thetranscriptional regulation of the human telomerase catalytic subunit hTERT," Database:Bibliotheque Numerique RERO DOC [online], Notice #5527, 183-202 (Feb. 28, 2006)[retrieved on Oct. 2, 2012, URL,doc.rero.ch/Im .php?ur1=1000,40,5,20060228172017-D1/1.sub.--TheseBM.sub.--Renaud, pdf. cited by applicant.

Primary Examiner: Cheu; JacobAttorney, Agent or Firm: Leydig, Voit & Mayer, Ltd.

Parent Case Text

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a divisional of copending U.S. patent application Ser. No. 12/439,063, filedMay 19, 2009, which claims the benefit of U.S. Provisional Patent Application No. 60/841,342, filedAug. 31, 2006, which is incorporated by reference.

INCORPORATION-BY-REFERENCE OF MATERIAL ELECTRONICALLY FILED

Incorporated by reference in its entirety herein is a computer-readable nucleotide/amino acid sequencelisting submitted concurrently herewith and identified as follows: One 161,782 bytes Byte ASCII(Text) file named "710345_ST25.txt," created on May 2, 2012.

Claims

What is claimed is:

1. An isolated or purified polypeptide comprising an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 26-42.

2. A method of detecting a cancer characterized by abnormal BORIS expression in a mammalsuspected of having cancer, wherein the expression of the one or more polypeptides in the tissue orbody fluid is upregulated as compared to expression of the one or more polypeptides, which methodcomprises testing for the expression of one or more of the polypeptides of claim 1 in a tissue or bodyfluid of a mammal in the absence of cancer.


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3. The method of claim 2, wherein testing for the expression of the one or more polypeptidescomprises contacting a sample of body fluid or tissue of the mammal with an antibody to the one ormore polypeptides, and detecting the binding of the antibody with one or more polypeptides from thesample.

4. The method of claim 2, wherein testing for the expression of the one or more polypeptidescomprises detecting the presence of one or more auto-antibodies to the one or more polypeptides.

5. The method of claim 4, wherein detecting the presence of one or more auto-antibodies to the one ormore polypeptides comprises contacting a sample of body fluid or tissue of the mammal with a probecomprising an immunogenic portion of the amino acid sequence of the one or more polypeptides, anddetecting the binding of the probe with an auto-antibody from the sample.

6. The method of claim 2, wherein the method comprises testing for the expression of two or moredifferent polypeptides, each of which comprises an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 26-42.

7. The method of claim 2, wherein the method further comprises comparing the expression of the oneor more polypeptides in the mammal with a control.

8. The method of claim 7, wherein the control is a BORIS expression pattern of a mammal known tobe afflicted with a particular cancer associated with abnormal BORIS expression.

9. A kit for the detection of BORIS expression in a mammal, which kit comprises (a) a probe setcomprising one or more probes that bind to (i) a BORIS isoform polypeptide, or (ii) an auto-antibodyto a BORIS isoform polypeptide, wherein the BORIS isoform polypeptide comprises an amino acidsequence selected from the group consisting of SEQ ID NOs: 26-42, and (b) a reagent that facilitatesthe detection of the probe.

10. The kit of claim 9, wherein the probe set comprises one or more auto-antibodies to a BORISisoform polypeptide.

11. The kit of claim 9, wherein the probe set comprises one or more BORIS isoform polypeptides.

12. The kit of claim 9, wherein the kit further comprises a BORIS expression profile of one or moretypes of cancer.

13. An antibody or antibody fragment that binds to the polypeptide of claim 1.

14. A composition comprising the antibody or antibody fragment of claim 13 and a carrier.

15. A method of treating or preventing a cancer associated with abnormal BORIS expression in amammal comprising administering the antibody or antibody fragment of claim 13 to a mammalafflicted with a cancer associated with abnormal BORIS expression, wherein the antibody selectively


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binds to a BORIS isoform polypeptide.

16. A cell comprising the polypeptide of claim 1.

17. The method of claim 2, wherein the cancer is testes cancer.

Description

FIELD OF THE INVENTION

This invention pertains to BORIS isoform polypeptides and related compounds and compositions, andto the use of such polypeptides, compounds, and compositions for the detection and treatment ofdiseases associated with abnormal BORIS expression, such as cancer.

BACKGROUND OF THE INVENTION

The identification of tumor-associated antigens recognized by a mammalian immune system is usefulfor the diagnosis and treatment of cancer. A variety of tumor-associated antigens have been identified,including cancer/testis antigens that are expressed in cancer cells, but not in normal tissues other thantestis. Only a minority of tumor-associated antigens, however, are immunogenic to the mammal thatproduces them.

BORIS (Brother of the Regulator of Imprinted Sites) is a tumor-associated antigen, which is activatedin a wide range of human cancers. In fact, aberrant synthesis of the BORIS gene product has beenfound in over 300 primary tumors and cancer cell lines representing all major types of human cancerswith recurrent 20q13 chromosomal gains. BORIS activation has also been found in all of the standardNCI-60 cancer cell lines, which are maintained by the National Cancer Institute (NCI), and which arethought to be a reasonably complete representative set of human cancers.

BORIS also is a CTCF paralog, which contains all eleven zinc fingers of CTCF, and has been shownto promote cell growth leading to transformation (see Loukinov et al, Proc. Natl. Acad. Sci (USA) 99,6806-6811 (2002), and International Patent Application Publication WO 03/072799 (PCT/US03/05186)). BORIS has, therefore, also been referred to as "CTCF-like" or "CTCFL" protein. Onemechanism of action by which BORIS is thought to cause cancer through interference with themaintenance of an appropriate methylation pattern in the genome mediated by CCCTC binding factor(CTCF) (see Klenova et al., Seminars in Cancer Biology 12, 399-414 (2002)). The BORIS gene isbelieved to map to the cancer-associated amplification region of chromosome 20q13.

The detection of aberrant expression of cancer markers, such as prostate specific antigen (PSA) andcarcinoembryonic antigen (CEA), are known in the art. These assays, however, detect only a limitednumber of cancers and have limited positive predictive value for the detection or prognosis of new orrecurring cancer. Accordingly, there is a need in the art to identify additional antigens whoseexpression can be linked to hyperproliferative diseases, such as cancer, as well as methods ofdetecting the presence of such antigens to aid in the detection, diagnosis, prognostication, or research


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of such disease states.

The invention provides methods and compositions useful for the detection, diagnosis, prognostication,or research of diseases associated with abnormal BORIS expression, such as cancer. These and otheradvantages of the invention, as well as additional inventive features, will be apparent from thedescription of the invention provided herein.

BRIEF SUMMARY OF THE INVENTION

The invention provides a method of detecting a disease characterized by abnormal BORIS expressionin a mammal, including but not limited to cancer, which method comprises testing for the expressionof one or more BORIS isoforms in a tissue or body fluid of a mammal that does not express theBORIS isoform in the absence of disease.

The invention also provides a method of detecting a disease characterized by abnormal BORISexpression in a mammal, which method comprises testing for the expression of one or more BORISisoform mRNA transcripts in a tissue or body fluid of a mammal that does not express the BORISisoform in the absence of disease.

Also provided herein is a method of treating or preventing a disease associated with abnormal BORISexpression in a mammal. In one aspect, the method comprises administering a short interfering RNA(siRNA) molecule to a mammal afflicted with a disease associated with abnormal BORIS expression,wherein the siRNA molecule comprises a sequence of at least 10 contiguous nucleotides that iscomplimentary to a BORIS isoform mRNA transcript. In a related aspect, the method comprisesadministering an anti-BORIS antibody to a mammal afflicted with a disease associated with abnormalBORIS expression, wherein the anti-BORIS antibody selectively binds to a isoform polypeptide.

The invention additionally provides a method of inducing an immune response in a mammalcomprising administering a BORIS isoform to the mammal.

The invention further provides an isolated or purified polypeptide comprising an amino acid sequenceselected from the group consisting of SEQ ID NOs: 25-42, an isolated or purified nucleic acidcomprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-24, and acomposition comprising such a polypeptide or nucleic acid.

In a related aspect, the invention provides a kit for the detection of BORIS expression in a mammal,which kit comprises (a) a probe set comprising one or more probes that bind to (i) a BORISpolypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:25-42, (ii) an auto-antibody to a BORIS polypeptide comprising an amino acid sequence selectedfrom the group consisting of SEQ ID NOs: 25-42, or (iii) a BORIS isoform mRNA transcriptcomprising a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1-24, and (b)a reagent that facilitates the detection of the probe.

An array useful for the detection of BORIS expression in a mammal also is provided by the invention,the array comprising one or more probes immobilized on a substrate, wherein the probes bind to (i) a


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BORIS isoform comprising an amino acid sequence selected from the group consisting of SEQ IDNOs: 25-42, (ii) an auto-antibody to a BORIS isoform comprising an amino acid sequence selectedfrom the group consisting of SEQ ID NOs: 25-42, or (iii) an BORIS isoform mRNA transcriptcomprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-24.

The invention further provides a database comprising a BORIS expression profile of one or moredifferent types of cancer, wherein the database facilitates the comparison of a BORIS expressionprofile of a patient with the BORIS expression profile of one or more different types of cancer.

Also provided by the invention is a method of inducing an immune response to BORIS in a mammalcomprising administering to the mammal a BORIS isoform comprising an amino acid sequenceselected from the group consisting of SEQ ID NOs: 25-42.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D are illustrations depicting alternative splice variants expressed by the BORIS gene inthe human testes.

DETAILED DESCRIPTION OF THE INVENTION

The BORIS polypeptide disclosed in Klenova et al., Seminars in Cancer Biology 12, 399-414 (2002)comprises the amino acid sequence provided herein as SEQ ID NO: 43, and is encoded by the mRNAsequence provided herein as SEQ ID NO: 44. This BORIS polypeptide, however, is only one of afamily of polypeptides encoded by the BORIS gene. BORIS mRNA splice variants encoding BORISand BORIS isoforms are described herein, including twenty-four specific examples of BORIS isoformmRNA transcripts that encode seventeen different BORIS isoform polypeptides. The exemplaryBORIS isoform mRNA transcripts each comprise a nucleic acid sequence of SEQ ID NOs: 1-24, andthe seventeen BORIS isoform polypeptides comprise a nucleotide sequence of SEQ ID NOs: 25-42.The BORIS isoform mRNA transcripts and the polypeptides encoded thereby are set forth in Table 1.In particular, the BORIS isoform mRNA transcripts comprising the nucleotide sequences of SEQ IDNOs: 1, 2, and 3 encode a polypeptide comprising an amino acid sequence identical to that of thepreviously disclosed BORIS polypeptide (e.g., SEQ ID NO: 43). Although these mRNA transcriptsencode the same BORIS polypeptide, the mRNA transcripts are, themselves, alternative spice variantsof the previously disclosed BORIS mRNA and, therefore, comprise different nucleotide sequences.The other BORIS isoform polypeptides comprise amino acid sequences that are different from theBORIS polypeptide previously disclosed in Klenova et al., supra.

For the purposes of describing the invention, the terms "BORIS" and "BORIS polypeptide" shall beused to refer to the BORIS polypeptide comprising the amino acid sequence of SEQ ID NO: 43, andthe term "BORIS mRNA" shall be used to refer to an mRNA transcript having a nucleotide sequenceof SEQ ID NO: 44.

The terms "BORIS isoform" and "BORIS isoform polypeptide" shall be used herein to refer to apolypeptide encoded by a splice variant mRNA transcript of the BORIS gene, which has an aminoacid sequence that is different from SEQ ID NO: 43. Examples of BORIS isoform polypeptides


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include polypeptides comprising an amino acid sequence selected from the group consisting of SEQID NOs: 25-42. The term "BORIS isoform mRNA" shall be used to refer to an mRNA splice variantof the BORIS gene, which has a nucleotide sequence that is different from SEQ ID NO: 44. Examplesof BORIS isoform mRNA transcripts include mRNA molecules that comprise a nucleic acid sequenceencoding an amino acid sequence selected from the group consisting of SEQ ID NOs: 25-42, or anucleic acid sequence selected from the group consisting of SEQ ID NOs: 1-24.

The term "BORIS gene" shall be used herein to refer to the genomic sequence of BORIS, whichencodes the BORIS polypeptide as well as the BORIS mRNA splice variants (e.g., BORIS isoformmRNA transcripts) and BORIS isoform polypeptides.

As used herein, the term "isolated" means the removal of a nucleic acid or polypeptide molecule fromits natural environment. The term "purified" means that a given nucleic acid or polypeptide molecule,whether it has been removed from nature or synthesized and/or amplified under laboratory conditions,has been increased in purity, wherein "purity" is a relative term, not "absolute purity."

As used herein, the term "nucleic acid" is intended to encompass a polymer of DNA or RNA, (i.e., apolynucleotide), which can be single-stranded or double-stranded and which can contain non-naturalor altered nucleotides. Similarly, a "polypeptide" is intended to encompass a linear sequence of aminoacids (i.e., a primary protein structure) of any length, as well secondary, tertiary, and quaternaryprotein structures, any of which can contain non-natural or altered amino acids.

Some aspects of the invention are described with reference to the use of an antibody. It is intendedthat the use of an antibody can be substituted by the use of an antibody fragment of any of the variousknown forms (e.g., F(ab)2' fragments, single chain antibody variable region fragment (ScFv) chains,and the like). Thus, for the sake of brevity, term "antibody" as used herein is intended to encompassantibodies as well as antibody fragments. Wherever the term "antibody" is used, it is specificallycontemplated that an antibody fragment can be used instead.

The term "selectively binds" as used herein means to bind to a target molecule (e.g., polypeptide ornucleic acid) with a greater affinity or with preference as compared to another polypeptide or nucleicacid. Thus, for instance, a probe selectively binds a target BORIS isoform mRNA transcript if it bindssuch target with preference or greater affinity than to a nucleic acid that is not a BORIS isoformmRNA transcript. Similarly, an anti-BORIS antibody selectively binds a BORIS isoform if it bindssuch target isoform with preference or greater affinity than to a polypeptide that is not a BORISisoform. Selectively binds also can be used to mean that a molecule binds one BORIS isoformpolypeptide or mRNA transcript with preference, or greater affinity, than another BORIS isoformpolypeptide or mRNA transcript.

The invention provides a method of detecting a disease characterized by abnormal gene expression,such as a hyperproliferative disease involving abnormal BORIS expression (e.g., cancer) in amammal. In this respect, "abnormal BORIS expression" means the expression of BORIS in the tissuesor body fluids of a mammal that do not express the BORIS gene in the absence of disease, asdiscussed in greater detail herein.


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According to one aspect of the invention, the method comprises testing for the expression of one ormore BORIS isoforms in a tissue or body fluid of a mammal that does not express the BORIS isoformin the absence of disease. The one or more BORIS isoforms can, for example, comprise an amino acidsequence selected from the group consisting of SEQ ID NOs: 25-42. In a related aspect of theinvention, the method comprises testing for the expression of one or more BORIS isoform mRNAtranscripts in a tissue or body fluid of a mammal that does not express the BORIS isoform mRNA inthe absence of disease. The one or more BORIS isoform mRNA transcripts can comprise a nucleotidesequence selected from the group consisting of SEQ ID NOs: 1-24. The expression of a BORISisoform or BORIS isoform mRNA transcript, as described above, in such a tissue or fluid of themammal is indicative of the presence of disease in the mammal.

The terms "testing" and "detecting" (and permutations thereof) as used herein mean to investigate ordetermine the presence of a condition. Thus, for instance, "testing for" or "detecting" the expression ofa gene or gene product means to investigate or determine whether the gene is being expressed or thegene product is present.

Preferably, the method of detecting a disease comprises testing for the expression of more than oneBORIS isoform. For instance, the method can comprise testing for the expression of two or moreBORIS isoform polypeptides or BORIS isoform mRNA transcripts, preferably five or more, 10 ormore, 15 or more, or even all of such BORIS isoform polypeptides or mRNA transcripts. Whether themethod involves the detection of one BORIS isoform polypeptide or BORIS isoform mRNAtranscript, or more than one of BORIS isoform polypeptides or BORIS isoform mRNA transcripts, themethod of detecting a disease also can comprise testing for the expression of a BORIS polypeptidecomprising the amino acid sequence of SEQ ID NO: 43, or an mRNA transcript comprising thenucleotide sequence of SEQ ID NO: 44.

The method of the invention can be used to detect any disease characterized by or associated withabnormal BORIS expression including, but not limited, to the detection of cancer. As mentionedabove, BORIS mRNA has been detected in several hundred cancer and tumor cell lines representingmost of the major forms of cancer. Thus, the method of the invention can be used to detect any type ofcancer. Such cancers include, but are not limited to, cancer of the oral cavity and pharynx, thedigestive system (e.g., the esophagus, stomach, small intestine, colon, rectum, anus, liver, gall bladder,and pancreas), the respiratory system (e.g., the larynx, lung, and bronchus, including non-small celllung carcinoma), bones and joints (e.g., bony metastases), soft tissue, the skin (e.g., melanoma),breast, the genital system (e.g., the uterine cervix, uterine corpus, ovary vulva, vagina, prostate, testis,and penis), the urinary system (e.g., the urinary bladder, kidney, renal pelvis, and ureter), the eye andorbit, the brain and nervous system (e.g., glioma), or the endocrine system (e.g., thyroid). The canceralso can be a lymphoma (e.g., Hodgkin's disease and Non-Hodgkin's lymphoma), multiple myeloma,or leukemia (e.g., acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloidleukemia, chronic myeloid leukemia, and the like).

Furthermore, as demonstrated herein, not all cancers are associated with the expression of the sameBORIS isoforms. Accordingly, by testing for the expression of one or more different BORIS isoforms,it is possible to generate a BORIS expression pattern that can be used to distinguish between differenttypes of cancers, or to detect a specific type of cancer. Thus, the method of detecting a disease


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associated with abnormal BORIS expression preferably comprises a step of comparing the BORISexpression of the mammal to a control, which comparison can be used, for example, to classify thetype of disease with which the mammal might be afflicted. Any suitable control can be used for thispurpose. Typically, the control can be provided by a BORIS expression pattern corresponding to aparticular type of disease or cancer (e.g., the BORIS expression pattern of a mammal known to beafflicted with a particular type of disease or cancer).

Testing for the expression of one or more BORIS isoforms or BORIS isoform mRNA transcripts canbe performed using any suitable technique. Typically, a sample of the tissue or body fluid of themammal that does not express the BORIS gene (i.e., does not express the BORIS polypeptide or anyisoform thereof) in the absence of disease is obtained, and the sample is tested for the expression of aBORIS isoform or BORIS isoform mRNA transcript. The BORIS gene is normally expressed only inthe testes and ovaries. Accordingly, a sample of any tissue or body fluid other than a testicular orovarian tissue sample can be used. The sample can be a solid sample or the sample can be fluid, suchas a sample of body fluid. For instance, a section of whole tissue can be used forimmunohistochemistry-based analysis, or can be homogenized to liquefy the components found in thetissue. The sample preferably is a fluid. Suitable fluid samples include, but are not limited to, blood,serum, plasma, lymph, and interstitial fluid.

Testing for the expression of one or more BORIS isoforms can comprise, for example, directlydetecting one or more BORIS isoform polypeptides, or detecting one or more mRNA transcripts thatencode a BORIS isoform polypeptide. Suitable methods of detecting protein levels in a sampleinclude Western Blotting, radio-immunoassay, and Enzyme-Linked Immunosorbant Assay (ELISA).Such methods are described in Nakamura et al., Handbook of Experimental Immunology, 4th ed.,Wol. 1, Chapter 27, Blackwell Scientific Publ., Oxford, 1987. When detecting proteins in a sampleusing an immunoassay, the sample is typically contacted with antibodies or antibody fragments (e.g.,F(ab)2' fragments, single chain antibody variable region fragment (ScFv) chains, and the like) thatspecifically bind the target protein (e.g., BORIS isoform polypeptide). Thus, BORIS isoformpolypeptides can be detected, for example, by contacting a sample of the tissue or body fluid of themammal with an antibody or antibody fragment to the BORIS isoform, and detecting the binding ofthe antibody or antibody fragment with a BORIS isoform from the sample. Antibodies and otherpolypeptides suitable for detecting BORIS isoform polypeptides in conjunction with immunoassaysare commercially available and/or can be prepared by routine methods, such as methods discussedelsewhere herein (e.g., Harlow et al., Antibodies: A Laboratory Manual, Cold Spring HarborPublishers, Cold Spring Harbor, N.Y., 1988).

The immune complexes formed upon incubating the sample with the antibody are subsequentlydetected by any suitable method. In general, the detection of immune complexes is well-known in theart and can be achieved through the application of numerous approaches. These methods are generallybased upon the detection of a label or marker, such as any radioactive, fluorescent, biological orenzymatic tags or labels of standard use in the art. U.S. patents concerning the use of such labelsinclude U.S. Pat. Nos. 3,817,837, 3,850,752, 3,939,350, 3,996,345, 4,277,437, 4,275,149 and4,366,241.

For example, the antibody used to form the immune complexes can, itself, be linked to a detectable


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label, thereby allowing the presence of or the amount of the primary immune complexes to bedetermined. Alternatively, the first added component that becomes bound within the primary immunecomplexes can be detected by means of a second binding ligand that has binding affinity for the firstantibody. In these cases, the second binding ligand is, itself, often an antibody, which can be termed a"secondary" antibody. The primary immune complexes are contacted with the labeled, secondarybinding ligand, or antibody, under conditions effective and for a period of time sufficient to allow theformation of secondary immune complexes. The secondary immune complexes are then washed toremove any non-specifically bound labeled secondary antibodies or ligands, and the remaining labelin the secondary immune complexes is then detected.

Other methods include the detection of primary immune complexes by a two-step approach. A secondbinding ligand, such as an antibody, that has binding affinity for the first antibody can be used to formsecondary immune complexes, as described above. After washing, the secondary immune complexescan be contacted with a third binding ligand or antibody that has binding affinity for the secondantibody, again under conditions effective and for a period of time sufficient to allow the formation ofimmune complexes (tertiary immune complexes). The third ligand or antibody is linked to adetectable label, allowing detection of the tertiary immune complexes thus formed. A number of otherassays are contemplated; however, the invention is not limited as to which method is used.

Similarly, mRNA transcripts encoding a BORIS isoform can be detected by any suitable technique.Typically, a sample of the tissue or body fluid of the mammal (e.g., the RNA material of such asample) is contacted with a nucleic acid probe that binds to an mRNA transcript encoding a BORISisoform, and the binding of the nucleic acid probe with a BORIS isoform from the sample is detected.Suitable methods of detecting or measuring mRNA include, for example, Northern Blotting, reverse-transcription PCR(RT-PCR), and real-time RT-PCR. Such methods are described in Sambrook et al.,Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor Press, Cold Spring Harbor,N.Y. 1989. Of these methods, real-time RT-PCR is typically preferred. In real-time RT-PCR, which isdescribed in Bustin, J. Mol. Endocrinology. 25: 169-193 (2000), PCRs are carried out in the presenceof a labeled (e.g., fluorogenic) oligonucleotide probe that hybridizes to the amplicons. The probes canbe double-labeled, for example, with a reporter fluorochrome and a quencher fluorochrome. When theprobe anneals to the complementary sequence of the amplicon during PCR, the Taq polymerase,which possesses 5' nuclease activity, cleaves the probe such that the quencher fluorochrome isdisplaced from the reporter fluorochrome, thereby allowing the latter to emit fluorescence. Theresulting increase in emission, which is directly proportional to the level of amplicons, is monitoredby a spectrophotometer. The cycle of amplification at which a particular level of fluorescence isdetected by the spectrophotometer is called the threshold cycle, CT. This value is used to comparelevels of amplicons. Probes suitable for detecting mRNA levels of the biomarkers are commerciallyavailable and/or can be prepared by routine methods, such as methods discussed elsewhere herein.Specific protocols for these and other methods of detecting polypeptides and mRNA transcripts insamples of mammalian tissues and body fluids are well known in the art (see, e.g., Sambrook et al.,supra).

Alternatively, the expression of BORIS isoforms can be tested indirectly by detecting the presence ofauto-antibodies to the BORIS isoforms in the mammal. Without wishing to be bound to any particulartheory, it is believed that the abnormal expression of BORIS isoforms in tissues and body fluids where


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BORIS isoforms are not normally found (e.g., other than the testes or ovaries) causes the immunesystem of the mammal to produce antibodies to the BORIS isoforms that can be detected in a sample(e.g., the tissues, sera, or bloodstream) obtained from the diseased mammal. In the absence of such adisease, the BORIS isoforms are confined to the tissues and organs in which they are normally foundin a non-diseased mammal, and the immune system of the mammal does not produce antibodiesagainst the BORIS isoforms. Thus, a sample taken from a non-diseased mammal (e.g., a mammalwithout a disease characterized by abnormal BORIS expression) will not contain anti-BORIS isoformantibodies. Accordingly, by detecting the presence or absence of anti-BORIS isoform antibodies in thesample of a mammal, the method of the invention enables a determination as to whether the mammalhas a disease characterized by abnormal BORIS expression, such as cancer.

Any suitable method of detecting anti-BORIS auto-antibodies in a sample can be used.Auto-antibodies to the BORIS isoforms can be detected, for instance, by contacting a sample of tissueor body fluid of the mammal with one or more BORIS isoforms or immunogenic portions thereof(e.g., one or more isolated or purified polypeptides comprising an immunogenic portion of the aminoacid sequence of any of SEQ ID NOs: 25-42). The sample can be contacted with a BORISpolypeptide using any suitable method known in the art. Preferably, the sample is contacted with aBORIS polypeptide in vitro or ex vivo. In vitro and ex vivo methods for detecting antibodies in asample are well known in the art and include, for example, enzyme-linked immunosorbent assay(ELISA), affinity chromatography, and radioimmunoassay (RIA).

By "immunogenic" or "immunoreactive" portion of a BORIS isoform is meant any portion of thefull-length BORIS isoform (e.g., SEQ ID NOs: 25-42) that can generate an immune response in amammal in vivo, bind to an anti-BORIS antibody or autoantibody in vivo or in vitro, or comprises oneor more epitopes of a BORIS isoform. As used herein, the term "portion" is synonymous with theterm "fragment," both of which are used to refer to contiguous part of a polypeptide comprising about5 or more amino acids, such as about 10 or more, about 15 or more, about 20 or more, about 25 ormore, or even about 30 or more amino acids). Of course, a full length BORIS isoform can provide theimmunogenic portion; however, it can be more convenient to use a shorter portion of a BORISisoform. One can determine whether any given portion of a BORIS isoform is immunogenic usingroutine techniques in view of the disclosures provided herein. For example, anti-BORIS antibodies toa BORIS isoform can be obtained from a mammal by introducing the BORIS isoform, or portionthereof, into the mammal and subsequently harvesting antibodies from the mammal using routinetechniques. The given "test" portion of the BORIS isoform can be contacted with the anti-BORISantibodies, and the binding affinity of the antibody to the portion of the BORIS isoform can bemeasured to determine whether the anti-BORIS antibodies bind to the given "test" portion of theBORIS isoform. If the antibodies bind to the test portion of the BORIS isoform, the test portion of theBORIS isoform is considered immunogenic. Other methods of determining whether a given portion ofa BORIS isoform is immunogenic are available.

Suitable immunogenic portions of a BORIS isoform include the amino-terminal portion of a BORISisoform (the "N-terminal domain"), defined as the region extending from the amino-terminal up to thezinc finger domain, or at least some portion thereof comprising about 100 or more amino acids (e.g.,200 or more, 250 or more, 300 or more, 400 or more, or 500 or more amino acids). Another suitableportion of a BORIS isoform polypeptide includes the carboxyl-terminal portion (the "C-terminal


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domain"), defined as the region starting after the zinc-finger domain and terminating at the carboxyl-terminus of BORIS, or at least some portion thereof comprising about 75 or more amino acids (e.g.,about 100 or more, about 200 or more, about 300 or more, or about 400 or more amino acids).

The immunogenic portion of the BORIS isoform can be part of a larger polypeptide construct thatcomprises an amino acid sequence that is different from that of the native BORIS isoform. Forinstance, the immunogenic portion of a BORIS isoform can be part of a polypeptide constructcomprising one or more different immunogenic portions of one or more different BORIS isoformslinked together, for example, by non-native amino acid sequences. Such a polypeptide construct mightcomprise, for instance, at least a portion of each of the N-terminal domain and the C-terminal domainof one or more different BORIS isoforms, as described herein. More preferably, the BORISpolypeptide construct comprises the entire N-terminal domain and C-terminal domain of one or moreBORIS isoforms. It is further preferred that the BORIS polypeptide construct excludes any zinc fingerdomain of the BORIS isoform.

Even smaller portions of a BORIS isoform can provide an immunogenic portion, provided that aBORIS isoform epitope is present in the portion or fragment. By "epitope" is meant a sequence on anantigen that is recognized by an antibody or an antigen receptor. Epitopes also are referred to in the artas "antigenic determinants." An immunogenic portion of the BORIS isoform can be less than about660, 200, 150, 100, 60, 50, 30, 20, 15, or 12 amino acid residues in length, so long as it can be boundby an anti-BORIS antibody. The immunogenic portion of the BORIS isoform preferably comprises atleast about 10, 11, or 12 amino acids; however, immunogenic portions of a BORIS isoformcomprising fewer than 11 amino acids (e.g., about 4, 6, 8, or 10 or more amino acids) also are withinthe scope of the invention. Of course, the preferred number of amino acids also can be expressed interms of ranges within any of the above-described preferred limits (e.g., 10-200 amino acids, 10-100amino acids, 10-50 amino acids, 10-20 amino acids, etc.).

An immunogenic portion of a BORIS isoform also can be provided by a variant of the amino acidsequence of a BORIS isoform. As used herein, the term "variant" is used to refer to a sequence that isaltered in the specific amino acid or nucleotide sequence, but retains the required function of thenative sequence. With respect to the immunogenic portion of a BORIS isoform, a variant of theBORIS isoform retains the function of binding to an antibody to the BORIS isoform. BORIS isoformvariants can be generated and characterized for their ability to bind with an anti-BORIS antibody or afunctional fragment thereof (e.g., a Fab or F'(ab).sub.2) using the information provided herein. Forexample, BORIS isoform variants can be generated using, for example, site-directed or randommutagenesis of a nucleic acid sequence encoding a BORIS isoform, as provided herein. The bindingcharacteristics of the BORIS variant thus produced can be determined, for example, by measuring thebinding affinity of antibodies to a BORIS isoform to the variant. Such antibodies can be obtained, forinstance, from the serum of a mammal inoculated with a native BORIS isoform, or from the serum ofa mammal with cancer.

A variant of a BORIS isoform desirably shares one or more regions of amino acid sequence identitywith a native BORIS isoform. In this regard, the variant preferably comprises an amino acid sequencethat is at least about 50% identical (e.g., at least about 60%, at least about 70%, at least about 80%, orat least about 90% identical) to the amino acid sequence of a native BORIS isoform. More preferably,


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the variant comprises an amino acid sequence that is at least about 75% identical (e.g., at least about85%, or at least about 95% identical) to an amino acid sequence of a native BORIS isoform. Mostpreferably, the polypeptide comprises an amino acid sequence that is at least about 90% identical(e.g., at least about 95%, at least about 97%, or at least about 99% identical) to an amino acidsequence of a native BORIS isoform. As used herein, sequence identity is as determined using thewell-known BLAST algorithms (e.g., BLASTp, BLAST 2.1, BL2SEQ, and later versions thereof)).Variants of a BORIS isoform capable of binding to anti-BORIS antibodies preferably have at least 5,6, or 7 amino acid residues that are identical to the amino acid sequence of a native BORIS isoformover a window of eight amino acid residues.

Any immunogenic portion of a BORIS isoform can be used alone or in conjunction with otherimmunogenic portions of the same or different BORIS isoforms. The immunogenic portion of aBORIS isoform, whether used alone or in conjunction with other immunogenic portions of a BORISisoform, also can be part of a larger polypeptide (e.g., inserted into (or otherwise attached to) another(i.e., "non-BORIS") protein). Without intending to be bound by any particular theory, it is believedthat different individuals will have immunogenic responses to BORIS isoforms based on the MHCmolecules expressed on their antigen presenting cells (e.g., macrophages). Accordingly, the portion ofBORIS isoforms that is immunogenic can vary from individual to individual. Moreover, anautoreactive antibody response directed against both the N-terminal and C-terminal domains ofBORIS isoforms has been detected in some cancer patients. Thus, it is preferably the use of more thanone immunogenic portion of the BORIS isoforms (e.g., more than one BORIS isoform epitope).When more than one immunogenic portion is used, the different immunogenic portions can beprovided, for example, by several discontiguous polypeptides used simultaneously (e.g., two or morepolypeptides each comprising a different immunogenic portion of a BORIS isoform) or by a singlepolypeptide comprising two or more different immunogenic portions of BORIS (e.g., linked by anon-native linker sequence).

In a preferred embodiment of the invention, two or more immunogenic portions of one or moreBORIS isoforms are linked by a flexible linker amino acid sequence. Such a construct also cancomprise an immunogenic portion of the BORIS polypeptide. Flexible linkers are used in the art tojoin two distinct polypeptides, such as, for example, in the construction of fusion or chimeric proteins.Thus, for example, an N-terminal domain portion and a C-terminal domain portion of one or moreBORIS isoforms can be linked via a flexible linker sequence to form a single polypeptide molecule.The flexible linker can be any suitable amino acid sequence that can be used to join to separatepolypeptide domains. In this regard, the flexible linker preferably comprises about 5 or more aminoacids (e.g., about 6 or more, 7 or more, or 9 or more amino acids), more preferably about 10 or moreamino acids (e.g., about 11 or more, 12 or more, or 14 or more amino acids), and most preferablyabout 15 or more amino acids (e.g., about 17 or more, 20 or more, or 25 or more amino acids). Linkersequences as well as methods for joining polypeptide domains using flexible linkers are known in theart (see, e.g., Imanishi et al., Biochem. Biophys. Res. Commun., 333(1), 167-73 (2005); Lin et al.,Eur. Cytokine Netw., 15(3), 240-6 (2004)).

The BORIS isoforms or immunogenic portions thereof can be joined to other biomolecules, such as,for example, proteins, polypeptides, lipids, carbohydrates, prenyl, and acyl moieties, and nucleicacids. For instance, the BORIS isoforms or immunogenic portions thereof can be attached to a


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signaling moiety (also known as a detectable label). The identity and use of signaling moieties iswell-known in the art. A signaling moiety is a molecule capable of indicating the presence of ananalyte or reagent in a sample, usually after manipulation of the sample. Such manipulations ofteninclude incubating a sample and appropriate detection reagents under conditions allowing twomoieties to bind together, if present, and then removing any of the labeled moiety from the sample viawashing, filtration, or other suitable techniques. Other methods of working with signaling moieties arewell-known in the art. Suitable signaling moieties include, but are not limited to, fluorescentmolecules (e.g., green fluorescent protein), fluorescent quenchers, epitopes and haptens for antibodiesthat do not recognize BORIS (e.g., the well-known FLAG epitope), enzymes (e.g., chromogenic orluminescent (such as horse radish peroxidase or .beta.-galactosidase)), a nucleic acid that can beamplified or specifically hybridized to a probe, biotin, avidin or streptavidin, lectins and colloids.Methods for linking proteins with detectable labels and solid supports are well-known in the art.

The antibody or autoantibody detected in accordance with a method of the invention preferably bindswith greater affinity to BORIS or a BORIS isoform than to CCCTC-binding-factor (CTCF), or theantibody or autoantibody does not bind CTCF at all. Thus, the method of the invention preferablycomprises detecting an anti-BORIS isoform antibody or autoantibody with a binding affinity forBORIS or a BORIS isoform that is greater than its binding affinity for CTCF. This is particularlyadvantageous where the portion of BORIS used comprises the zinc-finger domain of BORIS. Morepreferably, the dissociation constant (K.sub.d) of binding under standard conditions between theantibody detected by the method of the invention and BORIS is at least 10-fold less, more preferablyat least 100-fold less, or even 1000-fold less than the K.sub.d of binding between the same antibodyand CTCF. In some embodiments, binding of antibodies in a patient's serum to CTCF can be used as anegative control. When antibodies or autoantibodies to a particular BORIS isoform are desired, themethod preferably comprises detecting such an antibody or autoantibody with a greater bindingaffinity for the desired target BORIS isoform than for other BORIS isoforms.

In a preferred embodiment, the method of detecting cancer or method of detecting anti-BORISantibodies includes determining the class and/or subclass of the antibodies present in the patient'sbody, or sample derived therefrom, that are reactive with BORIS. One of ordinary skill in the art willappreciate that the five major human immunoglobulin classes (or "isotypes") are immunoglobulin M(i.e., IgM), IgD, IgG, IgA, and IgE, which are typically defined by the structure of the constantregions of the antibody heavy chain. The light chain of a human antibody molecule is typicallyclassified in the art as either a lambda (.lamda.) chain or a kappa (.kappa.) chain. IgG antibodies canbe subdivided further into four subtypes (i.e., IgG1, IgG2, IgG3, and IgG4), whereas IgA antibodiestypically are subdivided into two subtypes (i.e., IgA1 and IgA2). It is well-known in the art how todetermine the class and subclass of isolated or purified antibodies. For example, BORIS-reactiveantibodies can be isolated from a human's serum by immunochromatography. Wells of microtiterplates can be coated with 10 .mu.g/ml of anti-human immunoglobin overnight at 4.degree. C. Afterblocking with 5% BSA, the plates are reacted with 10 .mu.g/ml of a monoclonal antibody or purifiedisotype controls, at ambient temperature for two hours. The wells can then be reacted with humanIgG1-specific, IgG2-specific, IgG3-specific or IgG4-specific or human IgM-specific alkalinephosphatase-conjugated probes. After washing, the plates can be developed with a luminogenic orchromogenic substrate and analyzed for light or color development.


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The methods of detecting a disease and detecting abnormal BORIS expression can be used in differentways. For example, the method can be used simply to establish the existence of a disease state for thepurposes of diagnosis or screening. In addition, the method can be used, for example, to monitor thestatus (e.g., progression or regression) of a disease state, such as by comparing the level ofanti-BORIS antibodies (or BORIS expression levels) from different samples over time. Such a usewould be helpful in monitoring the response of patients to a particular therapeutic regimen.

In a related aspect, the invention also provides a method of detecting abnormal BORIS expression forpurposes other than the detection of disease. The detection of abnormal BORIS expression can beused for any suitable purpose, such as for prognosticating, monitoring, or researching diseasescharacterized by abnormal gene expression, especially abnormal BORIS expression, includingwithout limitation hyperproliferative diseases such as cancer. For instance, the methods of detectingabnormal BORIS expression is can be used to monitor the effect of drugs and other therapies onvarious diseases, especially various cancers described herein, in connection with the development ofnew or existing drugs or therapies, or as part of an established therapy regimen. Also, the methods ofdetecting abnormal BORIS expression can be used to generate BORIS expression profiles, which, inturn, can be used in accordance with methods of screening for, detecting, diagnosing, prognosticating,monitoring, or researching disease. The method of detecting abnormal BORIS expression cancomprise testing for the expression of one or more BORIS isoforms comprising an amino acidsequence selected from the group consisting of SEQ ID NOs: 25-42, or testing for the expression ofone or more BORIS isoform mRNA transcripts comprising a nucleotide sequence selected from thegroup consisting of SEQ ID NOs: 1-24, in the tissue of a mammal that does not express the BORISisoform in the absence of a disease. All other aspects of the method of detecting abnormal BORISexpression are as described with respect to the method of detecting a disease associated with abnormalBORIS expression.

The mammal used in conjunction with the methods described herein can be any suitable mammal,such as dogs, cats, cows, goats, pigs, mice, rats, guinea pigs, rabbits, gerbils, monkeys, and hamsters.The mammal preferably is a human.

Isolated or Purified Polypeptide, Nucleic Acid, Antibody, Cell, and Composition

The invention provides an isolated or purified polypeptide comprising, consisting essentially of, orconsisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 25-42, or animmunogenic portion thereof. The immunogenic portion of a BORIS isoform can comprise, consistessentially of, or consist of any of those immunogenic portions described herein as useful inconjunction with the method of detecting a disease or method of detecting an anti-BORISautoantibody. The term "consisting essentially of" is used herein to mean that the polypeptide cannotcomprise any other biologically active amino acid sequence, but can contain other non-biologicallyactive sequences or other components such as regulatory or signal sequences, reporter constructs,linker molecules, targeting or delivery components, and the like.

If desired, the isolated or purified polypeptide can be modified, for instance, by glycosylation,amidation, carboxylation, or phosphorylation, or by the creation of acid addition salts, amides, esters,in particular C-terminal esters, and N-acyl derivatives of the polypeptide molecules of the invention.


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The polypeptide molecules also can be dimerized or polymerized. Moreover, the polypeptidemolecules can be modified to create polypeptide derivatives by forming covalent or non-covalentcomplexes with other moieties in accordance with methods known in the art. Covalently-boundcomplexes can be prepared by linking the chemical moieties to functional groups on the side chains ofamino acids comprising the polypeptides, or at the N- or C-terminus.

The isolated or purified polypeptide can be manufactured using any suitable method. In this regard,nucleic acid sequences encoding BORIS isoforms or immunogenic portions thereof can besynthetically produced using, for example, the nucleic acid sequences provided herein, and expressedin an appropriate host cell, thereby resulting in production of a BORIS isoform or immunogenicportion thereof. Alternatively, BORIS isoforms and immunogenic portions thereof can be synthesizedusing, for example, the amino acid sequences disclosed herein and protein synthesis methods knownin the art. Alternatively, BORIS isoforms can be isolated from a mammal, and, as desired,immunogenic portions thereof can be generated using proteases that cleave within the full-lengthBORIS isoforms. As discussed above, BORIS isoforms or immunogenic portions thereof can belabeled with a signaling moiety or detectable label, or linked to a solid support.

The invention also provides an isolated or purified nucleic acid comprising, consisting essentially ofor consisting of a nucleic acid sequence encoding an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 25-42, or an immunogenic portion thereof, as well as an isolated orpurified nucleic acid comprising, consisting essentially of, or consisting of a nucleotide selected fromthe group consisting of SEQ ID NOs: 1-24. The term "consisting essentially of" is used herein tomean that the nucleic acid cannot comprise any other sequence that codes for a biologically activeprotein, but can contain other nucleic acid sequences or other components such as regulatorysequences, reporter constructs, linker molecules, and the like.

The present invention also provides a vector comprising an above-described isolated or purifiednucleic acid molecule. A nucleic acid molecule as described above can be cloned into any suitablevector and can be used to transform or transfect any suitable host. The selection of vectors andmethods to construct them are commonly known to persons of ordinary skill in the art and aredescribed in general technical references (see, in general, "Recombinant DNA Part D," Methods inEnzymology, Vol. 153, Wu and Grossman, eds., Academic Press (1987)).

Suitable vectors include those designed for propagation and expansion or for expression or both.Examples of suitable vectors include plasmids, phagemids, cosmids, viruses, and other vehiclesderived from viral or bacterial sources. Preferably, the vector is a viral vector and is selected from thegroup consisting of an adenovirus, adeno-associated virus, retroviruses, SV40-type viruses, polyomaviruses, Epstein Barr viruses, papillomaviruses, herpes virus, vaccinia virus and polio virus. Mostpreferably, the vector is an adenoviral vector.

When an adenoviral vector is used in the context of the present invention, the adenoviral vector can bederived from any serotype of adenovirus. Adenoviral stocks that can be employed as a source ofadenovirus can be amplified from the adenoviral serotypes 1 through 51, which are currently availablefrom the American Type Culture Collection (ATCC, Manassas, Va.), or from any other serotype ofadenovirus available from any other source. For instance, an adenovirus can be of subgroup A (e.g.,


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serotypes 12, 18, and 31), subgroup B (e.g., serotypes 3, 7, 11, 14, 16, 21, 34, and 35), subgroup C(e.g., serotypes 1, 2, 5, and 6), subgroup D (e.g., serotypes 8, 9, 10, 13, 15, 17, 19, 20, 22-30, 32, 33,36-39, and 42-47), subgroup E (serotype 4), subgroup F (serotypes 40 and 41), or any otheradenoviral serotype. Preferably, however, an adenovirus is of serotype 2, 5 or 9. However, non-groupC adenoviruses can be used to prepare adenoviral vectors for delivery of one or more non-nativenucleic acid sequences to a desired tissue. Preferred adenoviruses used in the construction ofnon-group C adenoviral vectors include Ad12 (group A), Ad7 (group B), Ad30 and Ad36 (group D),Ad4 (group E), and Ad41 (group F). Non-group C adenoviral vectors, methods of producingnon-group C adenoviral vectors, and methods of using non-group C adenoviral vectors are disclosedin, for example, U.S. Pat. Nos. 5,801,030; 5,837,511; and 5,849,561 and International PatentApplications WO 97/12986 and WO 98/53087.

In preferred embodiments, the adenoviral vector of the present invention is deficient in one or morereplication-essential gene functions. Regions contained within the adenoviral genome which areessential for replication include E1a, E1b, E2, E4, and L1-L5. By "deficient" is meant a disruptioncontained within at least one of the above-mentioned regions such that the gene product encoded bythe region is produced in a reduced amount as compared to normal levels. Suitable disruptions includepoint mutations, substitutions, deletions, insertions, and inversions. Typically, the adenoviral vector isdeficient in one or more replication-essential gene functions of the E1a, E1b, E3 and/or E4 region.

A nucleic acid sequence encoding a marker protein, such as green fluorescent protein or luciferasealso can be present in the vector. Such marker proteins are useful in vector construction anddetermining vector migration. Marker proteins also can be used to determine points of injection inorder to efficiently space injections of a vector composition to provide a widespread area of treatment,if desired. Alternatively, a nucleic acid sequence encoding a selection factor, which also is useful invector construction protocols, can be part of the adenoviral vector.

Negative selection genes may be incorporated into any of the above-described vectors. A preferredembodiment is an HSV tk gene cassette (Zjilstra et al., Nature, 342: 435 (1989); Mansour et al.,Nature, 336: 348 (1988); Johnson et al., Science, 245: 1234 (1989): Adair et al., PNAS, 86: 4574(1989); Capecchi, M., Science, 244: 1288 (1989), incorporated herein by reference) operably linked toa viral promoter in a viral vector. The tk expression cassette (or other negative selection expressioncassette) is inserted into the viral genome, for example, as a replacement for a substantial deletion of anon-essential viral gene. Other negative selection genes will be apparent to those of skill in the art.

The vector of the present invention can comprise a native or non-native regulatory sequence operablylinked to an isolated or purified nucleic acid molecule as described above. If more than one nucleotidesequence is included in the nucleic acid molecule, each sequence can be operably linked to its ownregulatory sequence. The "regulatory sequence" is typically a promoter sequence or promoter-enhancer combination, which facilitates the efficient transcription and translation of the nucleic acidto which it is operably linked. The regulatory sequence can, for example, be a mammalian or viralpromoter, such as a constitutive or inducible promoter. Exemplary viral promoters which functionconstitutively in eukaryotic cells include, for example, promoters from the simian virus, papillomavirus, adenovirus, human immunodeficiency virus, Rous sarcoma virus, cytomegalovirus, Moloneyleukemia virus and other retroviruses, and Herpes simplex virus. Other constitutive promoters are


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known to those of ordinary skill in the art. The promoters useful as regulatory sequences of theinvention also include inducible promoters. Inducible promoters are expressed in the presence of aninducing agent. For example, the metallothionein promoter is induced to promote transcription andtranslation in the presence of certain metal ions. Other inducible promoters are known to those ofordinary skill in the art and can be used in the context of the invention, when desired. The selection ofpromoters, e.g., strong, weak, inducible, tissue-specific and developmental-specific, is within the skillin the art. Similarly, the combining of a nucleic acid molecule as described above with a promoter isalso within the skill in the art.

The term "operably linked" as used herein can be defined when a nucleic acid molecule and theregulatory sequence are covalently linked in such a way as to place the expression of the nucleotidecoding sequence under the influence or control of the regulatory sequence. Thus, a regulatorysequence would be operably linked to a nucleic acid molecule if the regulatory sequence were capableof effecting transcription of that nucleic acid molecule such that the resulting transcript is translatedinto the desired protein or polypeptide.

The present invention further provides a cell (i.e., a host cell) comprising an isolated or purifiednucleic acid molecule or a vector as described above, preferably a cell that expresses a BORISisoform or immunogenic portion thereof, as described herein. Examples of host cells include, but arenot limited to, a prokaryotic or eurkaryotic host cell. Prokaryotic cells include those derived from E.coli, B. subtilis, P. aerugenosa, S. cerevisiae, and N. crassa. Preferably, the host cell is derived from amammal, such as a human.

An antibody (polyclonal or monoclonal) to a BORIS isoform or immunogenic portion thereof also iscontemplated as part of the invention, as well as a cell line that produces a monoclonal antibody to aBORIS isoform or immunogenic portion. Such "hybridoma cell lines" desirably produce amonoclonal antibody that is specific for a BORIS isoform. Methods of making polyclonal antibodiesand hybridomas are known in the art (see, e.g., Roitt I., Immunology, 4.sup.th Ed., Mosby, N.Y.(1996)). Typically, the antibody will be specific for a region of a BORIS isoform or a region of animmunogenic portion of a BORIS isoform. Typically, the region will be the N- or C-terminal portionof the BORIS isoform. Alternatively, the antibody can be specific for a zinc finger region of a BORISisoform. Such an antibody will have a greater affinity for zinc finger regions of a BORIS isoform ascompared to other proteins containing similar zinc finger regions (e.g., CTCF); thus being able todistinguish between the two molecules. Antibodies of the invention can be employed for bothdiagnostic and therapeutic applications as they are described herein.

The invention further provides a composition comprising an isolated or purified polypeptide, nucleicacid, or antibody as described herein and a carrier, preferably a pharmaceutically acceptable carrier.The phrase "pharmaceutically acceptable carrier," as used herein, refers to a carrier that does notinterfere with the effectiveness of the biological activity of the active ingredients and which is nottoxic to the host or patient. The pharmaceutical compositions of the present invention can be in avariety of forms. These include, for example, solid, semi-solid and liquid dosage forms, such astablets, pills, powders, liquid solutions or suspensions, liposomes, injectable and infusible solutions.Inhalable preparations, such as aerosols, are also included. Preferred formulations are those directedto oral, intranasal and parenteral applications, but it will be appreciated that the preferred farm will


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depend on the particular diagnostic or therapeutic application. The methods for the formulation andpreparation of pharmaceutical compositions are well known in the art and are described in, forexample, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17thed. (1985), The Merck Index, 11th ed., (Merck & Co. 1989), and Langer, Science, 249, 1527-1533(1990).

The composition can comprise more than one active ingredient. Alternatively, or additionally, thecomposition can comprise another pharmaceutically active agent or drug. For example, when treatingcancer, other anticancer compounds can be used in conjunction with the composition of the presentinvention and include, but are not limited to, all of the known anticancer compounds approved formarketing in the United States and those that will become approved in the future. See, for example,Table 1 and Table 2 of Boyd, Current Therapy in Oncology, Section 1. Introduction to CancerTherapy (J. E. Niederhuber, ed.), Chapter 2, by B.C. Decker, Inc., Philadelphia, 1993, pp. 11-22. Moreparticularly, these other anticancer compounds include doxorubicin, bleomycin, vincristine,vinblastine, VP-16, VW-26, cisplatin, carboplatin, procarbazine, and taxol for solid tumors in general;alkylating agents, such as BCNU, CCNU, methyl-CCNU and DTIC, for brain or kidney cancers; andantimetabolites, such as 5-FU and methotrexate, for colon cancer.

The compounds and compositions described herein can be used for any purpose. In addition to beinguseful in the method of detecting a disease and method of detecting abnormal BORIS expression, thecompounds and compositions described herein can be used for other purposes, such as for inducing animmune response in a mammal. Such immune responses have multiple uses. For example, antibodiesand other immunity-related molecules specific for BORIS can be isolated and used for research,control reagents useful in a method for detecting BORIS expression in a mammal, and as a method fordestroying cancer cells that are present or could arise in a mammal. In this regard, the inventionprovides, as a related aspect, a method of inducing an immune response in a mammal comprisingadministering to a mammal a BORIS polypeptide as defined herein. Suitable methods ofadministration are known in the art. All other aspects of the method of inducing an immune responseare as previously described herein.

Method of Treating a Disease Associated with Abnormal BORIS Expression

The invention provides a method of treating or preventing a disease associated with abnormal BORISexpression in a mammal comprising administering to a mammal that exhibits abnormal BORISexpression an inhibitor of a BORIS isoform. The inhibitor of the BORIS isoform can be anycompound and/or molecule or any other agent capable of inhibiting the normal function of the BORISisoform, or capable of inhibiting the expression of the BORIS isoform at the DNA or RNA level.Typically, the inhibitor of BORIS is a small molecule, an antibody, an antisense molecule, or aribozyme molecule. It is also conceivable to provide an inhibitor of a BORIS isoform that comprises amolecule (e.g., a zinc finger binding protein) that recognizes zinc finger binding domains specific for aBORIS isoform and can therefore initiate its inhibition. It will be understood that when such zincfinger binding proteins are used, these molecules will be employed to specifically recognize zincfinger binding domains of a BORIS isoform as compared to other proteins comprising similar zincfinger binding domains (e.g., CTCF), such that the normal function of these similar proteins is notinhibited. Methods of identifying these inhibitors are well known in the art and can be accomplished


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without any undue experimentation using a variety of in vitro assays.

By "treating" is meant the amelioration of a pathologic state of any symptom thereof, in whole or inpart. By "preventing" is meant the protection, in whole or in part, against a particular pathologic state,including, but not limited to, the prevention of the onset of any one or more symptoms of a pathologicstate. One of ordinary skill in the art will appreciate that any degree of protection from, oramelioration of, a pathologic state is beneficial to a mammal.

According to a preferred aspect of the invention, the method of treating or preventing a diseaseassociated with abnormal BORIS expression in a mammal comprises administering a short interferingRNA (siRNA) molecule to a mammal afflicted with a disease associated with abnormal BORISexpression, wherein the siRNA molecule comprises a sequence of at least about 10 contiguousnucleotides, preferably at least about 15 nucleotides, or even at least about 20 nucleotides (typically21 nucleotides) that is complimentary to a portion or fragment of a BORIS isoform mRNA transcript(e.g., an mRNA transcript comprising a nucleotide sequence selected from the group consisting ofSEQ ID NOs: 1-24). Methods of designing siRNA molecules are known in the art. Typically, thesiRNA will have a 3' dinucleotide overhang (preferably UU residues). Accordingly, the target sitegenerally will be chosen to be a site with an appropriate dinucleotide at the start position, such as an"AA" dinucleotide along with the appropriate number of 3' nucleotides. The siRNA, of course, willhave the complimentary sequence.

According to another preferred aspect of the invention, method of treating or preventing a diseaseassociated with abnormal BORIS expression in a mammal comprises administering an anti-BORISisoform antibody to a mammal afflicted with a disease associated with abnormal BORIS expression,wherein the anti-BORIS isoform antibody selectively binds to a BORIS isoform polypeptide (e.g., aBORIS isoform polypeptide comprising an amino acid sequence selected from the group consisting ofSEQ ID NOs: 25-42). Suitable anti-BORIS isoform antibodies, including BORIS isoform-specificantibodies, can be generated given the information provided herein and routine techniques, aspreviously described.

Suitably, the inhibitor will be administered as part of a composition comprising a carrier. Suitablecarriers and routes of administration are as described with respect to the other aspects of the invention.

Kit and Array Useful for Detecting BORIS Expression

The invention provides a kit useful for detecting BORIS expression comprising (a) a probe setcomprising one or more probes that bind to (i) a BORIS isoform polypeptide comprising an aminoacid sequence selected from the group consisting of SEQ ID NOs: 25-42, (ii) an auto-antibody to aBORIS isoform polypeptide comprising an amino acid sequence selected from the group consisting ofSEQ ID NOs: 25-42, or (iii) a BORIS isoform mRNA transcript comprising a nucleic acid sequenceselected from the group consisting of SEQ ID NOs: 1-24, and (b) a reagent that facilitates thedetection of the probe.

The probe set can comprise one or more one or more antibodies, one or more polypeptides, or one ormore nucleic acids (i.e., polynucleotides) depending upon whether the target to be detected in the


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sample is a BORIS isoform (in which can an antibody probe is useful), an auto-antibody to BORIS (inwhich case a polypeptide probe is useful), or a BORIS isoform mRNA transcript (in which case anucleic acid probe is useful). Probes that specifically bind the respective target molecules can bedesigned using routine techniques. The probe specifically binds a target BORIS isoform polypeptide,auto-antibody, or mRNA transcript with preference over other molecules in the sample, such that theprobe can be used to differentiate between the target molecule and the other molecules in the sample.

Polynucleotide and polypeptide probes can be generated by any suitable method known in the art (see,e.g., Sambrook et al., supra). For example, polynucleotide probes that specifically bind to BORISisoform mRNA transcripts can be created using the nucleic acid sequences of BORIS isoform mRNAtranscripts themselves (as disclosed herein) by routine techniques (e.g., PCR or synthesis). By way offurther illustration, a polynucleotide probe that binds to the mRNA transcript of a particular BORISisoform can be provided by a polynucleotide comprising a nucleic acid sequence that iscomplementary to the mRNA sequence or a fragment thereof, or sufficiently complementary to thesequence or fragment thereof that it will selectively bind to the sequence (e.g., bind to the targetmRNA transcript with greater affinity than to other mRNA transcripts in the sample). The exactnature of the polynucleotide probe is not critical to the invention; any probe that will selectively bindthe mRNA target can be used. Typically, the polynucleotide probes will comprise about 10 or morenucleic acids (e.g., about 20 or more, 50 or more, or 100 or more nucleic acids). Generally, the probewill contain fewer than 50 nucleotides. Thus, for example, the polynucleotide probe can comprise,consist essentially of, or consist of a fragment of any of SEQ ID NOs: 1-24 or complement thereof. Inorder to confer sufficient specificity, the nucleic acid probe will have a sequence identity to acompliment of the target sequence of about 90% or more, preferably about 95% or more (e.g., about98% or more or about 99% or more) as determined, for example, using the well-known Basic LocalAlignment Search Tool (BLAST) algorithm (available through the National Center for BiotechnologyInformation (NCBI), Bethesda, Md.). More preferably, the probe will comprise no more than one ortwo base-pair mismatches with the target sequence.

Similarly, polypeptide probes that bind to the BORIS isoform polypeptides described herein can becreated using the amino acid sequences of the BORIS isoforms, disclosed herein, and routinetechniques. For example, antibodies or antibody fragments to the BORIS isoforms can be generated ina mammal using routine techniques, which antibodies can be harvested to serve as probes for theBORIS isoforms. The exact nature of the polypeptide probe is not critical to the invention; any probethat will selectively bind to the BORIS isoform target can be used. Preferred polypeptide probesinclude antibodies and antibody fragments antibodies or antibody fragments (e.g., F(ab).sub.2'fragments, single chain antibody variable region fragment (ScFv) chains, and the like). Antibodiessuitable for detecting the biomarkers can be prepared by routine methods, and are commerciallyavailable. See, for instance, Harlow et al., Antibodies: A Laboratory Manual, Cold Spring HarborPublishers, Cold Spring Harbor, N.Y., 1988.

The reagent that facilitates detection of the probe can be any suitable reagent known in the art. Forexample, the reagent can be a molecule or compound that can be used to label the probe or the targetmolecules in the sample before or after contacting the sample with the probe. Specific examples ofsuch reagents include, without limitation, a radioisotope, a fluorophore (e.g., fluoresceinisothiocyanate (FITC), phycoerythrin (PE)), an enzyme (e.g., alkaline phosphatase, horseradish


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peroxidase), and element particles (e.g., gold particles).

The kit can further comprise one or more BORIS expression profiles (e.g., the expression profile ofone or more BORIS isoforms) corresponding to one or more types of diseases or cancers. The BORISexpression profile for a given type of disease or cancer can be generated, for example, by testing forthe expression of the BORIS isoforms and/or the BORIS polypeptide in a mammal or population ofmammals known to be afflicted with the disease or cancer, or by testing for the expression of BORISisoforms and/or the BORIS polypeptide in a cell line representative of a specific cell line. Preferably,the BORIS expression profile is generated from a mammal or, more preferably, a population ofmammals known to be afflicted with a particular disease. The BORIS expression profile can serve as areference by which to compare the BORIS expression of a given mammal of an unknown diseasestate in order to determine whether the mammal, in fact, has a disease or propensity to develop adisease.

Preferably, the BORIS expression profiles are provided in the form of a database comprising theBORIS expression profile of one or more different types of cancer or other diseases associated withabnormal BORIS expression, wherein the database facilitates the comparison of a BORIS expressionprofile of a patient with the BORIS expression profile of one or more different types of cancer. Suchdatabases that facilitate the comparison of the BORIS expression profile of a patient with the BORISexpression profile of one or more different types of cancer or other diseases include, for example,searchable databases, especially searchable electronic databases.

The probes of the probe set can be immobilized on a suitable substrate, so as to provide an array. Inthis respect, the invention also provides an array useful for the detection of BORIS expression in amammal, the array comprising one or more probes immobilized on a substrate, wherein the probesbind to (i) a BORIS isoform comprising an amino acid sequence selected from the group consisting ofSEQ ID NOs: 25-42, (ii) an auto-antibody to a BORIS isoform comprising an amino acid sequenceselected from the group consisting of SEQ ID NOs: 25-42, or (iii) a BORIS isoform mRNA transcriptcomprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-24.

The substrate can be any rigid or semi-rigid support to which polynucleotides or polypeptides can becovalently or non-covalently attached. Suitable substrates include membranes, filters, chips, slides,wafers, fibers, beads, gels, capillaries, plates, polymers, microparticles, and the like. Materials that aresuitable for substrates include, for example, nylon, glass, ceramic, plastic, silica, aluminosilicates,borosilicates, metal oxides such as alumina and nickel oxide, various clays, nitrocellulose, and thelike.

The polynucleotide or polypeptide probes can be attached to the substrate in a pre-determined 1- or2-dimensional arrangement, such that the pattern of hybridization or binding to a probe is easilycorrelated with the expression of a particular BORIS isoform. Because the probes are located atspecified locations on the substrate, the hybridization or binding patterns and intensities create aunique expression profile, which can be interpreted in terms of the expression of particular BORISisoforms.

The array can comprise other elements common to polynucleotide and polypeptide arrays. For


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instance, the array also can include one or more elements that serve as a control, standard, orreference molecule, such as a housekeeping gene or portion thereof (e.g., PBGD, GAPDH), to assistin the normalization of expression levels or the determination of nucleic acid quality and bindingcharacteristics, reagent quality and effectiveness, hybridization success, analysis thresholds andsuccess, etc. These other common aspects of the arrays or the addressable elements, as well asmethods for constructing and using arrays, including generating, labeling, and attaching suitableprobes to the substrate, consistent with the invention are well-known in the art. Other aspects of thearray are as previously described herein with respect to the methods of the invention.

The kit or array can comprise a single probe for a single BORIS isoform polypeptide, mRNAtranscript, or autoantibody. However, the kit or array advantageously comprises more than one probe,such as two or more, three or more, four or more, five or more, 10 or more, 15 or more, or even 20 ormore different probes that each bind to a different BORIS isoform polypeptide, mRNA transcript, orautoantibody (or even a different probe for each of the BORIS isoform polypeptides, mRNAtranscripts, or autoantibodies identified herein).

The kit or array can further comprise probes for polypeptides, mRNA transcripts, or autoantibodiesother than BORIS isoform polypeptides, mRNA transcripts or autoantibodies. For example, it isdesirable for the kit or array to comprise a probe for a BORIS polypeptide comprising the amino acidsequence of SEQ ID NO: 43, the mRNA transcript encoding such a BORIS polypeptide (e.g., anmRNA transcript comprising the nucleic acid sequence of SEQ ID NO: 44), or an autoantibody tosuch a BORIS polypeptide. Other probes also can be included, such as probes that bind to other tumorantigens or other genetic cancer markers. Nevertheless, it may be convenient in some instances tolimit the total number of different probes for ease of use. Thus, for instance, the kit or array cancomprise less than about 1000 different probes, or less than about 500 different probes, such as lessthan about 100 different probes, or even less than about 50 different probes (e.g., less than about 30different probes).

The following examples further illustrate the invention but, of course, should not be construed as inany way limiting its scope.

EXAMPLE 1

This example illustrates the identification of multiple BORIS isoforms in the human testes.

RT-PCR was used to identify and sequence the mRNA transcripts of 24 different mRNA splicevariants of the BORIS gene expressed in the human testes. The 24 mRNA splice variants are depictedin Figures A, B, C, and D, which encode 18 different BORIS isoform polypeptides. The nucleotidesequences of the mRNA splice variants, as well as the amino acid sequences encoded by the mRNAsplice variants, are set forth in Table 1.

EXAMPLE 2

This example illustrates the generation of isoform-specific anti-BORIS antibodies, and the use of suchantibodies to identify BORIS isoforms in the human testes.


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Isoform-specific anti-BORIS antibodies were generated to three different BORIS isoforms (SEQ IDNOs: 25, 27, and 32) by immunizing rabbits with synthetic peptides specific to each isoform. Inparticular, peptides CKYASVEVKPFLDLKLHGILVEAAVQVTPSVTNSRI (SEQ ID NO: 45) andCYKQAFYYSYKIYIGNNMHSLL (SEQ ID NO: 46) were used to develop antibodies to the isoformcomprising SEQ ID NO: 25; peptides CLLGSSDSHASVSGAGITDARHHA (SEQ ID NO: 47) andCITDARHHAWLIVLLELVEMGFYHVSHS (SEQ ID NO: 48) were used to generate antibodies tothe isoform comprising SEQ ID NO: 27; and peptides CPPGLHHPKAGLGPEDPLPGQLRHTAG(SEQ ID NO: 49) and GQLRHTTAGTGLSSLLQGPLC (SEQ ID NO: 50) were used to generateantibodies to the isoform comprising SEQ ID NO: 32. The rabbits were immunized with the peptidesconjugated to keyhole limpet hemocyanin (KLH). Thereafter, peptide-specific antibodies were affinitypurified on a column using the same peptides. The isoform-specific anti-BORIS antibodies weresuccessfully used to detect the three different BORIS isoforms in the tissue of the human testes.

EXAMPLE 3

This example demonstrates the expression pattern of BORIS isoforms in the NCI-60 cell lines.

RT-PCR was used to test for the expression of six different BORIS isoforms in each of the NCI-60cell lines. The NCI-60 cell line panel is considered to be representative of the vast majority of humancancer types. The results are presented in Table 1, wherein a "+" indicates positive expression, and ablank indicates no expression.

As illustrated by the results in Table 2, each of the NCI-60 cell lines showed expression of at least oneisoform of BORIS. Moreover, different cancers exhibited different BORIS isoform expressionpatterns. These results show that BORIS isoform expression patterns can be used to differentiatebetween different types of cancers.

TABLE-US-00001 TABLE 1 mRNA Splice Nucleotide Amino Acid Variant Sequence SequenceBORIS A1 SEQ ID NO: 1 SEQ ID NO: 43 BORIS A2 SEQ ID NO: 2 SEQ ID NO: 43 BORIS C1SEQ ID NO: 3 SEQ ID NO: 43 BORIS A4 SEQ ID NO: 4 SEQ ID NO: 25 BORIS C2 SEQ ID NO: 5SEQ ID NO: 25 BORIS B1 SEQ ID NO: 6 SEQ ID NO: 26 BORIS C3 SEQ ID NO: 7 SEQ ID NO:27 BORIS B2 SEQ ID NO: 8 SEQ ID NO: 28 BORIS B3 SEQ ID NO: 9 SEQ ID NO: 29 BORIS C4SEQ ID NO: 10 SEQ ID NO: 30 BORIS C5 SEQ ID NO: 11 SEQ ID NO: 31 BORIS A5 SEQ IDNO: 12 SEQ ID NO: 32 BORIS A6 SEQ ID NO: 13 SEQ ID NO: 33 BORIS B4 SEQ ID NO: 14SEQ ID NO: 34 BORIS B5 SEQ ID NO: 15 SEQ ID NO: 35 BORIS C6 SEQ ID NO: 16 SEQ IDNO: 36 BORIS B6 SEQ ID NO: 17 SEQ ID NO: 37 BORIS B7 SEQ ID NO: 18 SEQ ID NO: 37BORIS C7 SEQ ID NO: 19 SEQ ID NO: 38 BORIS C8 SEQ ID NO: 20 SEQ ID NO: 39 BORIS C9SEQ ID NO: 21 SEQ ID NO: 38 BORIS F6 SEQ ID NO: 22 SEQ ID NO: 40 BORIS F7 SEQ ID NO:23 SEQ ID NO: 41 BORIS A3 SEQ ID NO: 24 SEQ ID NO: 42 BORIS SEQ ID NO: 44 SEQ ID NO:43

TABLE-US-00002 TABLE 2 K562 MOLT-4 CEM RPMI8226 HL-60 SF-295 SF-539 SNB-19HS578T MDAMB435 COLO-- 205 HCC-2998 BORISA4/C2 + + + + + + + + + BORIS C3 + BORISA5 + + + + BORIS B1 + BORIS F6 + + BORIS F7 + + HCT-116 HCT-15 HT-29 KM12 SW-620


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A549 EKVX HOP-62 HOP-92 NCI-H322 NCI-H22- 6 BORISA4/C2 + + + + + + + + + + BORIS C3+ + BORIS A5 + + + + BORIS B1 + + + + BORIS F6 + BORIS F7 + NCI-H23 NCI-H460 NCI-H522LOX M14 MALME3M SK-MEL-2 SK-MEL28 SK-MEL-5 UACC- -257 UACC-62 BORISA4/C2 ++ + + + + + + + + BORIS C3 + + BORIS A5 + + + + + BORIS B1 BORIS F6 BORIS F7 + ARD-RESOVCAR-3 OVCAR-4 OVCAR-5 OVCAR-8 786-0 ACHN RXF-393 SN12C TK-10 U- O-31 PC-3BORISA4/C2 + + + + + + + + + + BORIS C3 + + BORIS A5 + + BORIS B1 + + BORIS F6 + +BORIS F7 + + + + +

All references, including publications, patent applications, and patents, cited herein are herebyincorporated by reference to the same extent as if each reference were individually and specificallyindicated to be incorporated by reference and were set forth in its entirety herein.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing theinvention (especially in the context of the following claims) are to be construed to cover both thesingular 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. Wherever the invention is describedwith reference to open-ended terms (e.g., comprising), it is specifically contemplated that a qualifiedor closed-ended term (e.g., consisting essentially of or consisting of) can be used instead. Recitationof ranges of values herein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unless otherwise indicated herein, andeach separate value is incorporated into the specification as if it were individually recited herein. Allmethods described herein can be performed in any suitable order unless otherwise indicated herein orotherwise 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 notpose a limitation on the scope of the invention unless otherwise claimed. No language in thespecification should be construed as indicating any non-claimed element as essential to the practice ofthe invention.

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

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5NAHomo sapiens cccc tccccccagt atctcagtgc ctcctgtggg ccctcctccc ctccttatcc 6cctc agatctcccaggccccctgc aggccctcgt gccctcctta cttccccccc ctccca gcgccccctg cggggccctc ctcccttcct catccacttcaaccccaagg gtcatt atggcagcca ctgagatctc tgtcctttct gagcaattca ccaagatcaa 24cgag ttgatgccgg aaaaaggcctgaaggaggag gaaaaagacg gagtgtgcag 3aagac catcggagcc ctagtgagtt ggaggccgag cgtacctctg gggccttcca


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36cgtc ctggaggaag aagtggagct ggtgctggcc ccctcggagg agagcgagaa 42cctg accctgcaga cggtgcacttcacttctgaa gctgtggagt tgcaggatat 48gctg agcatacagc agcaagaagg ggtgcaggtg gtggtgcaac agcctggccc54gctg tggcttgagg aagggccccg gcagagcctg cagcagtgtg tggccattag 6agcaa gagctgtact ccccgcaagagatggaggtg ttgcagttcc acgctctaga 66tgtg atggtggcca gtgaagacag taagttagcg gtgagcctgg ctgaaactgc72gatc aagctcgagg aagagcagga gaagaaccag ttattggctg aaagaacaaa 78gctc ttttttgtgg aaacaatgtcaggagatgaa agaagtgacg aaattgttct 84ttca aattcaaatg tggaagaaca agaggatcaa cctacagctg gtcaagcaga9aaaag gccaaatcta caaaaaatca aagaaagaca aagggagcaa aaggaacctt 96tgat gtctgcatgt tcacctcttctagaatgtca agttttaatc gtcatatgaa tcacacc agtgagaagc ctcacctgtg tcacctctgc ctgaaaacct tccgtacggt tctgctgcggaaccatg ttaacaccca cacaggaacc aggccctaca agtgtaacga caacatg gcatttgtca ccagtggaga actcgtccgacacaggcgct ataaacatac tgagaaa ccctttaaat gttccatgtg caagtatgcc agtgtggagg caagtaaatt gcgccatgtccgatccc acactgggga gcgccccttt cagtgttgcc agtgcagcta cagcaga gatacctaca agctgaaacg ccacatgagaacgcactcag gtgagaagcc cgaatgc cacatctgcc acacccgctt cacccagagc gggaccatga aaatacatat gcagaaacacggcgaaa atgtccccaa ataccagtgt ccccattgtg ccaccatcat acggaaa agcgacctac gtgtgcatat gcgcaacttgcatgcttaca gcgctgcaga gaaatgc cgctactgtt ctgctgtctt ccatgaacgc tatgccctca ttcagcacca aactcataagaatgaga agaggttcaa gtgcaaacac tgcagttatg cctgcaagca acgtcat atgaccgctc acattcgtac ccacactggagagaaaccat tcacctgcct ttgcaat aaatgtttcc gacagaagca acttctaaac gctcacttca ggaaatacca tgcaaat ttcatcccgactgtttacaa atgctccaag tgtggcaaag gcttttcccg gattaac ctgcacagac attcggagaa gtgtggatca ggggaagcaaagtcggctgc aggaaag ggaagaagaa caagaaagag gaagcagacc atcctgaagg aagccacaaa tcagaag gaagctgcgaagggatggaa ggaagccgcg aacggagacg aagctgctgc 2gaggct tccaccacga agggagaaca gttcccagga gagatgtttcctgtcgcctg 2gaaacc acagccagag tcaaagagga agtggatgaa ggcgtgacct gtgaaatgct 2aacacg atggataagtgagagggatt cgggttgcgt gttcactgcc cccaattcct 222agtt agaagttttt agcatttaag gtgtgaaatg ctcctcaacacgatggataa 228gaga gtcaggttgc atgttcactg cccctaattc ctaaagcaag ttagaaattt 234tttt ctttgaaaca attaagttcatgacaatgga tgacacaagt ttgaggtagt 24gaatt gttctcctgt ttgtagctgg atatttcaaa gaaacattgc aggtatttta 246ttttaaaccttgaa tgagagggta acacctcaaa cctatggatt cattcacttg 252gcaa ggtggcccac aatgagtgag tagtgatttttggatatttc aaaatagtct 258gcta gtgcttccac agtcaaagct ggacattttt atgttgcatt atatacaccc 264tttc taataatatatggttttaaa cattaaagac aaatgttttt atacaaatga 27ctaca aaatttaaag ctaccataat gcttttaatt agttctaaat tcaaccaaaa276ttac tcttataaaa aggaaaactg agtaggaaat gaaatactag attagactag 282agga ataaatcgat tttactttggtataggagca aggttcacct ttagattttt 288tctt ttaattatgc tccttggcag gtatgaaatt gccctggtta cattccatta 294attagtatttcact ccataaccct tttttctgct aaaactactc tttttatatt 3aaataa ttggcagagt gagaagaaac ataaaatcag ataaggcaaatgtgtacctg 3gaattt gtactttttc ataatgccca gtgattagtg agtatttccc ttttgccagt 3aagatt tttccaccct cgagcagcgtgagagatgcc tctttaacac ttgaaattca 3tatctg gatacagagg cagatttttc ttcattgctt agttgagcag tttgttttgc 324cctgtctccacccc tgtatttcaa gatcattgat aagccctaaa ttcaaattct 33tatgg accttttatt gaaaatatca caagttcaga atccctatacaatgtgaata 336aata atttcccagc aggaagagca ttatattctc tttgtaccag caaattaatt 342aact cacatgagat ttaaattctgtgggctgtag tatgccatca ttgtgactga 348gcaa tggtttctta atttttttac tgttatttaa agatgtttta cataattcaa 354gaaatgacttaaaa ttgcaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 36NAHomo sapiens 2attccacccc tccccccagtatctcagtgc ctcctgtggg ccctcctccc ctccttatcc 6cctc agatctccca ggccccctgc aggccctcgt gccctccttacttccccccc ctccca gcgccccctg cggggccctc ctcccttcct catccacttc aaccccaagc cggcgg ccggctgtgggctgcagcac gcggtgcacg aggcagagcc cacaagccaa 24agtg ggccgagcat tccggccacg ccttccgcgg ccaagtcattatggcagcca 3atctc tgtcctttct gagcaattca ccaagatcaa agaactcgag ttgatgccgg 36gcct gaaggaggaggaaaaagacg gagtgtgcag agagaaagac catcggagcc 42agtt ggaggccgag cgtacctctg gggccttcca ggacagcgtcctggaggaag 48agct ggtgctggcc ccctcggagg agagcgagaa gtacatcctg accctgcaga 54actt cacttctgaagctgtggagt tgcaggatat gagcttgctg agcatacagc 6gaagg ggtgcaggtg gtggtgcaac agcctggccc tgggttgctgtggcttgagg 66cccg gcagagcctg cagcagtgtg tggccattag tatccagcaa gagctgtact 72aaga gatggaggtgttgcagttcc acgctctaga ggagaatgtg atggtggcca 78acag taagttagcg gtgagcctgg ctgaaactgc tggactgatcaagctcgagg 84agga gaagaaccag ttattggctg aaagaacaaa ggagcagctc ttttttgtgg 9atgtc aggagatgaa


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agaagtgacg aaattgttct cacagtttca aattcaaatg 96aaca agaggatcaa cctacagctg gtcaagcaga tgctgaaaaggccaaatcta aaaatca aagaaagaca aagggagcaa aaggaacctt ccactgtgat gtctgcatgt cctcttc tagaatgtcaagttttaatc gtcatatgaa aactcacacc agtgagaagc acctgtg tcacctctgc ctgaaaacct tccgtacggt cactctgctgcggaaccatg acaccca cacaggaacc aggccctaca agtgtaacga ctgcaacatg gcatttgtca gtggaga actcgtccgacacaggcgct ataaacatac tcatgagaaa ccctttaaat ccatgtg caagtatgcc agtgtggagg caagtaaatt gaagcgccatgtccgatccc ctgggga gcgccccttt cagtgttgcc agtgcagcta tgccagcaga gatacctaca tgaaacg ccacatgagaacgcactcag gtgagaagcc ttacgaatgc cacatctgcc cccgctt cacccagagc gggaccatga aaatacatat tctgcagaaacacggcgaaa tccccaa ataccagtgt ccccattgtg ccaccatcat tgcacggaaa agcgacctac tgcatat gcgcaacttgcatgcttaca gcgctgcaga gctgaaatgc cgctactgtt ctgtctt ccatgaacgc tatgccctca ttcagcacca gaaaactcataagaatgaga ggttcaa gtgcaaacac tgcagttatg cctgcaagca ggaacgtcat atgaccgctc ttcgtac ccacactggagagaaaccat tcacctgcct ttcttgcaat aaatgtttcc agaagca acttctaaac gctcacttca ggaaatacca cgatgcaaatttcatcccga tttacaa atgctccaag tgtggcaaag gcttttcccg ctggattaac ctgcacagac cggagaa gtgtggatcaggggaagcaa agtcggctgc ttcaggaaag ggaagaagaa 2aaagag gaagcagacc atcctgaagg aagccacaaagggtcagaag gaagctgcga 2atggaa ggaagccgcg aacggagacg aagctgctgc tgaggaggct tccaccacga 2agaacagttcccagga gagatgtttc ctgtcgcctg cagagaaacc acagccagag 222agga agtggatgaa ggcgtgacct gtgaaatgctcctcaacacg atggataagt 228gatt cgggttgcgt gttcactgcc cccaattcct aaagcaagtt agaagttttt 234taaggtgtgaaatg ctcctcaaca cgatggataa gtgagagaga gtcaggttgc 24cactg cccctaattc ctaaagcaag ttagaaatttttagcatttt ctttgaaaca 246ttca tgacaatgga tgacacaagt ttgaggtagt gtctagaatt gttctcctgt 252ctgg atatttcaaagaaacattgc aggtatttta taaaagtttt aaaccttgaa 258ggta acacctcaaa cctatggatt cattcacttg atattggcaaggtggcccac 264tgag tagtgatttt tggatatttc aaaatagtct agaccagcta gtgcttccac 27aagct ggacattttt atgttgcattatatacaccc atgatatttc taataatata 276taaa cattaaagac aaatgttttt atacaaatga attttctaca aaatttaaag 282taatgcttttaatt agttctaaat tcaaccaaaa aatgttttac tcttataaaa 288actg agtaggaaat gaaatactag attagactagaaaataagga ataaatcgat 294ttgg tataggagca aggttcacct ttagattttt gtattctctt ttaattatgc 3tggcag gtatgaaattgccctggtta cattccatta ttgcttatta gtatttcact 3aaccct tttttctgct aaaactactc tttttatatt tgtaaaataa ttggcagagt3agaaac ataaaatcag ataaggcaaa tgtgtacctg taaggaattt gtactttttc 3tgccca gtgattagtg agtatttccc ttttgccagttgacaagatt tttccaccct 324gcgt gagagatgcc tctttaacac ttgaaattca tttctatctg gatacagagg 33ttttc ttcattgcttagttgagcag tttgttttgc tgccaacctg tctccacccc 336tcaa gatcattgat aagccctaaa ttcaaattct taagatatgg accttttatt342atca caagttcaga atccctatac aatgtgaata tgtggaaata atttcccagc 348agca ttatattctc tttgtaccag caaattaatttaactcaact cacatgagat 354tctg tgggctgtag tatgccatca ttgtgactga atttgtgcaa tggtttctta 36tttac tgttatttaaagatgtttta cataattcaa taaaatgaaa tgacttaaaa 366aaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa a 37DNAHomosapiens 3agggtaaagc aggggccctg ccaggcctcc gagggagtgt gcttggtctg gccgagggct 6ccaa gtctgggtgggctcgaggcc actaggccca aagcctgcct ggctctgagg taggtc tagaaccgtg cacgagggga atgcctgctc gggcccgaacctcgctgggc ggtgtg cactggcccg gggcctgctt ggacctgaaa cttgctaggc ccaggatatg 24ccga gagcctgctgggcccaaacc ttactaggcc caggatgttc actgactgaa 3tcagg cctaaccttg ctaggcccag gatatgcact gggccagagtgtgctcaggc 36ttgc caggcgcagg atgtgtgctg gccctaagcc tgctgaggcc caaacctgtt 42aggg ttttgtacaa aatcctgctttagcctaaat cctgcttagc cttgaccccc 48accc aagccagatc agcattgttc tgaccctact aagtccaaaa ccttttgagg 54cttgtttcaactcc aaagcctgct aggttccagc accccccgca tccctcctca 6ccccc ttctcccccc tatggaaacc gcttgcttatttttcaaaca ggccaagtca 66cagc cactgagatc tctgtccttt ctgagcaatt caccaagatc aaagaactcg 72tgccggaaaaaggc ctgaaggagg aggaaaaaga cggagtgtgc agagagaaag 78ggag ccctagtgag ttggaggccg agcgtacctctggggccttc caggacagcg 84agga agaagtggag ctggtgctgg ccccctcgga ggagagcgag aagtacatcc 9ctgcagacggtgcac ttcacttctg aagctgtgga gttgcaggat atgagcttgc 96taca gcagcaagaa ggggtgcagg tggtggtgcaacagcctggc cctgggttgc ggcttga ggaagggccc cggcagagcc tgcagcagtg tgtggccatt agtatccagc agctgtactccccgcaa gagatggagg tgttgcagtt ccacgctcta gaggagaatg tggtggc cagtgaagac agtaagttag cggtgagcctggctgaaact gctggactga agctcga ggaagagcag gagaagaacc agttattggc tgaaagaaca aaggagcagc tttttgtggaaacaatg tcaggagatg aaagaagtga cgaaattgtt ctcacagttt attcaaa tgtggaagaa caagaggatc aacctacagc


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tggtcaagca gatgctgaaa ccaaatc tacaaaaaat caaagaaaga caaagggagc aaaaggaacc ttccactgtg tctgcatgttcacctct tctagaatgt caagttttaa tcgtcatatg aaaactcaca gtgagaa gcctcacctg tgtcacctct gcctgaaaaccttccgtacg gtcactctgc ggaacca tgttaacacc cacacaggaa ccaggcccta caagtgtaac gactgcaaca catttgtcaccagtgga gaactcgtcc gacacaggcg ctataaacat actcatgaga cctttaa atgttccatg tgcaagtatg ccagtgtggaggcaagtaaa ttgaagcgcc tccgatc ccacactggg gagcgcccct ttcagtgttg ccagtgcagc tatgccagca atacctacaagctgaaa cgccacatga gaacgcactc aggtgagaag ccttacgaat acatctg ccacacccgc ttcacccaga gcgggaccatgaaaatacat attctgcaga acggcga aaatgtcccc aaataccagt gtccccattg tgccaccatc attgcacgga gcgacctacgtgtgcat atgcgcaact tgcatgctta cagcgctgca gagctgaaat 2ctactg ttctgctgtc ttccatgaac gctatgccctcattcagcac cagaaaactc 2gaatga gaagaggttc aagtgcaaac actgcagtta tgcctgcaag caggaacgtc 2gaccgctcacattcgt acccacactg gagagaaacc attcacctgc ctttcttgca 222gttt ccgacagaag caacttctaa acgctcacttcaggaaatac cacgatgcaa 228tccc gactgtttac aaatgctcca agtgtggcaa aggcttttcc cgctggatta 234acagacattcggag aagtgtggat caggggaagc aaagtcggct gcttcaggaa 24agaag aacaagaaag aggaagcaga ccatcctgaaggaagccaca aagggtcaga 246ctgc gaagggatgg aaggaagccg cgaacggaga cgaagctgct gctgaggagg 252ccacgaagggagaa cagttcccag gagagatgtt tcctgtcgcc tgcagagaaa 258ccag agtcaaagag gaagtggatg aaggcgtgacctgtgaaatg ctcctcaaca 264ataa gtgagaggga ttcgggttgc gtgttcactg cccccaattc ctaaagcaag 27agtttttagcattta aggtgtgaaa tgctcctcaa cacgatggat aagtgagaga 276ggtt gcatgttcac tgcccctaat tcctaaagcaagttagaaat ttttagcatt 282gaaa caattaagtt catgacaatg gatgacacaa gtttgaggta gtgtctagaa 288tcct gtttgtagctggatatttca aagaaacatt gcaggtattt tataaaagtt 294cttg aatgagaggg taacacctca aacctatgga ttcattcacttgatattggc 3tggccc acaatgagtg agtagtgatt tttggatatt tcaaaatagt ctagaccagc 3gcttcc acagtcaaag ctggacatttttatgttgca ttatatacac ccatgatatt 3ataata tatggtttta aacattaaag acaaatgttt ttatacaaat gaattttcta 3atttaaagctaccata atgcttttaa ttagttctaa attcaaccaa aaaatgtttt 324ataa aaaggaaaac tgagtaggaa atgaaatactagattagact agaaaataag 33aatcg attttacttt ggtataggag caaggttcac ctttagattt ttgtattctc 336ttat gctccttggcaggtatgaaa ttgccctggt tacattccat tattgcttat 342ttca ctccataacc cttttttctg ctaaaactac tctttttata tttgtaaaat348caga gtgagaagaa acataaaatc agataaggca aatgtgtacc tgtaaggaat 354tttt tcataatgcc cagtgattagtgagtatttc ccttttgcca gttgacaaga 36ccacc ctcgagcagc gtgagagatg cctctttaac acttgaaatt catttctatc 366cagaggcagatttt tcttcattgc ttagttgagc agtttgtttt gctgccaacc 372cacc cctgtatttc aagatcattg ataagcccta aattcaaattcttaagatat 378ttta ttgaaaatat cacaagttca gaatccctat acaatgtgaa tatgtggaaa 384ccca gcaggaagag cattatattctctttgtacc agcaaattaa tttaactcaa 39atgag atttaaattc tgtgggctgt agtatgccat cattgtgact gaatttgtgc 396ttcttaattttttt actgttattt aaagatgttt tacataattc aataaaatga 4acttaa aattgcaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaaaaa 49DNAHomo sapiens 4attccacccc tccccccagt atctcagtgc ctcctgtggg ccctcctccc ctccttatcc 6cctcagatctccca ggccccctgc aggccctcgt gccctcctta cttccccccc ctccca gcgccccctg cggggccctc ctcccttcctcatccacttc aaccccaagg gtcatt atggcagcca ctgagatctc tgtcctttct gagcaattca ccaagatcaa 24cgag ttgatgccggaaaaaggcct gaaggaggag gaaaaagacg gagtgtgcag 3aagac catcggagcc ctagtgagtt ggaggccgag cgtacctctggggccttcca 36cgtc ctggaggaag aagtggagct ggtgctggcc ccctcggagg agagcgagaa 42cctg accctgcagacggtgcactt cacttctgaa gctgtggagt tgcaggatat 48gctg agcatacagc agcaagaagg ggtgcaggtg gtggtgcaacagcctggccc 54gctg tggcttgagg aagggccccg gcagagcctg cagcagtgtg tggccattag 6agcaa gagctgtactccccgcaaga gatggaggtg ttgcagttcc acgctctaga 66tgtg atggtggcca gtgaagacag taagttagcg gtgagcctggctgaaactgc 72gatc aagctcgagg aagagcagga gaagaaccag ttattggctg aaagaacaaa 78gctc ttttttgtggaaacaatgtc aggagatgaa agaagtgacg aaattgttct 84ttca aattcaaatg tggaagaaca agaggatcaa cctacagctggtcaagcaga 9aaaag gccaaatcta caaaaaatca aagaaagaca aagggagcaa aaggaacctt 96tgat gtctgcatgttcacctcttc tagaatgtca agttttaatc gtcatatgaa tcacacc agtgagaagc ctcacctgtg tcacctctgc ctgaaaaccttccgtacggt tctgctg cggaaccatg ttaacaccca cacaggaacc aggccctaca agtgtaacga caacatg gcatttgtcaccagtggaga actcgtccga cacaggcgct ataaacatac tgagaaa ccctttaaat gttccatgtg caagtatgcc agtgtggaggtaaagccatt ggacttg aagcttcatg gcatcttagt agaggctgct gtacaagtta ctccaagtgt taacagt agaatctgtt acaaacaggctttttattat tcatataaaa tttatgcagg taatatg cattctcttt tatgaagtta aaatagaaaa ttggatttct ttgtttcttt tactaat


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tagtgaaaat aatatgtaaa ggtttacaaa ttacaaataa accatctgtg aaaaaaa aaaaaaaaaa aaaaaaaaa mo sapiens5agggtaaagc aggggccctg ccaggcctcc gagggagtgt gcttggtctg gccgagggct 6ccaa gtctgggtgg gctcgaggccactaggccca aagcctgcct ggctctgagg taggtc tagaaccgtg cacgagggga atgcctgctc gggcccgaac ctcgctgggcggtgtg cactggcccg gggcctgctt ggacctgaaa cttgctaggc ccaggatatg 24ccga gagcctgctg ggcccaaaccttactaggcc caggatgttc actgactgaa 3tcagg cctaaccttg ctaggcccag gatatgcact gggccagagt gtgctcaggc36ttgc caggcgcagg atgtgtgctg gccctaagcc tgctgaggcc caaacctgtt 42aggg ttttgtacaa aatcctgctt tagcctaaatcctgcttagc cttgaccccc 48accc aagccagatc agcattgttc tgaccctact aagtccaaaa ccttttgagg 54cttg tttcaactccaaagcctgct aggttccagc accccccgca tccctcctca 6ccccc ttctcccccc tatggaaacc gcttgcttat ttttcaaacaggccaagtca 66cagc cactgagatc tctgtccttt ctgagcaatt caccaagatc aaagaactcg 72tgcc ggaaaaaggcctgaaggagg aggaaaaaga cggagtgtgc agagagaaag 78ggag ccctagtgag ttggaggccg agcgtacctc tggggccttccaggacagcg 84agga agaagtggag ctggtgctgg ccccctcgga ggagagcgag aagtacatcc 9ctgca gacggtgcacttcacttctg aagctgtgga gttgcaggat atgagcttgc 96taca gcagcaagaa ggggtgcagg tggtggtgca acagcctggccctgggttgc ggcttga ggaagggccc cggcagagcc tgcagcagtg tgtggccatt agtatccagc agctgta ctccccgcaagagatggagg tgttgcagtt ccacgctcta gaggagaatg tggtggc cagtgaagac agtaagttag cggtgagcct ggctgaaactgctggactga agctcga ggaagagcag gagaagaacc agttattggc tgaaagaaca aaggagcagc tttttgt ggaaacaatgtcaggagatg aaagaagtga cgaaattgtt ctcacagttt attcaaa tgtggaagaa caagaggatc aacctacagc tggtcaagcagatgctgaaa ccaaatc tacaaaaaat caaagaaaga caaagggagc aaaaggaacc ttccactgtg tctgcat gttcacctcttctagaatgt caagttttaa tcgtcatatg aaaactcaca gtgagaa gcctcacctg tgtcacctct gcctgaaaac cttccgtacggtcactctgc ggaacca tgttaacacc cacacaggaa ccaggcccta caagtgtaac gactgcaaca catttgt caccagtggagaactcgtcc gacacaggcg ctataaacat actcatgaga cctttaa atgttccatg tgcaagtatg ccagtgtgga ggtaaagccattcttggact agcttca tggcatctta gtagaggctg ctgtacaagt tactccaagt gtaactaaca gaatctg ttacaaacag gctttttattattcatataa aatttatgca ggaaataata attctct tttatgaagt taaaatagaa aattggattt ctttgtttct ttgattacta agtgaaaataatatgta

aaggtttaca aattacaaat aaaccatctg tggttaaaaa aaaaaaa aaaaaaaaaa a 26DNAHomo sapiens 6ggcaccagacgcggtgcacg aggcagagcc acaagccaaa gacggagtgg gccgagcatt 6acgc cttccgcggc caagtcatta tggcagccactgagatctct gtcctttctg attcac caagatcaaa gaactcgagt tgatgccgga aaaaggcctg aaggaggagg agacggagtgtgcaga gagaaagacc atcggagccc tagtgagttg gaggccgagc 24ctgg ggccttccag gacagcgtcc tggaggaagaagtggagctg gtgctggccc 3gagga gagcgagaag tacatcctga ccctgcagac ggtgcacttc acttctgaag 36agttgcaggatatg agcttgctga gcatacagca gcaagaaggg gtgcaggtgg 42aaca gcctggccct gggttgctgt ggcttgaggaagggccccgg cagagcctgc 48gtgt ggccattagt atccagcaag agctgtactc cccgcaagag atggaggtgt 54tccacgctctagag gagaatgtga tggtggccag tgaagacagt aagttagcgg 6ctggc tgaaactact ggactgatca agctcgaggaagagcaggag aagaaccagt 66ctga aagaacaaag gagcagctct tttttgtgga aacaatgtca ggagatgaaa 72acgaaattgttctc acagtttcaa attcaaatgt ggaagaacaa gaggatcaac 78ctgg tcaagcagat gctgaaaagg ccaaatctacaaaaaatcaa agaaagacaa 84caaa aggaaccttc cactgtgatg tctgcatgtt cacctcttct agaatgtcaa 9aatcg tcatatgaaaactcacacca gtgagaagcc tcacctgtgt cacctctgcc 96cctt ccgtacggtc actctgctgc ggaaccatgt taacacccacacaggaacca cctacaa gtgtaacgac tgcaacatgg catttgtcac cagtggagaa ctcgtccgac ggcgcta taaacatactcatgagaaac cctttaaatg ttccatgtgc aagtatgcca tggaggc aagtaaattg aagcgccatg tccgatccca cactggggagcgcccctttc gttgcca gtgcagctat gccagcagag atacctacaa gctgaaacgc cacatgagaa actcagg tgagaagccttacgaatgcc acatctgcca cacccgcttc acccagagcg ccatgaa aatacatatt ctgcagaaac acggcgaaaa tgtccccaaataccagtgtc attgtgc caccatcatt gcacggaaaa gcgacctacg tgtgcatatg cgcaacttgc cttacag cgctgcagagctgaaatgcc gctactgttc tgctgtcttc catgaacgct ccctcat tcagcaccag aaaactcata agaatgagaa gaggttcaagtgcaaacact gttatgc ctgcaagcag gaacgtcata tgaccgctca cattcgtacc cacactggag aaccatt cacctgcctttcttgcaata aatgtttccg acagaagcaa cttctaaacg acttcag gaaataccac gatgcaaatt tcatcccgac tgtttacaaatgctccaagt gcaaagg cttttcccgc tggattaacc tgcacagaca ttcggagaag tgtggatcag aagcaaa gtcggctgct


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tcaggaaagg gaagaagaac aagaaagagg aagcagacca tgaagga agccacaaag ggtcagaagg aagctgcgaagggatggaag gaagccgcga gagacga agctgctgct gaggaggctt ccaccacgaa gggagaacag ttcccaggag tgtttcctgtcgcctgc agagaaacca cagccagagt caaagaggaa gtggatgaag 2gacctg tgaaatgctc ctcaacacga tggataattccgcaggctgt acaggaagga 2gttggt atctgcctgg cttctgggga ggcctcagga aacttacaat caaggcagaa 2aagagggagtaggcgc gtcacatggt gaaagcagga gcgagagagg gggaggcgcc 222ctct gaacgaccag attccttgag aaccgccactgtcatgagga cagcaccaag 228gtgc taaatcattc ctaagaaacc gcccccgtga tccagtcacc tcctaccagg 234ctccaacactgggg attacaattc aacatgagct ttggccaggg acaaatatcc 24atatc atgtatttta ctacaaccaa atgtatgttaatttcaaaaa cagataacat 246gttt gaaaacgtga aaaaaaaaaa aaaaaaaaaa aaaaaa 25DNAHomo sapiens7agggtaaagc aggggccctg ccaggcctcc gagggagtgt gcttggtctg gccgagggct 6ccaa gtctgggtgg gctcgaggccactaggccca aagcctgcct ggctctgagg taggtc tagaaccgtg cacgagggga atgcctgctc gggcccgaac ctcgctgggcggtgtg cactggcccg gggcctgctt ggacctgaaa cttgctaggc ccaggatatg 24ccga gagcctgctg ggcccaaaccttactaggcc caggatgttc actgactgaa 3tcagg cctaaccttg ctaggcccag gatatgcact gggccagagt gtgctcaggc36ttgc caggcgcagg atgtgtgctg gccctaagcc tgctgaggcc caaacctgtt 42aggg ttttgtacaa aatcctgctt tagcctaaatcctgcttagc cttgaccccc 48accc aagccagatc agcattgttc tgaccctact aagtccaaaa ccttttgagg 54cttg tttcaactccaaagcctgct aggttccagc accccccgca tccctcctca 6ccccc ttctcccccc tatggaaacc gcttgcttat ttttcaaacaggccaagtca 66cagc cactgagatc tctgtccttt ctgagcaatt caccaagatc aaagaactcg 72tgcc ggaaaaaggcctgaaggagg aggaaaaaga cggagtgtgc agagagaaag 78ggag ccctagtgag ttggaggccg agcgtacctc tggggccttccaggacagcg 84agga agaagtggag ctggtgctgg ccccctcgga ggagagcgag aagtacatcc 9ctgca gacggtgcacttcacttctg aagctgtgga gttgcaggat atgagcttgc 96taca gcagcaagaa ggggtgcagg tggtggtgca acagcctggccctgggttgc ggcttga ggaagggccc cggcagagcc tgcagcagtg tgtggccatt agtatccagc agctgta ctccccgcaagagatggagg tgttgcagtt ccacgctcta gaggagaatg tggtggc cagtgaagac agtaagttag cggtgagcct ggctgaaactactggactga agctcga ggaagagcag gagaagaacc agttattggc tgaaagaaca aaggagcagc tttttgt ggaaacaatgtcaggagatg aaagaagtga cgaaattgtt ctcacagttt attcaaa tgtggaagaa caagaggatc aacctacagc tggtcaagcagatgctgaaa ccaaatc tacaaaaaat caaagaaaga caaagggagc aaaaggaacc ttccactgtg tctgcat gttcacctcttctagaatgt caagttttaa tcgtcatatg aaaactcaca gtgagaa gcctcacctg tgtcacctct gcctgaaaac cttccgtacggtcactctgc ggaacca tgttaacacc cacacaggaa ccaggcccta caagtgtaac gactgcaaca catttgt caccagtggagaactcgtcc gacacaggcg ctataaacat actcatgaga cctttaa atgttccatg tgcaagtatg ccagtgtgga ggcaagtaaattgaagcgcc tccgatc ccacactggg gagcgcccct ttcagtgttg ccagtgcagc tatgccagca ataccta caagctgaaacgccacatga gaacgcactc aggtgagaag ccttacgaat acatctg ccacacccgc ttcacccaga gcgggaccat gaaaatacatattctgcaga acggcga aaatgtcccc aaataccagt gtccccattg tgccaccatc attgcacgga gcgacct acgtgtgcatatgcgcaact tgcatgctta cagcgctgca gagctgaaat 2ctactg ttctgctgtc ttccatgaac gctatgccct cattcagcaccagaaaactc 2gaatga gaagaggttc aagtgcaaac actgcagtta tgcctgcaag caggaacgtc 2gaccgc tcacattcgtacccacactg gagagaaacc attcacctgc ctttcttgca 222gttt ccgacagaag caacttctaa acgctcactt caggaaataccacgatgcaa 228tccc gactgtttac aaatgctcca agtgtggcaa aggcttttcc cgctggatta 234acag acattcggagaagtgtggat caggggaagc aaagtcggct gcttcaggaa 24agaag aacaagaaag aggaagcaga ccatcctgaa ggaagccacaaagggtcaga 246ctgc gaagggatgg aaggaagccg cgaacggaga cggtgtgatc tcagctcacc 252tctg cctcctgggttcaagtgatt ctcatgcctc agtctccgga gctgggatta 258cccg ccaccacgcc tggctaattg ttctattatt tttagtagagatggggtttt 264tctc tcactcctga cctcaagtga tctgcccgcc tcggcctccc aaagtggtgg 27caggc atgagcccctgtgcctggcc tgatggcacc agttttgtgg atctcagtgt 276tcat atccaagaac tgggtcttct tgtctccctc catccaccaaaaaaaaaaaa 282 28268Homo sapiens 8ggcaccagac gcggtgcacg aggcagagcc cacaagccaa agacggagtgggccgagcat 6cacg ccttccgcgg agcaaaagga accttccact gtgatgtctg catgttcacc ctagaa tgtcaagttt taatcgtcatatgaaaactc acaccagtga gaagcctcac gtcacc tctgcctgaa aaccttccgt acggtcactc tgctgcggaa ccatgttaac24acag gaaccaggcc ctacaagtgt aacgactgca acatggcatt tgtcaccagt 3actcg tccgacacag gcgctataaacatactcatg agaaaccctt taaatgttcc 36aagt atgccagtgt ggaggcaagt aaattgaagc gccatgtccg atcccacact 42cgcccctttcagtg ttgccagtgc agctatgcca gcagagatac ctacaagctg 48caca tgagaacgca ctcaggtgag aagccttacg


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aatgccacat ctgccacacc 54accc agagcgggac catgaaaata catattctgc agaaacacgg cgaaaatgtc 6ataccagtgtcccca ttgtgccacc atcattgcac ggaaaagcga cctacgtgtg 66cgca acttgcatgc ttacagcgct gcagagctgaaatgccgcta ctgttctgct 72catg aacgctatgc cctcattcag caccagaaaa ctcataagaa tgagaagagg 78tgcaaacactgcag ttatgcctgc aagcaggaac gtcatatgac cgctcacatt 84caca ctggagagaa accattcacc tgcctttcttgcaataaatg tttccgacag 9acttc taaacgctca cttcaggaaa taccacgatg caaatttcat cccgactgtt 96tgct ccaagtgtggcaaaggcttt tcccgctgga ttaacctgca cagacattcg aagtgtg gatcagggga agcaaagtcg gctgcttcag gaaagggaagaagaacaaga aggaagc agaccatcct gaaggaagcc acaaagggtc agaaggaagc tgcgaaggga aaggaag ccgcgaacggagacggtgtg atctcagctc accgcaacct ctgcctcctg tcaagtg attctcatgc ctcagtctcc ggagctggga ttacagatgcccgccaccac tggctaa ttgttctatt atttttagta gagatggggt tttaccatgt ctctcactcc cctcaag tgatctgccc gcctcggcctcccaaagtgg tgggattaca ggcatgagcc gtgcctg gcctgatggc accagttttg tggatctcag tgtttctttt catatccaag tgggtcttcttgtctcc ctccatccac caaaaaaaaa aaaaaaaaa mo sapiens 9ggcaccagac gcggtgcacg aggcagagcccacaagccaa agacggagtg ggccgagcat 6cacg ccttccgcgc tcgaggaaga gcaggagaag aaccagttat tggctgaaagaaggag cagctctttt ttgtggaaac aatgtcagga gatgaaagaa gtgacgaaat ctcaca gtttcaaatt caaatgtgga agaacaagaggatcaaccta cagctggtca 24tgct gaaaaggcca aatctacaaa aaatcaaaga aagacaaagg gagcaaaagg 3tccactgtgatgtct gcatgttcac ctcttctaga atgtcaagtt ttaatcgtca 36aact cacaccagtg agaagcctca cctgtgtcacctctgcctga aaaccttccg 42cact ctgctgcgga accatgttaa cacccacaca ggaaccaggc cctacaagtg 48ctgcaacatggcat ttgtcaccag tggagaactc gtccgacaca ggcgctataa 54tcat gagaaaccct ttaaatgttc catgtgcaagtatgccagtg tggaggcaag 6tgaag cgccatgtcc gatcccacac tggggagcgc ccctttcagt gttgccagtg 66tgccagcagagata cctacaagct gaaacgccac atgagaacgc actcaggtga 72ttac gaatgccaca tctgccacac ccgcttcacccagagcggga ccatgaaaat 78tctg cagaaacacg gcgaaaatgt ccccaaatac cagtgtcccc attgtgccac 84tgcacggaaaagcg acctacgtgt gcatatgcgc aacttgcatg cttacagcgc 9agctg aaatgccgct actgttctgc tgtcttccatgaacgctatg ccctcattca 96gaaa actcataaga atgagaagag gttcaagtgc aaacactgca gttatgcctg gcaggaacgtcatatga ccgctcacat tcgtacccac actggagaga aaccattcac cctttct tgcaataaat gtttccgaca gaagcaacttctaaacgctc acttcaggaa ccacgat gcaaatttca tcccgactgt ttacaaatgc tccaagtgtg gcaaaggctt ccgctggattaacctgc acagacattc ggagaagtgt ggatcagggg aagcaaagtc tgcttca ggaaagggaa gaagaacaag aaagaggaagcagaccatcc tgaaggaagc aaagggt cagaaggaag ctgcgaaggg atggaaggaa gccgcgaacg gagacggtgt ctcagctcaccgcaacc tctgcctcct gggttcaagt gattctcatg cctcagtctc agctggg attacagatg cccgccacca cgcctggctaattgttctat tatttttagt gatgggg ttttaccatg tctctcactc ctgacctcaa gtgatctgcc cgcctcggcc caaagtg gtgggattacaggcatgagc ccctgtgcct ggcctgatgg caccagtttt gatctca gtgtttcttt tcatatccaa gaactgggtc ttcttgtctccctccatcca aaaaaaa aaaaaaaaaa 43o sapiens aaagc aggggccctg ccaggcctcc gagggagtgt gcttggtctggccgagggct 6ccaa gtctgggtgg gctcgaggcc actaggccca aagcctgcct ggctctgagg taggtc tagaaccgtgcacgagggga atgcctgctc gggcccgaac ctcgctgggc ggtgtg cactggcccg gggcctgctt ggacctgaaa cttgctaggcccaggatatg 24ccga gagcctgctg ggcccaaacc ttactaggcc caggatgttc actgactgaa 3tcagg cctaaccttgctaggcccag gatatgcact gggccagagt gtgctcaggc 36ttgc caggcgcagg atgtgtgctg gccctaagcc tgctgaggcccaaacctgtt 42aggg ttttgtacaa aatcctgctt tagcctaaat cctgcttagc cttgaccccc 48accc aagccagatc agcattgttctgaccctact aagtccaaaa ccttttgagg 54cttg tttcaactcc aaagcctgct aggttccagc accccccgca tccctcctca 6cccccttctcccccc tatggaaacc gcttgcttat ttttcaaaca ggccaagtca 66cagc cactgagatc tctgtccttt ctgagcaattcaccaagatc aaagaactcg 72tgcc ggaaaaaggc ctgaaggagg aggaaaaaga cggagtgtgc agagagaaag 78ggagccctagtgag ttggaggccg agcgtacctc tggggccttc caggacagcg 84agga agaagtggag ctggtgctgg ccccctcggaggagagcgag aagtacatcc 9ctgca gacggtgcac ttcacttctg aagctgtgga gttgcaggat atgagcttgc 96tacagcagcaagaa ggggtgcagg tggtggtgca acagcctggc cctgggttgc ggcttga ggaagggccc cggcagagcc tgcagcagtgtgtggccatt agtatccagc agctgta ctccccgcaa gagatggagg tgttgcagtt ccacgctcta gaggagaatg tggtggccagtgaagac agtaagttag cggtgagcct ggctgaaact actggactga agctcga ggaagagcag gagaagaacc agttattggctgaaagaaca aaggagcagc tttttgt ggaaacaatg tcaggagatg aaagaagtga cgaaattgtt ctcacagttt attcaaatgtggaagaa caagaggatc aacctacagc tggtcaagca gatgctgaaa ccaaatc tacaaaaaat caaagaaaga caaagggagc


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aaaaggaacc ttccactgtg tctgcat gttcacctct tctagaatgt caagttttaa tcgtcatatg aaaactcaca gtgagaa gcctcacctgtgtcacctct gcctgaaaac cttccgtacg gtcactctgc ggaacca tgttaacacc cacacaggaa ccaggcccta caagtgtaacgactgcaaca catttgt caccagtgga gaactcgtcc gacacaggcg ctataaacat actcatgaga cctttaa atgttccatgtgcaagtatg ccagtgtgga ggcaagtaaa ttgaagcgcc tccgatc ccacactggg gagcgcccct ttcagtgttg ccagtgcagctatgccagca ataccta caagctgaaa cgccacatga gaacgcactc agaagcaact tctaaacgct ttcagga aataccacgatgcaaatttc atcccgactg tttacaaatg ctccaagtgt aaaggct tttcccgctg gattaacctg cacagacatt cggagaagtgtggatcaggg gcaaagt cggctgcttc aggaaaggga agaagaacaa gaaagaggaa gcagaccatc 2aggaag ccacaaagggtcagaaggaa gctgcgaagg gatggaagga agccgcgaac 2acggtg tgatctcagc tcaccgcaac ctctgcctcc tgggttcaagtgattctcat 2cagtct ccggagctgg gattacagat gcccgccacc acgcctggct aattgttcta 222ttag tagagatggg gttttaccatgtctctcact cctgacctca agtgatctgc 228cggc ctcccaaagt ggtgggatta caggcatgag cccctgtgcc tggcctgatg234gttt tgtggatctc agtgtttctt ttcatatcca agaactgggt cttcttgtct 24catcc accaaaaaaa aaaaaaaaaa a243DNAHomo sapiens aaagc aggggccctg ccaggcctcc gagggagtgt gcttggtctg gccgagggct 6ccaagtctgggtgg gctcgaggcc actaggccca aagcctgcct ggctctgagg taggtc tagaaccgtg cacgagggga atgcctgctcgggcccgaac ctcgctgggc ggtgtg cactggcccg gggcctgctt ggacctgaaa cttgctaggc ccaggatatg 24ccgagagcctgctg ggcccaaacc ttactaggcc caggatgttc actgactgaa 3tcagg cctaaccttg ctaggcccag gatatgcactgggccagagt gtgctcaggc 36ttgc caggcgcagg atgtgtgctg gccctaagcc tgctgaggcc caaacctgtt 42agggttttgtacaa aatcctgctt tagcctaaat cctgcttagc cttgaccccc 48accc aagccagatc agcattgttc tgaccctactaagtccaaaa ccttttgagg 54cttg tttcaactcc aaagcctgct aggttccagc accccccgca tccctcctca 6ccccc ttctcccccctatggaaacc gcttgcttat ttttcaaaca ggccaagtca 66cagc cactgagatc tctgtccttt ctgagcaatt caccaagatcaaagaactcg 72tgcc ggaaaaaggc ctgaaggagg aggaaaaaga cggagtgtgc agagagaaag 78ggag ccctagtgagttggaggccg agcgtacctc tggggccttc caggacagcg 84agga agaagtggag ctggtgctgg ccccctcgga ggagagcgagaagtacatcc 9ctgca gacggtgcac ttcacttctg aagctgtgga gttgcaggat atgagcttgc 96taca gcagcaagaaggggtgcagg tggtggtgca acagcctggc cctgggttgc ggcttga ggaagggccc cggcagagcc tgcagcagtg tgtggccattagtatccagc agctgta ctccccgcaa gagatggagg tgttgcagtt ccacgctcta gaggagaatg tggtggc cagtgaagacagtaagttag cggtgagcct ggctgaaact actggactga agctcga ggaagagcag gagaagaacc agttattggc tgaaagaacaaaggagcagc tttttgt ggaaacaatg tcaggagatg aaagaagtga cgaaattgtt ctcacagttt attcaaa tgtggaagaacaagaggatc aacctacagc tggtcaagca gatgctgaaa ccaaatc tacaaaaaat caaagaaaga caaagggagc aaaaggaaccttccactgtg tctgcat gttcacctct tctagaatgt caagttttaa tcgtcatatg aaaactcaca gtgagaa gcctcacctg tgtcacctctgcctcctggg ttcaagtgat tctcatgcct tctccgg agctgggatt acagatgccc gccaccacgc ctggctaatt gttctattat tagtagagatggggttt taccatgtct ctcactcctg acctcaagtg atctgcccgc ggcctcc caaagtggtg ggattacagg catgagcccctgtgcctggc ctgatggcac ttttgtg gatctcagtg tttcttttca tatccaagaa ctgggtcttc ttgtctccct tccacca aaaaaaaaaaaaaaaaa 297DNAHomo sapiens acccc tccccccagt atctcagtgc ctcctgtggg ccctcctccc ctccttatcc 6cctcagatctccca ggccccctgc aggccctcgt gccctcctta cttccccccc ctccca gcgccccctg cggggccctc ctcccttcctcatccacttc aaccccaagg gtcatt atggcagcca ctgagatctc tgtcctttct gagcaattca ccaagatcaa 24cgag ttgatgccggaaaaaggcct gaaggaggag gaaaaagacg gagtgtgcag 3aagac catcggagcc ctagtgagtt ggaggccgag cgtacctctggggccttcca 36cgtc ctggaggaag aagtggagct ggtgctggcc ccctcggagg agagcgagaa 42cctg accctgcagacggtgcactt cacttctgaa gctgtggagt tgcaggatat 48gctg agcatacagc agcaagaagg ggtgcaggtg gtggtgcaacagcctggccc 54gctg tggcttgagg aagggccccg gcagagcctg cagcagtgtg tggccattag 6agcaa gagctgtactccccgcaaga gatggaggtg ttgcagttcc acgctctaga 66tgtg atggtggcca gtgaagacag taagttagcg gtgagcctggctgaaactgc 72gatc aagctcgagg aagagcagga gaagaaccag ttattggctg aaagaacaaa 78gctc ttttttgtggaaacaatgtc aggagatgaa agaagtgacg aaattgttct 84ttca aattcaaatg tggaagaaca agaggatcaa cctacagctggtcaagcaga 9aaaag gccaaatcta caaaaaatca aagaaagaca aagggagcaa aaggaacctt 96tgat gtctgcatgttcacctcttc tagaatgtca agttttaatc gtcatatgaa tcacacc agtgagaagc ctcacctgtg tcacctctgc ctgaaaaccttccgtacggt tctgctg cggaaccatg ttaacaccca cacaggaacc aggccctaca agtgtaacga caacatg gcatttgtcaccagtggaga actcgtccga cacaggcgct ataaacatac tgagaaa ccctttaaat gttccatgtg caagtatgcc agtgtggagg


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caagtaaatt gcgccat gtccgatccc acactgggga gcgccccttt cagtgttgcc agtgcagcta cagcaga gatacctacaagctgaaacg ccacatgaga acgcactcag gtgagaagcc cgaatgc cacatctgcc acacccgctt cacccagagc gggaccatgaaaatacatat gcagaaa cacggcgaaa atgtccccaa ataccagtgt ccccattgtg ccaccatcat acggaaa agcgacctacgtgtgcatat gcgcaacttg catgcttaca gcgctgcaga gaaatgc cgctactgtt ctgctgtctt ccatgaacgc tatgccctcattcagcacca aactcat aagaatgaga agaggttcaa gtgcaaacac tgcagttatg cctgcaagca acgtcat atgaccgctcacattcgtac ccacactgga gagaaaccat tcacctgcct ttgcaat aaatgtttcc gacagaagca acttctaaac gctcacttcaggaaatacca tgcaaat ttcatcccga ctgtttacaa atgctccaag tgtggcaaag gcttttcccg

gattctc tgggttggga actcggaagt ggctgaactg ggtggtcctg gctcagggcc cctgagg ctgcagtcag gatgtccgccagggctgcat catccgaagg ctggactggg agaggat ccacttccag gacagctccg ccacacaact gctggcaccg gcctcagttc2ctacag ggacctctct gcagggctgc ttgagtgtcc tcctgactca gagcaagtga 2gtgcaa gtaggaagcc atggtgccttttgcagtcta gtcctaaaag cggcacaaca 2gctgtg ggggctcaca cctgtaatcc cagtacttcg ggaggccaag gcaggtggat222aggc caggagctca agaccagcct ggccaacatg gtgaaaccct gtctctacga 228aaaa aaaaaaa 2297NAHomosapiens acccc tccccccagt atctcagtgc ctcctgtggg ccctcctccc ctccttatcc 6cctc agatctccca ggccccctgcaggccctcgt gccctcctta cttccccccc ctccca gcgccccctg cggggccctc ctcccttcct catccacttc aaccccaagg gtcattatggcagcca ctgagatctc tgtcctttct gagcaattca ccaagatcaa 24cgag ttgatgccgg aaaaaggcct gaaggaggaggaaaaagacg gagtgtgcag 3aagac catcggagcc ctagtgagtt ggaggccgag cgtacctctg gggccttcca 36cgtcctggaggaag aagtggagct ggtgctggcc ccctcggagg agagcgagaa 42cctg accctgcaga cggtgcactt cacttctgaagctgtggagt tgcaggatat 48gctg agcatacagc agcaagaagg ggtgcaggtg gtggtgcaac agcctggccc 54gctgtggcttgagg aagggccccg gcagagcctg cagcagtgtg tggccattag 6agcaa gagctgtact ccccgcaaga gatggaggtgttgcagttcc acgctctaga 66tgtg atggtggcca gtgaagacag taagttagcg gtgagcctgg ctgaaactac 72gatcaagctcgagg aagagcagga gaagaaccag ttattggctg aaagaacaaa 78gctc ttttttgtgg aaacaatgtc aggagatgaaagaagtgacg aaattgttct 84ttca aattcaaatg tggaagaaca agaggatcaa cctacagctg gtcaagcaga 9aaaaggccaaatcta caaaaaatca aagaaagaca aagggagcaa aaggaacctt 96tgat gtctgcatgt tcacctcttc tagaatgtcaagttttaatc gtcatatgaa tcacacc agtgagaagc ctcacctgtg tcacctctgc ctgaaaacct tccgtacggt tctgctg cggaaccatgttaacaccca cacaggaacc aggccctaca agtgtaacga caacatg gcatttgtca ccagtggaga actcgtccga cacaggcgctataaacatac tgagaaa ccctttaaat gttccatgtg caagtatgcc agtgtggagg caagtaaatt gcgccat gtccgatcccacactgggga gcgccccttt cagtgttgcc agtgcagcta cagcaga gatacctaca agctgaaacg ccacatgaga acgcactcaggtgagaagcc cgaatgc cacatctgcc acacccgctt cacccagagc gggaccatga aaatacatat gcagaaa cacggcgaaaatgtccccaa ataccagtgt ccccattgtg ccaccatcat acggaaa agcgacctac gtgtgcatat gcgcaacttg catgcttacagcgctgcaga gaaatgc cgctactgtt ctgctgtctt ccatgaacgc tatgccctca ttcagcacca aactcat aagaatgagaagaggttcaa gtgcaaacac tgcagttatg cctgcaagca acgtcat atgaccgctc acattcgtac ccacactgga gagaaaccattcacctgcct ttgcaat aaatgtttcc gacagaagca acttctaaac gctcacttca ggaaatacca tgcaaat ttcatcccga ctgtttacaaatgctccaag tgtggcaaag gcttttcccg gattacc tcaaaatgga gtggcttaaa accacaaaca tttatcacct gacagattct ggttgggaactcggaag tggctgaact gggtggtcct ggctcagggc cactcctgag gcagtca ggatgtccgc cagggctgca tcatccgaaggctggactgg ggccagagga 2cttcca ggacagctcc gccacacaac tgctggcacc ggcctcagtt ccttgctaca 2cctctctgcagggctg cttgagtgtc ctcctgactc agagcaagtg agagagtgca 2ggaagc catggtgcct tttgcagtct agtcctaaaagcggcacaac agccagctgt 222tcac acctgtaatc ccagtacttc gggaggccaa ggcaggtgga taacttgagg 228gctcaagaccagcc tggccaacat ggtgaaaccc tgtctctacg aaaaaaaaaa 234aa 2348NAHomo sapiens cagacgcggtgcacg aggcagagcc acaagccaaa gacggagtgg gccgagcatt 6acgc cttccgcgct cgaggaagag caggagaagaaccagttatt ggctgaaaga aggagc agctcttttt tgtggaaaca atgtcaggag atgaaagaag tgacgaaatt tcacag tttcaaattcaaatgtggaa gaacaagagg atcaacctac agctggtcaa 24gctg aaaaggccaa atctacaaaa aatcaaagaa agacaaagggagcaaaagga 3ccact gtgatgtctg catgttcacc tcttctagaa tgtcaagttt taatcgtcat 36actc acaccagtga gaagcctcacctgtgtcacc tctgcctgaa aaccttccgt 42actc tgctgcggaa ccatgttaac acccacacag gaaccaggcc ctacaagtgt48tgca acatggcatt tgtcaccagt ggagaactcg tccgacacag gcgctataaa 54catg agaaaccctt taaatgttcc atgtgcaagt


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atgccagtgt ggaggcaagt 6gaagc gccatgtccg atcccacact ggggagcgcc cctttcagtg ttgccagtgc 66gccagcagagatac ctacaagctg aaacgccaca tgagaacgca ctcaggtgag 72tacg aatgccacat ctgccacacc cgcttcacccagagcgggac catgaaaata 78ctgc agaaacacgg cgaaaatgtc cccaaatacc agtgtcccca ttgtgccacc 84gcacggaaaagcga cctacgtgtg catatgcgca acttgcatgc ttacagcgct 9gctga aatgccgcta ctgttctgct gtcttccatgaacgctatgc cctcattcag 96aaaa ctcataagaa tgagaagagg ttcaagtgca aacactgcag ttatgcctgc caggaacgtcatatgac cgctcacatt cgtacccaca ctggagagaa accattcacc ctttctt gcaataaatg tttccgacag aagcaacttctaaacgctca cttcaggaaa cacgatg caaatttcat cccgactgtt tacaaatgct ccaagtgtgg caaaggcttt cgctgga ttctctgggttgggaactcg gaagtggctg aactgggtgg tcctggctca ccactcc tgaggctgca gtcaggatgt ccgccagggc tgcatcatccgaaggctgga gggccag aggatccact tccaggacag ctccgccaca caactgctgg caccggcctc tccttgc tacagggacctctctgcagg gctgcttgag tgtcctcctg actcagagca gagagag tgcaagtagg aagccatggt gccttttgca gtctagtcctaaaagcggca cagccag ctgtgggggc tcacacctgt aatcccagta cttcgggagg ccaaggcagg ataactt gaggccaggagctcaagacc agcctggcca acatggtgaa accctgtctc gaaaaaa aaaaaaaaaa aa 5mo sapiens cagac gcggtgcacgaggcagagcc acaagccaaa gacggagtgg gccgagcatt 6acgc cttccgcgga gcaaaaggaa ccttccactg tgatgtctgcatgttcacct tagaat gtcaagtttt aatcgtcata tgaaaactca caccagtgag aagcctcacc tcacct ctgcctgaaa accttccgtacggtcactct gctgcggaac catgttaaca 24cagg aaccaggccc tacaagtgta acgactgcaa catggcattt gtcaccagtg3ctcgt ccgacacagg cgctataaac atactcatga gaaacccttt aaatgttcca 36agta tgccagtgtg gaggcaagtaaattgaagcg ccatgtccga tcccacactg 42gccc ctttcagtgt tgccagtgca gctatgccag cagagatacc tacaagctga48acat gagaacgcac tcaggtgaga agccttacga atgccacatc tgccacaccc 54ccca gagcgggacc atgaaaatacatattctgca gaaacacggc gaaaatgtcc 6tacca gtgtccccat tgtgccacca tcattgcacg gaaaagcgac ctacgtgtgc66gcaa cttgcatgct tacagcgctg cagagctgaa atgccgctac tgttctgctg 72atga acgctatgcc ctcattcagcaccagaaaac tcataagaat gagaagaggt 78gcaa acactgcagt tatgcctgca agcaggaacg tcatatgacc gctcacattc84acac tggagagaaa ccattcacct gcctttcttg caataaatgt ttccgacaga 9cttct aaacgctcac ttcaggaaat accacgatgcaaatttcatc ccgactgttt 96gctc caagtgtggc aaaggctttt cccgctgggt gttgtattag ttatctattt tatgaca gattacctcaaaatggagtg gcttaaaacc acaaacattt atcacctgac ttctctg ggttgggaac tcggaagtgg ctgaactggg tggtcctggctcagggccac tgaggct gcagtcagga tgtccgccag ggctgcatca tccgaaggct ggactggggc aggatcc acttccaggacagctccgcc acacaactgc tggcaccggc ctcagttcct tacaggg acctctctgc agggctgctt gagtgtcctc ctgactcagagcaagtgaga tgcaagt aggaagccat ggtgcctttt gcagtctagt cctaaaagcg gcacaacagc ctgtggg ggctcacacctgtaatccca gtacttcggg aggccaaggc aggtggataa gaggcca ggagctcaag accagcctgg ccaacatggt gaaaccctgtctctacgaaa aaaaaaa aaaaa 336DNAHomo sapiens aaagc aggggccctg ccaggcctcc gagggagtgt gcttggtctggccgagggct 6ccaa gtctgggtgg gctcgaggcc actaggccca aagcctgcct ggctctgagg taggtc tagaaccgtgcacgagggga atgcctgctc gggcccgaac ctcgctgggc ggtgtg cactggcccg gggcctgctt ggacctgaaa cttgctaggcccaggatatg 24ccga gagcctgctg ggcccaaacc ttactaggcc caggatgttc actgactgaa 3tcagg cctaaccttgctaggcccag gatatgcact gggccagagt gtgctcaggc 36ttgc caggcgcagg atgtgtgctg gccctaagcc tgctgaggcccaaacctgtt 42aggg ttttgtacaa aatcctgctt tagcctaaat cctgcttagc cttgaccccc 48accc aagccagatc agcattgttctgaccctact aagtccaaaa ccttttgagg 54cttg tttcaactcc aaagcctgct aggttccagc accccccgca tccctcctca 6cccccttctcccccc tatggaaacc gcttgcttat ttttcaaaca ggccaagtca 66cagc cactgagatc tctgtccttt ctgagcaattcaccaagatc aaagaactcg 72tgcc ggaaaaaggc ctgaaggagg aggaaaaaga cggagtgtgc agagagaaag 78ggagccctagtgag ttggaggccg agcgtacctc tggggccttc caggacagcg 84agga agaagtggag ctggtgctgg ccccctcggaggagagcgag aagtacatcc 9ctgca gacggtgcac ttcacttctg aagctgtgga gttgcaggat atgagcttgc 96tacagcagcaagaa ggggtgcagg tggtggtgca acagcctggc cctgggttgc ggcttga ggaagggccc cggcagagcc tgcagcagtgtgtggccatt agtatccagc agctgta ctccccgcaa gagatggagg tgttgcagtt ccacgctcta gaggagaatg tggtggccagtgaagac agtaagttag cggtgagcct ggctgaaact actggactga agctcga ggaagagcag gagaagaacc agttattggctgaaagaaca aaggagcagc tttttgt ggaaacaatg tcaggagatg aaagaagtga cgaaattgtt ctcacagttt attcaaatgtggaagaa caagaggatc aacctacagc tggtcaagca gatgctgaaa ccaaatc tacaaaaaat caaagaaaga caaagggagcaaaagaacct tccactgtga ctgcatg ttcacctctt ctagaatgtc aagttttaat cgtcatatga aaactcacac tgagaag cctcacctgt


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gtcacctctg cctgaaaacc ttccgtacgg tcactctgct gaaccat gttaacaccc acacaggaac caggccctac aagtgtaacgactgcaacat atttgtc accagtggag aactcgtccg acacaggcgc tataaacata ctcatgagaa ctttaaa tgttccatgt gcaagtatgccagtgtggag gaacgtcata tgaccgctca tcgtacc cacactggag agaaaccatt cacctgcctt tcttgcaata aatgtttccggaagcaa cttctaaacg ctcacttcag gaaataccac gatgcaaatt tcatcccgac ttacaaa tgctccaagt gtggcaaaggcttttcccgc tggattctct gggttgggaa ggaagtg gctgaactgg gtggtcctgg ctcagggcca ctcctgaggc tgcagtcaggtccgcca gggctgcatc atccgaaggc tggactgggg ccagaggatc cacttccagg 2ctccgc cacacaactg ctggcaccggcctcagttcc ttgctacagg gacctctctg 2gctgct tgagtgtcct cctgactcag agcaagtgag agagtgcaag taggaagcca2gccttt tgcagtctag tcctaaaagc ggcacaacag ccagctgtgg gggctcacac 222tccc agtacttcgg gaggccaaggcaggtggata acttgaggcc aggagctcaa 228cctg gccaacatgg tgaaaccctg tctctacgaa aaaaaaaaaa aaaaaa2336NAHomo sapiens cagac gcggtgcacg aggcagagcc cacaagccaa agacggagtg ggccgagcat 6cacgccttccgcgg agcaaaagga accttccact gtgatgtctg catgttcacc ctagaa tgtcaagttt taatcgtcat atgaaaactcacaccagtga gaagcctcac gtcacc tctgcctgaa aaccttccgt acggtcactc tgctgcggaa ccatgttaac 24acaggaaccaggcc ctacaagtgt aacgactgca acatggcatt tgtcaccagt 3actcg tccgacacag gcgctataaa catactcatgagaaaccctt taaatgttcc 36aagt atgccagtgt ggaggcaagt aaattgaagc gccatgtccg atcccacact 42cgcc cctttcagtgttgccagtgc agctatgcca gcagagatac ctacaagctg 48caca tgagaacgca ctcaggtaag ggctctggtg ctgaaggcctgatacctaca 54actc ttaaagcaag ctttaaaaaa ttacttttta ttggcacaat taaagttcaa 6aaagt ggatttttgc gtgccttcatgataaaagaa tcttgatctg tacttttacc 66tagc agtaagagag tctgcataga tactgtgcca caaccccact gtgtggagta 72aaagtatttgcttc cgtagatttt tcaggtattt aaaactcaac tcctggccag 78tggc tcaaacctgt aatcccagca ctttgggaggctgaggcagg aggatccctt 84agga gtttgagacc agcctggtca acatagggag accctgtctc tacgagtaat 9aattagctgggcctg gtggtgcaca cctgtggtcc cagctacttg ggaggctgaa 96gaat cacttgaacc caggaggttg aggctgcagtgagccgggat tgcgccacta tccagcc tgggtgacag agtgagaacc tgtctcaaaa aaaaagaaaa agtaaataaa aaataaaagtcaactcc ttaattcatt cttcaacttt aaggcaaaac ataaagtgtg cttttgt aacagaggta cttgatgtct tgtgttaaga atacatttatgtgtacttct ttattcg tacagcccca tggatgtgaa ccaccttgaa ctcttgcgta gccaccagat gggaagt catgtctctg gtccatcatggacacagctg tacttgacat aagctgtctg ttgattt gggagtctca tactaattgg gggttgtccg gtgagaaggg ggttgataaaggcttgg ggcaaaaaaa aaaaacactt tcagcacagg tggcctttgg caaggatcag tggaggg ggaatcactt tgttgtctgcatctcaggtg agaagcctta cgaatgccac tgccaca cccgcttcac ccagagcggg accatgaaaa tacatattct gcagaaacacgaaaatg tccccaaata ccagtgtccc cattgtgcca ccatcattgc acggaaaagc ctacgtg tgcatatgcg caacttgcatgcttacagcg ctgcagagct gaaatgccgc tgttctg ctgtcttcca tgaacgctat gccctcattc agcaccagaa aactcataaggagaaga ggttcaagtg caaacactgc agttatgcct gcaagcagga acgtcatatg gctcaca ttcgtaccca cactggagagaaaccattca cctgcctttc ttgcaataaa ttccgac agaagcaact tctaaacgct cacttcagga aataccacga tgcaaatttc ccgactgtttacaaatg ctccaagtgt ggcaaaggct tttcccgctg gattaacctg agacatt cggagaagtg tggatcaggg gaagcaaagtcggctgcttc aggaaaggga 2gaacaa gaaagaggaa gcagaccatc ctgaaggaag ccacaaaggg tcagaaggaa 2cgaagggatggaagga agccgcgaac ggagacgaag ctgctgctga ggaggcttcc 2cgaagg gagaacagtt cccaggagag atgtttcctgtcgcctgcag agaaaccaca 222gtca aagaggaagt ggatgaaggc gtgacctgtg aaatgctcct caacacgatg 228tgagagggattcgg gttgcgtgtt cactgccccc aattcctaaa gcaagttaga 234tagc atttaaggtg tgaaatgctc ctcaacacgatggataagtg agagagagtc 24gcatg ttcactgccc ctaattccta aagcaagtta gaaattttta gcattttctt 246aatt aagttcatgacaatggatga cacaagtttg aggtagtgtc tagaattgtt 252tttg tagctggata tttcaaagaa acattgcagg tattttataa aagttttaaa258atga gagggtaaca cctcaaacct atggattcat tcacttgata ttggcaaggt 264caat gagtgagtag tgatttttgg atatttcaaaatagtctaga ccagctagtg 27acagt caaagctgga catttttatg ttgcattata tacacccatg atatttctaa 276atgg ttttaaacattaaagacaaa tgtttttata caaatgaatt ttctacaaaa 282gcta ccataatgct tttaattagt tctaaattca accaaaaaat gttttactct288aagg aaaactgagt aggaaatgaa atactagatt agactagaaa ataaggaata 294tttt actttggtat aggagcaaggttcaccttta gatttttgta ttctctttta 3tgctcc ttggcaggta tgaaattgcc ctggttacat tccattattg cttattagta 3actccataaccctttt ttctgctaaa actactcttt ttatatttgt aaaataattg 3agtgag aagaaacata aaatcagata aggcaaatgt gtacctgtaaggaatttgta 3ttcata atgcccagtg attagtgagt atttcccttt tgccagttga caagattttt 324tcga gcagcgtgag agatgcctctttaacacttg aaattcattt ctatctggat 33ggcag atttttcttc attgcttagt tgagcagttt gttttgctgc caacctgtct 336ctgt


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atttcaagat cattgataag ccctaaattc aaattcttaa gatatggacc 342tgaa aatatcacaa gttcagaatc cctatacaatgtgaatatgt ggaaataatt 348cagg aagagcatta tattctcttt gtaccagcaa attaatttaa ctcaactcac 354ttta aattctgtgggctgtagtat gccatcattg tgactgaatt tgtgcaatgg 36taatt tttttactgt tatttaaaga tgttttacat aattcaataa aatgaaatga366attg caaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaa 375DNAHomo sapiens cagac gcggtgcacgaggcagagcc cacaagccaa agacggagtg ggccgagcat 6cacg ccttccgcgg agcaaaagga accttccact gtgatgtctgcatgttcacc ctagaa tgtcaagttt taatcgtcat atgaaaactc acaccagtga gaagcctcac gtcacc tctgcctgaa aaccttccgtacggtcactc tgctgcggaa ccatgttaac 24acag gaaccaggcc ctacaagtgt aacgactgca acatggcatt tgtcaccagt3actcg tccgacacag gcgctataaa catactcatg agaaaccctt taaatgttcc 36aagt atgccagtgt ggaggcaagt aaattgaagcgccatgtccg atcccacact 42cgcc cctttcagtg ttgccagtgc agctatgcca gcagagatac ctacaagctg 48cacatgagaacgca ctcaggtaag ggctctggtg ctgaaggcct gatacctaca 54actc ttaaagcaag ctttaaaaaa ttactttttattggcacaat taaagttcaa 6aaagt ggatttttgc gtgccttcat gataaaagaa tcttgatctg tacttttacc 66tagc agtaagagagtctgcataga tactgtgcca caaccccact gtgtggagta 72aaag tatttgctyc cgtagatttt tcaggtgaga agccttacgaatgccacatc 78accc gcttcaccca gagcgggacc atgaaaatac atattctgca gaaacacggc 84gtcc ccaaataccagtgtccccat tgtgccacca tcattgcacg gaaaagcgac 9tgtgc atatgcgcaa cttgcatgct tacagcgctg cagagctgaaatgccgctac 96gctg tcttccatga acgctatgcc ctcattcagc accagaaaac tcataagaat aagaggt tcaagtgcaaacactgcagt tatgcctgca agcaggaacg tcatatgacc cacattc gtacccacac tggagagaaa ccattcacct gcctttcttgcaataaatgt cgacaga agcaacttct aaacgctcac ttcaggaaat accacgatgc aaatttcatc actgttt acaaatgctc caagtgtggcaaaggctttt cccgctggat taacctgcac cattcgg agaagtgtgg atcaggggaa gcaaagtcgg ctgcttcagg aaagggaagaacaagaa agaggaagca gaccatcctg aaggaagcca caaagggtca gaaggaagct aagggat ggaaggaagc cgcgaacggagacgaagctg ctgctgagga ggcttccacc aagggag aacagttccc aggagagatg tttcctgtcg cctgcagaga aaccacagccgtcaaag aggaagtgga tgaaggcgtg acctgtgaaa tgctcctcaa cacgatggat tgagagg gattcgggtt gcgtgttcactgcccccaat tcctaaagca agttagaagt tagcatt taaggtgtga aatgctcctc aacacgatgg ataagtgaga gagagtcaggcatgttc actgccccta attcctaaag caagttagaa atttttagca ttttctttga aattaag ttcatgacaa tggatgacac aagtttgaggtagtgtctag aattgttctc tttgtag ctggatattt caaagaaaca ttgcaggtat tttataaaag ttttaaacct atgagag ggtaacacctcaaacctatg gattcattca cttgatattg gcaaggtggc caatgag tgagtagtga tttttggata tttcaaaata gtctagaccagctagtgctt cagtcaa agctggacat ttttatgttg cattatatac acccatgata tttctaataa 2tggttt taaacattaa agacaaatgtttttatacaa atgaattttc tacaaaattt 2ctacca taatgctttt aattagttct aaattcaacc aaaaaatgtt ttactcttat 2aggaaaactgagtagg aaatgaaata ctagattaga ctagaaaata aggaataaat 222tact ttggtatagg agcaaggttc acctttagatttttgtattc tcttttaatt 228cttg gcaggtatga aattgccctg gttacattcc attattgctt attagtattt 234ataa cccttttttctgctaaaact actcttttta tatttgtaaa ataattggca 24agaag aaacataaaa tcagataagg caaatgtgta cctgtaaggaatttgtactt 246aatg cccagtgatt agtgagtatt tcccttttgc cagttgacaa gatttttcca 252agca gcgtgagaga tgcctctttaacacttgaaa ttcatttcta tctggataca 258gatt tttcttcatt gcttagttga gcagtttgtt ttgctgccaa cctgtctcca 264tatttcaagatcat tgataagccc taaattcaaa ttcttaagat atggaccttt 27aaaat atcacaagtt cagaatccct atacaatgtgaatatgtgga aataatttcc

276gaag agcattatat tctctttgta ccagcaaatt aatttaactc aactcacatg 282aaat tctgtgggct gtagtatgcc atcattgtgactgaatttgt gcaatggttt 288tttt ttactgttat ttaaagatgt tttacataat tcaataaaat gaaatgactt 294gcaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaa 2985NAHomo sapiens aaagc aggggccctg ccaggcctcc gagggagtgtgcttggtctg gccgagggct 6ccaa gtctgggtgg gctcgaggcc actaggccca aagcctgcct ggctctgagg taggtctagaaccgtg cacgagggga atgcctgctc gggcccgaac ctcgctgggc ggtgtg cactggcccg gggcctgctt ggacctgaaacttgctaggc ccaggatatg 24ccga gagcctgctg ggcccaaacc ttactaggcc caggatgttc actgactgaa 3tcaggcctaaccttg ctaggcccag gatatgcact gggccagagt gtgctcaggc 36ttgc caggcgcagg atgtgtgctg gccctaagcctgctgaggcc caaacctgtt 42aggg ttttgtacaa aatcctgctt tagcctaaat cctgcttagc cttgaccccc 48accc aagccagatcagcattgttc tgaccctact aagtccaaaa ccttttgagg 54cttg tttcaactcc aaagcctgct aggttccagc accccccgcatccctcctca 6ccccc ttctcccccc tatggaaacc gcttgcttat ttttcaaaca ggccaagtca 66cagc cactgagatc tctgtccttt


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ctgagcaatt caccaagatc aaagaactcg 72tgcc ggaaaaaggc ctgaaggagg aggaaaaaga cggagtgtgc agagagaaag78ggag ccctagtgag ttggaggccg agcgtacctc tggggccttc caggacagcg 84agga agaagtggag ctggtgctggccccctcgga ggagagcgag aagtacatcc 9ctgca gacggtgcac ttcacttctg aagctgtgga gttgcaggat atgagcttgc96taca gcagcaagaa ggggtgcagg tggtggtgca acagcctggc cctgggttgc ggcttga ggaagggccc cggcagagcctgcagcagtg tgtggccatt agtatccagc agctgta ctccccgcaa gagatggagg tgttgcagtt ccacgctcta gaggagaatgtggtggc cagtgaagac agtaagttag cggtgagcct ggctgaaact actggactga agctcga ggaagagcag gagaagaaccagttattggc tgaaagaaca aaggagcagc tttttgt ggaaacaatg tcaggagatg aaagaagtga cgaaattgtt ctcacagtttattcaaa tgtggaagaa caagaggatc aacctacagc tggtcaagca gatgctgaaa ccaaatc tacaaaaaat caaagaaagacaaagggagc aaaaggaacc ttccactgtg tctgcat gttcacctct tctagaatgt caagttttaa tcgtcatatg aaaactcaca gtgagaagcctcacctg tgtcacctct gcctgaaaac cttccgtacg gtcactctgc ggaacca tgttaacacc cacacaggaa ccaggccctacaagtgtaac gactgcaaca catttgt caccagtgga gaactcgtcc gacacaggcg ctataaacat actcatgaga cctttaaatgttccatg tgcaagtatg ccagtgtgga ggcaagtaaa ttgaagcgcc tccgatc ccacactggg gagcgcccct ttcagtgttgccagtgcagc tatgccagca ataccta caagctgaaa cgccacatga gaacgcactc aggtaagggc tctggtgctg gcctgatacctacagtg ttaactctta aagcaagctt taaaaaatta ctttttattg caattaa agttcaaagg taaaagtgga tttttgcgtg ccttcatgataaaagaatct tctgtac ttttaccttt atttagcagt aagagagtct gcatagatac tgtgccacaa 2actgtg tggagtaaaa cacaaagtatttgcttccgt agatttttca ggtatttaaa 2aactcc tggccaggca tggtggctca aacctgtaat cccagcactt tgggaggctg2aggagg atcccttgag tccaggagtt tgagaccagc ctggtcaaca tagggagacc 222ctac gagtaattta aaaattagctgggcctggtg gtgcacacct gtggtcccag 228ggga ggctgaagca ggagaatcac ttgaacccag gaggttgagg ctgcagtgag234ttgc gccactacac tccagcctgg gtgacagagt gagaacctgt ctcaaaaaaa 24aaagt aaataaaaat aaataaaagtcaactcctta attcattctt caactttaag 246cata aagtgtgctg cttttgtaac agaggtactt gatgtcttgt gttaagaata 252tgtgtacttcttgg ttattcgtac agccccatgg atgtgaacca ccttgaactc 258agcc accagatgcg gggaagtcat gtctctggtccatcatggac acagctgtac 264taag ctgtctgggc ttgatttggg agtctcatac taattggggg ttgtccggtg 27ggggttgataaagga ggcttggggc aaaaaaaaaa aacactttca gcacaggtgg 276gcaa ggatcaggcc tggaggggga atcactttgttgtctgcatc tcaggtgaga 282acga atgccacatc tgccacaccc gcttcaccca gagcgggacc atgaaaatac 288tgcagaaacacggc gaaaatgtcc ccaaatacca gtgtccccat tgtgccacca 294cacg gaaaagcgac ctacgtgtgc atatgcgcaacttgcatgct tacagcgctg 3gctgaa atgccgctac tgttctgctg tcttccatga acgctatgcc ctcattcagc 3gaaaac tcataagaatgagaagaggt tcaagtgcaa acactgcagt tatgcctgca 3ggaacg tcatatgacc gctcacattc gtacccacac tggagagaaaccattcacct 3ttcttg caataaatgt ttccgacaga agcaacttct aaacgctcac ttcaggaaat 324atgc aaatttcatc ccgactgtttacaaatgctc caagtgtggc aaaggctttt 33tggat taacctgcac agacattcgg agaagtgtgg atcaggggaa gcaaagtcgg336cagg aaagggaaga agaacaagaa agaggaagca gaccatcctg aaggaagcca 342gtca gaaggaagct gcgaagggatggaaggaagc cgcgaacgga gacgaagctg 348agga ggcttccacc acgaagggag aacagttccc aggagagatg tttcctgtcg354gaga aaccacagcc agagtcaaag aggaagtgga tgaaggcgtg acctgtgaaa 36ctcaa cacgatggat aagtgagagggattcgggtt gcgtgttcac tgcccccaat 366agca agttagaagt ttttagcatt taaggtgtga aatgctcctc aacacgatgg372gaga gagagtcagg ttgcatgttc actgccccta attcctaaag caagttagaa 378agca ttttctttga aacaattaagttcatgacaa tggatgacac aagtttgagg 384ctag aattgttctc ctgtttgtag ctggatattt caaagaaaca ttgcaggtat 39aaaagttttaaacct tgaatgagag ggtaacacct caaacctatg gattcattca 396attg gcaaggtggc ccacaatgag tgagtagtgatttttggata tttcaaaata 4agacca gctagtgctt ccacagtcaa agctggacat ttttatgttg cattatatac 4atgata tttctaataatatatggttt taaacattaa agacaaatgt ttttatacaa 4attttc tacaaaattt aaagctacca taatgctttt aattagttct aaattcaacc42atgtt ttactcttat aaaaaggaaa actgagtagg aaatgaaata ctagattaga 426aata aggaataaat cgattttact ttggtataggagcaaggttc acctttagat 432attc tcttttaatt atgctccttg gcaggtatga aattgccctg gttacattcc 438gctt attagtatttcactccataa cccttttttc tgctaaaact actcttttta 444taaa ataattggca gagtgagaag aaacataaaa tcagataaggcaaatgtgta 45aagga atttgtactt tttcataatg cccagtgatt agtgagtatt tcccttttgc 456acaa gatttttcca ccctcgagcagcgtgagaga tgcctcttta acacttgaaa 462tcta tctggataca gaggcagatt tttcttcatt gcttagttga gcagtttgtt 468ccaacctgtctcca cccctgtatt tcaagatcat tgataagccc taaattcaaa 474agat atggaccttt tattgaaaat atcacaagttcagaatccct atacaatgtg 48gtgga aataatttcc cagcaggaag agcattatat tctctttgta ccagcaaatt 486actc aactcacatg


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agatttaaat tctgtgggct gtagtatgcc atcattgtga 492ttgt gcaatggttt cttaattttt ttactgttat ttaaagatgt tttacataat498aaat gaaatgactt aaaattgcaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 5a 563DNAHomo sapiens 2aagcaggggccctg ccaggcctcc gagggagtgt gcttggtctg gccgagggct 6ccaa gtctgggtgg gctcgaggcc actaggcccaaagcctgcct ggctctgagg taggtc tagaaccgtg cacgagggga atgcctgctc gggcccgaac ctcgctgggc ggtgtgcactggcccg gggcctgctt ggacctgaaa cttgctaggc ccaggatatg 24ccga gagcctgctg ggcccaaacc ttactaggcccaggatgttc actgactgaa 3tcagg cctaaccttg ctaggcccag gatatgcact gggccagagt gtgctcaggc 36ttgccaggcgcagg atgtgtgctg gccctaagcc tgctgaggcc caaacctgtt 42aggg ttttgtacaa aatcctgctt tagcctaaatcctgcttagc cttgaccccc 48accc aagccagatc agcattgttc tgaccctact aagtccaaaa ccttttgagg 54cttg tttcaactccaaagcctgct aggttccagc accccccgca tccctcctca 6ccccc ttctcccccc tatggaaacc gcttgcttat ttttcaaacaggccaagtca 66cagc cactgagatc tctgtccttt ctgagcaatt caccaagatc aaagaactcg 72tgcc ggaaaaaggcctgaaggagg aggaaaaaga cggagtgtgc agagagaaag 78ggag ccctagtgag ttggaggccg agcgtacctc tggggccttccaggacagcg 84agga agaagtggag ctggtgctgg ccccctcgga ggagagcgag aagtacatcc 9ctgca gacggtgcacttcacttctg aagctgtgga gttgcaggat atgagcttgc 96taca gcagcaagaa ggggtgcagg tggtggtgca acagcctggccctgggttgc ggcttga ggaagggccc cggcagagcc tgcagcagtg tgtggccatt agtatccagc agctgta ctccccgcaagagatggagg tgttgcagtt ccacgctcta gaggagaatg tggtggc cagtgaagac agtaagttag cggtgagcct ggctgaaactgctggactga agctcga ggaagagcag gagaagaacc agttattggc tgaaagaaca aaggagcagc tttttgt ggaaacaatgtcaggagatg aaagaagtga cgaaattgtt ctcacagttt attcaaa tgtggaagaa caagaggatc aacctacagc tggtcaagcagatgctgaaa ccaaatc tacaaaaaat caaagaaaga caaagggagc aaaaggaacc ttccactgtg tctgcat gttcacctcttctagaatgt caagttttaa tcgtcatatg aaaactcaca gtgagaa gcctcacctg tgtcacctct gcctgaaaac cttccgtacggtcactctgc ggaacca tgttaacacc cacacaggaa ccaggcccta caagtgtaac gactgcaaca catttgt caccagtggagaactcgtcc gacacaggcg ctataaacat actcatgaga cctttaa atgttccatg tgcaagtatg ccagtgtgga ggcaagtaaattgaagcgcc tccgatc ccacactggg gagcgcccct ttcagtgttg ccagtgcagc tatgccagca ataccta caagctgaaacgccacatga gaacgcactc aggtgagaag ccttacgaat acatctg ccacacccgc ttcacccaga gcgggaccat gaaaatacatattctgcaga acggcga aaatgtcccc aaataccagt gtccccattg tgccaccatc attgcacgga gcgacct acgattcctgggcctccctt ttccatgatc ttatttctct ttccaaaata 2acactg tgatacacaa aaatatgtta gcagaacaaa aaatttgacc cttttgccca2gattct ggagatgaga tgaatttttt tgaaaacctt tctgaaaggc gaaaggtgtt 2aaagtc ttcactttta tttttcatct ggaccattctgtcattgttg ccgtagatac 222atca caaaacacag tccagtgggg cttggtgggg cacaagtcta gccagttgct 228ttttgacaccatgg caaagtaaca tggtttatat ccatctcatg ccagtgggtg 234tcca catagcccta taagatgctt tataaacacattaattcttc cttcccatga 24tgaga aatcaagctc tctaaatgtc tgagtcactg tgggtaaggt ggagtagctc 246acag ctgtccattgtcatttggct tcttacacaa gtatcacaag accatcatgc 252ctta gatgagcaaa cccagccaga ccttaccatg tgtctcaggttaatttcaac 258aata acagggcact gacttctaac aacgagtgga ttatttaagg tgtgcatatg 264ttgc atgcttacagcgctgcagag ctgaaatgcc gctactgttc tgctgtcttc 27acgct atgccctcat tcagcaccag aaaactcata agaatgagaagaggttcaag 276cact gcagttatgc ctgcaagcag gaacgtcata tgaccgctca cattcgtacc 282ggag agaaaccattcacctgcctt tcttgcaata aatgtttccg acagaagcaa 288aacg ctcacttcag gaaataccac gatgcaaatt tcatcccgactgtttacaaa 294aagt gtggcaaagg cttttcccgc tggattaacc tgcacagaca ttcggagaag 3gatcag gggaagcaaagtcggctgct tcaggaaagg gaagaagaac aagaaagagg 3agacca tcctgaagga agccacaaag ggtcagaagg aagctgcgaagggatggaag 3ccgcga acggagacgg tgtgatctca gctcaccgca acctctgcct cctgggttca 3attctc atgcctcagtctccggagct gggattacag atgcccgcca ccacgcctgg 324gttc tattattttt agtagagatg gggttttacc atgtctctcactcctgacct 33gatct gcccgcctcg gcctcccaaa gtggtgggat tacaggcatg agcccctgtg 336ctga tggcaccagttttgtggatc tcagtgtttc ttttcatatc caagaactgg 342ttgt ctccctccat ccaccaaaaa aaaaaaaaaa aaa 34632AHomosapiens 2aagc aggggccctg ccaggcctcc gagggagtgt gcttggtctg gccgagggct 6ccaa gtctgggtgg gctcgaggccactaggccca aagcctgcct ggctctgagg taggtc tagaaccgtg cacgagggga atgcctgctc gggcccgaac ctcgctgggcggtgtg cactggcccg gggcctgctt ggacctgaaa cttgctaggc ccaggatatg 24ccga gagcctgctg ggcccaaaccttactaggcc caggatgttc actgactgaa 3tcagg cctaaccttg ctaggcccag gatatgcact gggccagagt gtgctcaggc36ttgc caggcgcagg atgtgtgctg gccctaagcc tgctgaggcc caaacctgtt 42aggg ttttgtacaa aatcctgctt tagcctaaat


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cctgcttagc cttgaccccc 48accc aagccagatc agcattgttc tgaccctact aagtccaaaa ccttttgagg 54cttg tttcaactccaaagcctgct aggttccagc accccccgca tccctcctca 6ccccc ttctcccccc tatggaaacc gcttgcttat ttttcaaacaggccaagtca 66cagc cactgagatc tctgtccttt ctgagcaatt caccaagatc aaagaactcg 72tgcc ggaaaaaggcctgaaggagg aggaaaaaga cggagtgtgc agagagaaag 78ggag ccctagtgag ttggaggccg agcgtacctc tggggccttccaggacagcg 84agga agaagtggag ctggtgctgg ccccctcgga ggagagcgag aagtacatcc 9ctgca gacggtgcacttcacttctg aagctgtgga gttgcaggat atgagcttgc 96taca gcagcaagaa ggggtgcagg tggtggtgca acagcctggccctgggttgc ggcttga ggaagggccc cggcagagcc tgcagcagtg tgtggccatt agtatccagc agctgta ctccccgcaagagatggagg tgttgcagtt ccacgctcta gaggagaatg tggtggc cagtgaagac agtaagttag cggtgagcct ggctgaaactactggactga agctcga ggaagagcag gagaagaacc agttattggc tgaaagaaca aaggagcagc tttttgt ggaaacaatgtcaggagatg aaagaagtga cgaaattgtt ctcacagttt attcaaa tgtggaagaa caagaggatc aacctacagc tggtcaagcagatgctgaaa ccaaatc tacaaaaaat caaagaaaga caaagggagc aaaaggaacc ttccactgtg tctgcat gttcacctcttctagaatgt caagttttaa tcgtcatatg aaaactcaca gtgagaa gcctcacctg tgtcacctct gcctgaaaac cttccgtacggtcactctgc ggaacca tgttaacacc cacacaggaa ccaggcccta caagtgtaac gactgcaaca catttgt caccagtggagaactcgtcc gacacaggcg ctataaacat actcatgaga cctttaa atgttccatg tgcaagtatg ccagtgtgga ggcaagtaaattgaagcgcc tccgatc ccacactggg gagcgcccct ttcagtgttg ccagtgcagc tatgccagca ataccta caagctgaaacgccacatga gaacgcactc aggtaagggc tctggtgctg gcctgat acctacagtg ttaactctta aagcaagctt taaaaaattactttttattg caattaa agttcaaagg taaaagtgga tttttgcgtg ccttcatgat aaaagaatct tctgtac ttttaccttt atttagcagtaagagagtct gcatagatac tgtgccacaa 2actgtg tggagtaaaa cacaaagtat ttgctyccgt agatttttca ggtgagaagc2cgaatg ccacatctgc cacacccgct tcacccagag cgggaccatg aaaatacata 2gcagaa acacggcgaa aatgtccccaaataccagtg tccccattgt gccaccatca 222ggaa aagcgaccta cgtgtgcata tgcgcaactt gcatgcttac agcgctgcag228aatg ccgctactgt tctgctgtct tccatgaacg ctatgccctc attcagcacc 234ctca taagaatgag aagaggttcaagtgcaaaca ctgcagttat gcctgcaagc 24cgtca tatgaccgct cacattcgta cccacactgg agagaaacca ttcacctgcc246gcaa taaatgtttc cgacagaagc aacttctaaa cgctcacttc aggaaatacc 252caaa tttcatcccg actgtttacaaatgctccaa gtgtggcaaa ggcttttccc 258ttaa cctgcacaga cattcggaga agtgtggatc aggggaagca aagtcggctg264gaaa gggaagaaga acaagaaaga ggaagcagac catcctgaag gaagccacaa 27cagaa ggaagctgcg aagggatggaaggaagccgc gaacggagac gaagctgctg 276aggc ttccaccacg aagggagaac agttcccagg agagatgttt cctgtcgcct282aaac cacagccaga gtcaaagagg aagtggatga aggcgtgacc tgtgaaatgc 288acac gatggataag tgagagggattcgggttgcg tgttcactgc ccccaattcc 294aagt tagaagtttt tagcatttaa ggtgtgaaat gctcctcaac acgatggata3agagag agtcaggttg catgttcact gcccctaatt cctaaagcaa gttagaaatt 3gcattt tctttgaaac aattaagttc atgacaatggatgacacaag tttgaggtag 3tagaat tgttctcctg tttgtagctg gatatttcaa agaaacattg caggtatttt 3aagttt taaaccttgaatgagagggt aacacctcaa acctatggat tcattcactt 324ggca aggtggccca caatgagtga gtagtgattt ttggatatttcaaaatagtc 33cagct agtgcttcca cagtcaaagc tggacatttt tatgttgcat tatatacacc 336attt ctaataatat atggttttaaacattaaaga caaatgtttt tatacaaatg 342ctac aaaatttaaa gctaccataa tgcttttaat tagttctaaa ttcaaccaaa 348tttactcttataaa aaggaaaact gagtaggaaa tgaaatacta gattagacta 354aagg aataaatcga ttttactttg gtataggagcaaggttcacc tttagatttt 36tctct tttaattatg ctccttggca ggtatgaaat tgccctggtt acattccatt 366tatt agtatttcactccataaccc ttttttctgc taaaactact ctttttatat 372aata attggcagag tgagaagaaa cataaaatca gataaggcaaatgtgtacct 378aatt tgtacttttt cataatgccc agtgattagt gagtatttcc cttttgccag 384agat ttttccaccc tcgagcagcgtgagagatgc ctctttaaca cttgaaattc 39tatct ggatacagag gcagattttt cttcattgct tagttgagca gtttgttttg 396acctgtctccaccc ctgtatttca agatcattga taagccctaa attcaaattc 4gatatg gaccttttat tgaaaatatc acaagttcag aatccctatacaatgtgaat 4ggaaat aatttcccag caggaagagc attatattct ctttgtacca gcaaattaat 4ctcaac tcacatgaga tttaaattctgtgggctgta gtatgccatc attgtgactg 42gtgca atggtttctt aattttttta ctgttattta aagatgtttt acataattca 426tgaaatgacttaaa attgcaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 432222745DNAHomo sapiens 22ttacaaatgctccaagtgtg gcaaaggctt ttcccgctgg attaacctgc acagacattc 6gtgt ggatcagggg aagcaaagtc ggctgcttcaggaaagggaa gaagaacaag aggaag cagaccatcc tgaaggaagc cacaaagggt cagaaggaag ctgcgaaggg aaggaagccgcgaacg gagacgaagc tgctgctgag gaggcttcca ccacgaaggg 24gttc ccaggagaga tgtttcctgt cgcctgcaga


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gaaaccacag ccagagtcaa 3aagtg gatgaaggcg tgacctgtga aatgctcctc aacacgatgg ataaacatct 36gatgttggatctgt atcaaagttt gtcatggatt ttcctttggg gagagtgcta 42atcg tactgttagc cactgcagta cattgagctccatagagaca gcgccggggc 48gagc cgtacgggca ctgggcgact ctgtgcctcg ctgaagaaaa ataactaaac 54aaaggagatcctaa gaagccgaga ggcaaaatgt catcatatgc attttttgtg 6ttgtc gggaggagca taagaagaag cactcagatgcttcagtcaa cttctcagag 66aaca agtgctcaga gaggtggaag accatgtctg ctaaagagaa aggaaaattt 72atggcaaaggcgga caaga 745236mo sapiens 23ccgactgttt acaaatgctc caagtgtggc aaaggctttt cccgctggattaacctgcac 6tcgg agaagtgtgg atcaggggaa gcaaagtcgg ctgcttcagg aaagggaaga caagaa agaggaagcagaccatcctg aaggaagcca caaagggtca gaaggaagct agggat ggaaggaagc cgcgaacgga gacgacatct tgcacagatgttggatctgt 24gttt gtcatggatt ttcctttggg gagagtgcta ttataaatcg tactgttagc 3cagta cattgagctc catagagacagcgccggggc aagtgagagc cgtacgggca 36gact ctgtgcctcg ctgaagaaaa ataactaaac atgggcaaag gagatcctaa42gaga ggcaaaatgt catcatatgc attttttgtg caaacttgtc gggaggagca 48gaag cactcagatg cttcagtcaa cttctcagagttttctaaca agtgctcaga 54gaag accatgtctg ctaaagagaa aggaaaattt gaggatatgg caaaggcgga 6 62DNAHomosapiens 24tcccaggccc cctgcaggcc ctcgtgccct ccttacttcc cccccgggtc tcccagcgcc 6gggg ccctcctcccttcctcatcc acttcaaccc caaggtattt ccgtgcccct gaccct cctcccctcc ttaggcgctc ccccactacc cagtcttccagtgccctgca ctcctc ctctccttat ccacccccac cccaggtctc ccagtgccct gtatgggacc 24ccct cctcatccac ccccccaggtccaccagtgc cccctctggg gtcctcctca

3gctcc ccctccccct ccctactccc cttcccccct gcccccacag tacatcaccc 36ccaa ccctgcctgg ctccgcccccttcacgcccc ctcttttccg ctccgcgcct 42tgcc accctccact ctcgcgccag cccggcggcg gccggctgtg ggctgcagca48gcac gaggcagagc ccacaagcca aagacggagt gggccgagca ttccggccac 54cgcg gccaagtcat tatggcagccactgagatct ctgtcctttc tgagcaattc 6gatca aagaactcga gttgatgccg gaaaaaggcc tgaaggagga ggaaaaagac66tgca gagagaaaga ccatcggagc cctagtgagt tggaggccga gcgtacctct 72ttcc aggacagcgt cctggaggaagaagtggagc tggtgctggc cccctcggag 78gaga agtacatcct gaccctgcag acggtgcact tcacttctga agctgtggag84gata tgagcttgct gagcatacag cagcaagaag gggtgcaggt ggtggtgcaa 9tggcc ctgggttgct gtggcttgaggaagggcccc ggcagagcct gcagcagtgt 96atta gtatccagca agagctgtac tccccgcaag agatggaggt gttgcagttcgctctag aggagaatgt gatggtggcc agtgaagaca gtaagttagc ggtgagcctg gaaactg ctggactgat caagctcgaggaagagcagg agaagaacca gttattggct agaacaa aggagcagct cttttttgtg gaaacaatgt caggagatga aagaagtgacattgttc tcacagtttc aaattcaaat gtggaagaac aagaggatca acctacagct caagcag atgctgaaaa ggccaaatctacaaaaaatc aaagaaagac aaagggagca ggaacct tccactgtga tgtctgcatg ttcacctctt ctagaatgtc aagttttaat catatgaaaactcacac cagtgagaag cctcacctgt gtcacctctg cctgaaaacc cgtacgg tcactctgct gcggaaccat gttaacacccacacaggaac caggccctac tgtaacg actgcaacat ggcatttgtc accagtggag aactcgtccg acacaggcgc aaacatactcatgagaa accctttaaa tgttccatgt gcaagtatgc cagtgtggag agtaaat tgaagcgcca tgtccgatcc cacactggggagcgcccctt tcagtgttgc tgcagct atgccagcag agatacctac aagctgaaac gccacatgag aacgcactca gtgcatatgcgcaactt gcatgcttac agcgctgcag agctgaaatg ccgctactgt gctgtct tccatgaacg ctatgccctc attcagcaccagaaaactca taagaatgag aggttca agtgcaaaca ctgcagttat gcctgcaagc aggaacgtca tatgaccgct attcgtacccacactgg agagaaacca ttcacctgcc tttcttgcaa taaatgtttc cagaagc aacttctaaa cgctcacttc aggaaataccacgatgcaaa tttcatcccg 2tttaca aatgctccaa gtgtggcaaa ggcttttccc gctggattaa cctgcacaga 2cggagaagtgtggatc aggggaagca aagtcggctg cttcaggaaa gggaagaaga 2gaaaga ggaagcagac catcctgaag gaagccacaaagggtcagaa ggaagctgcg 222tgga aggaagccgc gaacggagac gaagctgctg ctgaggaggc ttccaccacg 228gaacagttcccagg agagatgttt cctgtcgcct gcagagaaac cacagccaga 234gagg aagtggatga aggcgtgacc tgtgaaatgctcctcaacac gatggataag 24gggat tcgggttgcg tgttcactgc ccccaattcc taaagcaagt tagaagtttt 246ttaaggtgtgaaat gctcctcaac acgatggata agtgagagag agtcaggttg 252cact gcccctaatt cctaaagcaa gttagaaatttttagcattt tctttgaaac 258gttc atgacaatgg atgacacaag tttgaggtag tgtctagaat tgttctcctg 264gctg gatatttcaaagaaacattg caggtatttt ataaaagttt taaaccttga 27agggt aacacctcaa acctatggat tcattcactt gatattggcaaggtggccca 276gtga gtagtgattt ttggatattt caaaatagtc tagaccagct agtgcttcca 282aagc tggacatttt tatgttgcat


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tatatacacc catgatattt ctaataatat 288ttaa acattaaaga caaatgtttt tatacaaatg aattttctac aaaatttaaa 294ataatgcttttaat tagttctaaa ttcaaccaaa aaatgtttta ctcttataaa 3aaaact gagtaggaaa tgaaatacta gattagactagaaaataagg aataaatcga 3actttg gtataggagc aaggttcacc tttagatttt tgtattctct tttaattatg 3ttggca ggtatgaaattgccctggtt acattccatt attgcttatt agtatttcac 3taaccc ttttttctgc taaaactact ctttttatat ttgtaaaata attggcagag324gaaa cataaaatca gataaggcaa atgtgtacct gtaaggaatt tgtacttttt 33tgccc agtgattagt gagtatttcc cttttgccagttgacaagat ttttccaccc 336agcg tgagagatgc ctctttaaca cttgaaattc atttctatct ggatacagag 342tttt cttcattgcttagttgagca gtttgttttg ctgccaacct gtctccaccc 348ttca agatcattga taagccctaa attcaaattc ttaagatatg gaccttttat354tatc acaagttcag aatccctata caatgtgaat atgtggaaat aatttcccag 36agagc attatattct ctttgtacca gcaaattaatttaactcaac tcacatgaga 366ttct gtgggctgta gtatgccatc attgtgactg aatttgtgca atggtttctt 372ttta ctgttatttaaagatgtttt acataattca ataaaatgaa atgacttaaa 378aaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa 3822254mosapiens 25Met Ala Ala Thr Glu Ile Ser Val Leu Ser Glu Gln Phe Thr Lys Ilelu Leu Glu Leu Met ProGlu Lys Gly Leu Lys Glu Glu Glu Lys 2Asp Gly Val Cys Arg Glu Lys Asp His Arg Ser Pro Ser GluLeu Glu 35 4 Glu Arg Thr Ser Gly Ala Phe Gln Asp Ser Val Leu Glu Glu Glu 5Val Glu Leu Val LeuAla Pro Ser Glu Glu Ser Glu Lys Tyr Ile Leu65 7Thr Leu Gln Thr Val His Phe Thr Ser Glu Ala ValGlu Leu Gln Asp 85 9 Ser Leu Leu Ser Ile Gln Gln Gln Glu Gly Val Gln Val Val Val Gln Pro Gly ProGly Leu Leu Trp Leu Glu Glu Gly Pro Arg Gln Leu Gln Gln Cys Val Ala Ile Ser Ile Gln Gln Glu LeuTyr Ser Gln Glu Met Glu Val Leu Gln Phe His Ala Leu Glu Glu Asn Val Met Val Ala Ser Glu Asp SerLys Leu Ala Val Ser Leu Ala Glu Thr Gly Leu Ile Lys Leu Glu Glu Glu Gln Glu Lys Asn Gln LeuLeu Glu Arg Thr Lys Glu Gln Leu Phe Phe Val Glu Thr Met Ser Gly 2lu Arg Ser Asp Glu Ile Val LeuThr Val Ser Asn Ser Asn Val 222u Gln Glu Asp Gln Pro Thr Ala Gly Gln Ala Asp Ala Glu Lys225234s Ser Thr Lys Asn Gln Arg Lys Thr Lys Gly Ala Lys Gly Thr 245 25e His Cys Asp Val Cys MetPhe Thr Ser Ser Arg Met Ser Ser Phe 267g His Met Lys Thr His Thr Ser Glu Lys Pro His Leu Cys His275 28u Cys Leu Lys Thr Phe Arg Thr Val Thr Leu Leu Arg Asn His Val 29hr His Thr Gly Thr ArgPro Tyr Lys Cys Asn Asp Cys Asn Met33la Phe Val Thr Ser Gly Glu Leu Val Arg His Arg Arg TyrLys His 325 33r His Glu Lys Pro Phe Lys Cys Ser Met Cys Lys Tyr Ala Ser Val 345l Lys Pro Phe LeuAsp Leu Lys Leu His Gly Ile Leu Val Glu 355 36a Ala Val Gln Val Thr Pro Ser Val Thr Asn Ser ArgIle Cys Tyr 378n Ala Phe Tyr Tyr Ser Tyr Lys Ile Tyr Ala Gly Asn Asn Met385 39er Leu Leu267mosapiens 26Met Ala Ala Thr Glu Ile Ser Val Leu Ser Glu Gln Phe Thr Lys Ilelu Leu Glu Leu Met ProGlu Lys Gly Leu Lys Glu Glu Glu Lys 2Asp Gly Val Cys Arg Glu Lys Asp His Arg Ser Pro Ser GluLeu Glu 35 4 Glu Arg Thr Ser Gly Ala Phe Gln Asp Ser Val Leu Glu Glu Glu 5Val Glu Leu Val LeuAla Pro Ser Glu Glu Ser Glu Lys Tyr Ile Leu65 7Thr Leu Gln Thr Val His Phe Thr Ser Glu Ala ValGlu Leu Gln Asp 85 9 Ser Leu Leu Ser Ile Gln Gln Gln Glu Gly Val Gln Val Val Val Gln Pro Gly ProGly Leu Leu Trp Leu Glu Glu Gly Pro Arg Gln Leu Gln Gln Cys Val Ala Ile Ser Ile Gln Gln Glu LeuTyr Ser Gln Glu Met Glu Val Leu Gln Phe His Ala Leu Glu Glu Asn Val Met Val Ala Ser Glu Asp SerLys Leu Ala Val Ser Leu Ala Glu Thr Gly Leu Ile Lys Leu Glu Glu Glu Gln Glu Lys Asn Gln LeuLeu Glu Arg Thr Lys Glu Gln Leu Phe Phe Val Glu Thr Met Ser Gly 2lu Arg Ser Asp Glu Ile Val LeuThr Val Ser Asn Ser Asn Val 222u Gln Glu Asp Gln Pro Thr Ala Gly Gln Ala Asp Ala Glu Lys225234s Ser Thr Lys Asn Gln Arg Lys Thr Lys Gly Ala Lys Gly Thr 245 25e His Cys Asp Val Cys MetPhe Thr Ser Ser Arg Met Ser Ser Phe 267g His Met Lys Thr His Thr Ser Glu Lys Pro His Leu Cys His275 28u Cys Leu Lys Thr Phe Arg Thr Val Thr Leu Leu Arg Asn His Val 29hr His Thr Gly Thr ArgPro Tyr Lys Cys Asn Asp Cys Asn Met33la Phe Val Thr Ser Gly Glu Leu Val Arg His Arg Arg TyrLys His 325 33r His Glu Lys Pro Phe Lys Cys Ser Met Cys Lys Tyr Ala Ser Val 345a Ser Lys Leu LysArg His Val Arg Ser His Thr Gly Glu Arg 355 36o Phe Gln Cys Cys Gln Cys Ser Tyr Ala Ser ArgAsp Thr Tyr Lys 378s Arg His Met Arg Thr His Ser Gly Glu Lys Pro Tyr Glu Cys385 39le Cys HisThr Arg Phe Thr Gln Ser Gly Thr Met Lys Ile His 44eu Gln Lys His Gly Glu Asn Val Pro Lys Tyr Gln


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Cys Pro His 423a Thr Ile Ile Ala Arg Lys Ser Asp Leu Arg Val His Met Arg 435 44n Leu His Ala TyrSer Ala Ala Glu Leu Lys Cys Arg Tyr Cys Ser 456l Phe His Glu Arg Tyr Ala Leu Ile Gln His Gln LysThr His465 478n Glu Lys Arg Phe Lys Cys Lys His Cys Ser Tyr Ala Cys Lys 485 49n Glu Arg HisMet Thr Ala His Ile Arg Thr His Thr Gly Glu Lys 55he Thr Cys Leu Ser Cys Asn Lys Cys Phe ArgGln Lys Gln Leu 5525Leu Asn Ala His Phe Arg Lys Tyr His Asp Ala Asn Phe Ile Pro Thr 534r LysCys Ser Lys Cys Gly Lys Gly Phe Ser Arg Trp Ile Asn545 556s Arg His Ser Glu Lys Cys Gly Ser GlyGlu Ala Lys Ser Ala 565 57a Ser Gly Lys Gly Arg Arg Thr Arg Lys Arg Lys Gln Thr Ile Leu 589uAla Thr Lys Gly Gln Lys Glu Ala Ala Lys Gly Trp Lys Glu 595 6la Ala Asn Gly Asp Glu Ala Ala AlaGlu Glu Ala Ser Thr Thr Lys 662u Gln Phe Pro Gly Glu Met Phe Pro Val Ala Cys Arg Glu Thr625634a Arg Val Lys Glu Glu Val Asp Glu Gly Val Thr Cys Glu Met 645 65u Leu Asn Thr Met Asp AsnSer Ala Gly Cys Thr Gly Arg Met Met 667l Ser Ala Trp Leu Leu Gly Arg Pro Gln Glu Thr Tyr AsnGln 675 68y Arg Arg Arg Arg Gly Ser Arg Arg Val Thr Trp 69PRTHomo sapiens 27Met Ala Ala ThrGlu Ile Ser Val Leu Ser Glu Gln Phe Thr Lys Ilelu Leu Glu Leu Met Pro Glu Lys Gly Leu Lys GluGlu Glu Lys 2Asp Gly Val Cys Arg Glu Lys Asp His Arg Ser Pro Ser Glu Leu Glu 35 4 Glu Arg ThrSer Gly Ala Phe Gln Asp Ser Val Leu Glu Glu Glu 5Val Glu Leu Val Leu Ala Pro Ser Glu Glu SerGlu Lys Tyr Ile Leu65 7Thr Leu Gln Thr Val His Phe Thr Ser Glu Ala Val Glu Leu Gln Asp 85 9 SerLeu Leu Ser Ile Gln Gln Gln Glu Gly Val Gln Val Val Val Gln Pro Gly Pro Gly Leu Leu Trp Leu GluGlu Gly Pro Arg Gln Leu Gln Gln Cys Val Ala Ile Ser Ile Gln Gln Glu Leu Tyr Ser Gln Glu Met GluVal Leu Gln Phe His Ala Leu Glu Glu Asn Val Met Val Ala Ser Glu Asp Ser Lys Leu Ala Val Ser LeuAla Glu Thr Gly Leu Ile Lys Leu Glu Glu Glu Gln Glu Lys Asn Gln Leu Leu Glu Arg Thr Lys GluGln Leu Phe Phe Val Glu Thr Met Ser Gly 2lu Arg Ser Asp Glu Ile Val Leu Thr Val Ser Asn Ser AsnVal 222u Gln Glu Asp Gln Pro Thr Ala Gly Gln Ala Asp Ala Glu Lys225 234s Ser Thr Lys Asn GlnArg Lys Thr Lys Gly Ala Lys Gly Thr 245 25e His Cys Asp Val Cys Met Phe Thr Ser Ser Arg MetSer Ser Phe 267g His Met Lys Thr His Thr Ser Glu Lys Pro His Leu Cys His 275 28u Cys Leu LysThr Phe Arg Thr Val Thr Leu Leu Arg Asn His Val 29hr His Thr Gly Thr Arg Pro Tyr Lys Cys AsnAsp Cys Asn Met33la Phe Val Thr Ser Gly Glu Leu Val Arg His Arg Arg Tyr Lys His 325 33r HisGlu Lys Pro Phe Lys Cys Ser Met Cys Lys Tyr Ala Ser Val 345a Ser Lys Leu Lys Arg His Val Arg SerHis Thr Gly Glu Arg 355 36o Phe Gln Cys Cys Gln Cys Ser Tyr Ala Ser Arg Asp Thr Tyr Lys 378sArg His Met Arg Thr His Ser Gly Glu Lys Pro Tyr Glu Cys385 39le Cys His Thr Arg Phe Thr Gln SerGly Thr Met Lys Ile His 44eu Gln Lys His Gly Glu Asn Val Pro Lys Tyr Gln Cys Pro His 423a Thr IleIle Ala Arg Lys Ser Asp Leu Arg Val His Met Arg 435 44n Leu His Ala Tyr Ser Ala Ala Glu Leu LysCys Arg Tyr Cys Ser 456l Phe His Glu Arg Tyr Ala Leu Ile Gln His Gln Lys Thr His465 478n GluLys Arg Phe Lys Cys Lys His Cys Ser Tyr Ala Cys Lys 485 49n Glu Arg His Met Thr Ala His Ile ArgThr His Thr Gly Glu Lys 55he Thr Cys Leu Ser Cys Asn Lys Cys Phe Arg Gln Lys Gln Leu 5525LeuAsn Ala His Phe Arg Lys Tyr His Asp Ala Asn Phe Ile Pro Thr 534r Lys Cys Ser Lys Cys Gly LysGly Phe Ser Arg Trp Ile Asn545 556s Arg His Ser Glu Lys Cys Gly Ser Gly Glu Ala Lys Ser Ala 56557a Ser Gly Lys Gly Arg Arg Thr Arg Lys Arg Lys Gln Thr Ile Leu 589u Ala Thr Lys Gly Gln LysGlu Ala Ala Lys Gly Trp Lys Glu 595 6la Ala Asn Gly Asp Gly Val Ile Ser Ala His Arg Asn Leu CysLeu 662y Ser Ser Asp Ser His Ala Ser Val Ser Gly Ala Gly Ile Thr625 634a Arg His His Ala Trp LeuIle Val Leu Leu Phe Leu Val Glu 645 65t Gly Phe Tyr His Val Ser His Ser 664mo sapiens 28Met PheThr Ser Ser Arg Met Ser Ser Phe Asn Arg His Met Lys Thrhr Ser Glu Lys Pro His Leu Cys His LeuCys Leu Lys Thr Phe 2Arg Thr Val Thr Leu Leu Arg Asn His Val Asn Thr His Thr Gly Thr 35 4 ProTyr Lys Cys Asn Asp Cys Asn Met Ala Phe Val Thr Ser Gly 5Glu Leu Val Arg His Arg Arg Tyr LysHis Thr His Glu Lys Pro Phe65 7Lys Cys Ser Met Cys Lys Tyr Ala Ser Val Glu Ala Ser Lys Leu Lys85 9 His Val Arg Ser His Thr Gly Glu Arg Pro Phe Gln Cys Cys Gln Ser Tyr Ala Ser Arg


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Asp Thr Tyr Lys Leu Lys Arg His Met Arg His Ser Gly Glu Lys Pro Tyr Glu Cys His Ile Cys His ThrArg Thr Gln Ser Gly Thr Met Lys Ile His Ile Leu Gln Lys His Gly Glu Asn Val Pro Lys Tyr Gln CysPro His Cys Ala Thr Ile Ile Ala Lys Ser Asp Leu Arg Val His Met Arg Asn Leu His Ala Tyr Ser AlaGlu Leu Lys Cys Arg Tyr Cys Ser Ala Val Phe His Glu Arg 2la Leu Ile Gln His Gln Lys Thr His LysAsn Glu Lys Arg Phe 222s Lys His Cys Ser Tyr Ala Cys Lys Gln Glu Arg His Met Thr225 234s IleArg Thr His Thr Gly Glu Lys Pro Phe Thr Cys Leu Ser 245 25s Asn Lys Cys Phe Arg Gln Lys GlnLeu Leu Asn Ala His Phe Arg 267r His Asp Ala Asn Phe Ile Pro Thr Val Tyr Lys Cys Ser Lys 275 28sGly Lys Gly Phe Ser Arg Trp Ile Asn Leu His Arg His Ser Glu 29ys Gly Ser Gly Glu Ala Lys Ser AlaAla Ser Gly Lys Gly Arg33rg Thr Arg Lys Arg Lys Gln Thr Ile Leu Lys Glu Ala Thr Lys Gly 325 33nLys Glu Ala Ala Lys Gly Trp Lys Glu Ala Ala Asn Gly Asp Gly 345e Ser Ala His Arg Asn Leu CysLeu Leu Gly Ser Ser Asp Ser 355 36s Ala Ser Val Ser Gly Ala Gly Ile Thr Asp Ala Arg His His Ala378u Ile Val Leu Leu Phe Leu Val Glu Met Gly Phe Tyr His Val385 39is Ser2946o sapiens 29Met SerGly Asp Glu Arg Ser Asp Glu Ile Val Leu Thr Val Ser Asnsn Val Glu Glu Gln Glu Asp Gln Pro ThrAla Gly Gln Ala Asp 2Ala Glu Lys Ala Lys Ser Thr Lys Asn Gln Arg Lys Thr Lys Gly Ala 35 4 GlyThr Phe His Cys Asp Val Cys Met Phe Thr Ser Ser Arg Met 5Ser Ser Phe Asn Arg His Met Lys ThrHis Thr Ser Glu Lys Pro His65 7Leu Cys His Leu Cys Leu Lys Thr Phe Arg Thr Val Thr Leu Leu Arg85 9 His Val Asn Thr His Thr Gly Thr Arg Pro Tyr Lys Cys Asn Asp Asn Met Ala Phe Val Thr SerGly Glu Leu Val Arg His Arg Arg Lys His Thr His Glu Lys Pro Phe Lys Cys Ser Met Cys Lys Tyr SerVal Glu Ala Ser Lys Leu Lys Arg His Val Arg Ser His Thr Gly Glu Arg Pro Phe Gln Cys Cys Gln CysSer Tyr Ala Ser Arg Asp Tyr Lys Leu Lys Arg His Met Arg Thr His Ser Gly Glu Lys Pro Glu Cys HisIle Cys His Thr Arg Phe Thr Gln Ser Gly Thr Met 2le His Ile Leu Gln Lys His Gly Glu Asn Val ProLys Tyr Gln 222o His Cys Ala Thr Ile Ile Ala Arg Lys Ser Asp Leu Arg Val225 234t Arg Asn Leu HisAla Tyr Ser Ala Ala Glu Leu Lys Cys Arg 245 25r Cys Ser Ala Val Phe His Glu Arg Tyr Ala Leu IleGln His Gln 267r His Lys Asn Glu Lys Arg Phe Lys Cys Lys His Cys Ser Tyr 275 28a Cys Lys GlnGlu Arg His Met Thr Ala His Ile Arg Thr His Thr 29lu Lys Pro Phe Thr Cys Leu Ser Cys Asn LysCys Phe Arg Gln33ys Gln Leu Leu Asn Ala His Phe Arg Lys Tyr His Asp Ala Asn Phe 325 33e ProThr Val Tyr Lys Cys Ser Lys Cys Gly Lys Gly Phe Ser Arg 345e Asn Leu His Arg His Ser Glu LysCys Gly Ser Gly Glu Ala 355 36s Ser Ala Ala Ser Gly Lys Gly Arg Arg Thr Arg Lys Arg Lys Gln378e Leu Lys Glu Ala Thr Lys Gly Gln Lys Glu Ala Ala Lys Gly385 39ys Glu Ala Ala Asn Gly AspGly Val Ile Ser Ala His Arg Asn 44ys Leu Leu Gly Ser Ser Asp Ser His Ala Ser Val Ser Gly Ala 423eThr Asp Ala Arg His His Ala Trp Leu Ile Val Leu Leu Phe 435 44u Val Glu Met Gly Phe Tyr His ValSer His Ser 456RTHomo sapiens 3a Ala Thr Glu Ile Ser Val Leu Ser Glu Gln Phe Thr Lys Ilelu LeuGlu Leu Met Pro Glu Lys Gly Leu Lys Glu Glu Glu Lys 2Asp Gly Val Cys Arg Glu Lys Asp His ArgSer Pro Ser Glu Leu Glu 35 4 Glu Arg Thr Ser Gly Ala Phe Gln Asp Ser Val Leu Glu Glu Glu 5ValGlu Leu Val Leu Ala Pro Ser Glu Glu Ser Glu Lys Tyr Ile Leu65 7Thr Leu Gln Thr Val His Phe ThrSer Glu Ala Val Glu Leu Gln Asp 85 9 Ser Leu Leu Ser Ile Gln Gln Gln Glu Gly Val Gln Val Val ValGln Pro Gly Pro Gly Leu Leu Trp Leu Glu Glu Gly Pro Arg Gln Leu Gln Gln Cys Val Ala Ile Ser IleGln Gln Glu Leu Tyr Ser Gln Glu Met Glu Val Leu Gln Phe His Ala Leu Glu Glu Asn Val Met ValAla Ser Glu Asp Ser Lys Leu Ala Val Ser Leu Ala Glu Thr Gly Leu Ile Lys Leu Glu Glu Glu Gln GluLys Asn Gln Leu Leu Glu Arg Thr Lys Glu Gln Leu Phe Phe Val Glu Thr Met Ser Gly 2lu Arg SerAsp Glu Ile Val Leu Thr Val Ser Asn Ser Asn Val 222u Gln Glu Asp Gln Pro Thr Ala Gly Gln AlaAsp Ala Glu Lys225 234s Ser Thr Lys Asn Gln Arg Lys Thr Lys Gly Ala Lys Gly Thr 245 25e HisCys Asp Val Cys Met Phe Thr Ser Ser Arg Met Ser Ser Phe 267g His Met Lys Thr His Thr Ser GluLys Pro His Leu Cys His 275 28u Cys Leu Lys Thr Phe Arg Thr Val Thr Leu Leu Arg Asn His Val


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29hr His Thr Gly Thr Arg Pro Tyr Lys Cys Asn Asp Cys Asn Met33la Phe Val Thr Ser Gly Glu LeuVal Arg His Arg Arg Tyr Lys His 325 33r His Glu Lys Pro Phe Lys Cys Ser Met Cys Lys Tyr Ala SerVal 345a Ser Lys Leu Lys Arg His Val Arg Ser His Thr Gly Glu Arg 355 36o Phe Gln Cys Cys GlnCys Ser Tyr Ala Ser Arg Asp Thr Tyr Lys 378s Arg His Met Arg Thr His Ser Glu Ala Thr Ser LysArg Ser385 39ln Glu Ile Pro Arg Cys Lys Phe His Pro Asp Cys Leu Gln Met 44ln Val Trp Gln ArgLeu Phe Pro Leu Asp 42332PRTHomo sapiens 3a Ala Thr Glu Ile Ser Val Leu Ser Glu Gln Phe ThrLys Ilelu Leu Glu Leu Met Pro Glu Lys Gly Leu Lys Glu Glu Glu Lys 2Asp Gly Val Cys Arg Glu LysAsp His Arg Ser Pro Ser Glu Leu Glu 35 4 Glu Arg Thr Ser Gly Ala Phe Gln Asp Ser Val Leu GluGlu Glu 5Val Glu Leu Val Leu Ala Pro Ser Glu Glu Ser Glu Lys Tyr Ile Leu65 7Thr Leu Gln Thr ValHis Phe Thr Ser Glu Ala Val Glu Leu Gln Asp 85 9 Ser Leu Leu Ser Ile Gln Gln Gln Glu Gly Val GlnVal Val Val Gln Pro Gly Pro Gly Leu Leu Trp Leu Glu Glu Gly Pro Arg Gln Leu Gln Gln Cys Val AlaIle Ser Ile Gln Gln Glu Leu Tyr Ser Gln Glu Met Glu Val Leu Gln Phe His Ala Leu Glu Glu Asn ValMet Val Ala Ser Glu Asp Ser Lys Leu Ala Val Ser Leu Ala Glu Thr Gly Leu Ile Lys Leu Glu Glu GluGln Glu Lys Asn Gln Leu Leu Glu Arg Thr Lys Glu Gln Leu Phe Phe Val Glu Thr Met Ser Gly 2luArg Ser Asp Glu Ile Val Leu Thr Val Ser Asn Ser Asn Val 222u Gln Glu Asp Gln Pro Thr Ala GlyGln Ala Asp Ala Glu Lys225 234s Ser Thr Lys Asn Gln Arg Lys Thr Lys Gly Ala Lys Gly Thr 24525e His Cys Asp Val Cys Met Phe Thr Ser Ser Arg Met Ser Ser Phe 267g His Met Lys Thr His ThrSer Glu Lys Pro His Leu Cys His 275 28u Cys Leu Leu Gly Ser Ser Asp Ser His Ala Ser Val Ser GlyAla 29le Thr Asp Ala Arg His His Ala Trp Leu Ile Val Leu Leu Phe33eu Val Glu Met Gly Phe TyrHis Val Ser His Ser 325 33RTHomo sapiens 32Met Ala Ala Thr Glu Ile Ser Val Leu Ser Glu Gln PheThr Lys Ilelu Leu Glu Leu Met Pro Glu Lys Gly Leu Lys Glu Glu Glu Lys 2Asp Gly Val Cys Arg GluLys Asp His Arg Ser Pro Ser Glu Leu Glu 35 4 Glu Arg Thr Ser Gly Ala Phe Gln Asp Ser Val LeuGlu Glu Glu 5Val Glu Leu Val Leu Ala Pro Ser Glu Glu Ser Glu Lys Tyr Ile Leu65 7Thr Leu Gln ThrVal His Phe Thr Ser Glu Ala Val Glu Leu Gln Asp 85 9 Ser Leu Leu Ser Ile Gln Gln Gln Glu Gly ValGln Val Val Val Gln Pro Gly Pro Gly Leu Leu Trp Leu Glu Glu Gly Pro Arg Gln Leu Gln Gln Cys ValAla Ile Ser Ile Gln Gln Glu Leu Tyr Ser Gln Glu Met Glu Val Leu Gln Phe His Ala Leu Glu Glu AsnVal Met Val Ala Ser Glu Asp Ser Lys Leu Ala Val Ser Leu Ala Glu Thr Gly Leu Ile Lys Leu Glu GluGlu Gln Glu Lys Asn Gln Leu Leu Glu Arg Thr Lys Glu Gln Leu Phe Phe Val Glu Thr Met Ser Gly2lu Arg Ser Asp Glu Ile Val Leu Thr Val Ser Asn Ser Asn Val 222u Gln Glu Asp Gln Pro Thr Ala GlyGln Ala Asp Ala Glu Lys225 234s Ser Thr Lys Asn Gln Arg Lys Thr Lys Gly Ala Lys Gly Thr 24525e His Cys Asp Val Cys Met Phe Thr Ser Ser Arg Met Ser Ser Phe 267g His Met Lys Thr His ThrSer Glu Lys Pro His Leu Cys His 275 28u Cys Leu Lys Thr Phe Arg Thr Val Thr Leu Leu Arg AsnHis Val 29hr His Thr Gly Thr Arg Pro Tyr Lys Cys Asn Asp Cys Asn Met33la Phe Val Thr Ser GlyGlu Leu Val Arg His Arg Arg Tyr Lys His 325 33r His Glu Lys Pro Phe Lys Cys Ser Met Cys Lys TyrAla Ser Val 345a Ser Lys Leu Lys Arg His Val Arg Ser His Thr Gly Glu Arg 355 36o Phe Gln CysCys Gln Cys Ser Tyr Ala Ser Arg Asp Thr Tyr Lys 378s Arg His Met Arg Thr His Ser Gly Glu LysPro Tyr Glu Cys385 39le Cys His Thr Arg Phe Thr Gln Ser Gly Thr Met Lys Ile His 44eu Gln Lys HisGly Glu Asn Val Pro Lys Tyr Gln Cys Pro His 423a Thr Ile Ile Ala Arg Lys Ser Asp Leu Arg Val HisMet Arg 435 44n Leu His Ala Tyr Ser Ala Ala Glu Leu Lys Cys Arg Tyr Cys Ser 456l Phe His GluArg Tyr Ala Leu Ile Gln His Gln Lys Thr His465 478n Glu Lys Arg Phe Lys Cys Lys His Cys Ser TyrAla Cys Lys 485 49n Glu Arg His Met Thr Ala His Ile Arg Thr His Thr Gly Glu Lys 55he Thr CysLeu Ser Cys Asn Lys Cys Phe Arg Gln Lys Gln Leu 5525Leu Asn Ala His Phe Arg Lys Tyr His AspAla Asn Phe Ile Pro Thr 534r Lys Cys Ser Lys Cys Gly Lys Gly Phe Ser Arg Trp Ile Leu545 556l GlyAsn Ser Glu Val Ala Glu Leu Gly Gly Pro Gly Ser Gly 565 57o Leu Leu Arg Leu Gln Ser Gly CysPro Pro Gly Leu His His Pro 589a Gly Leu Gly Pro Glu Asp Pro Leu Pro Gly Gln Leu Arg His 595


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6hr Thr Ala Gly Thr Gly Leu Ser Ser Leu Leu Gln Gly Pro Leu Cys 662a Ala62533573PRTHomosapiens 33Met Ala Ala Thr Glu Ile Ser Val Leu Ser Glu Gln Phe Thr Lys Ilelu Leu Glu Leu Met ProGlu Lys Gly Leu Lys Glu Glu Glu Lys 2Asp Gly Val Cys Arg Glu Lys Asp His Arg Ser Pro Ser GluLeu Glu 35 4 Glu Arg Thr Ser Gly Ala Phe Gln Asp Ser Val Leu Glu Glu Glu 5Val Glu Leu Val LeuAla Pro Ser Glu Glu Ser Glu Lys Tyr Ile Leu65 7Thr Leu Gln Thr Val His Phe Thr Ser Glu Ala ValGlu Leu Gln Asp 85 9 Ser Leu Leu Ser Ile Gln Gln Gln Glu Gly Val Gln Val Val Val Gln Pro Gly ProGly Leu Leu Trp Leu Glu Glu Gly Pro Arg Gln Leu Gln Gln Cys Val Ala Ile Ser Ile Gln Gln Glu LeuTyr Ser Gln Glu Met Glu Val Leu Gln Phe His Ala Leu Glu Glu Asn Val Met Val Ala Ser Glu Asp SerLys Leu Ala Val Ser Leu Ala Glu Thr Gly Leu Ile Lys Leu Glu Glu Glu Gln Glu Lys Asn Gln LeuLeu Glu Arg Thr Lys Glu Gln Leu Phe Phe Val Glu Thr Met Ser Gly 2lu Arg Ser Asp Glu Ile Val LeuThr Val Ser Asn Ser Asn Val 222u Gln Glu Asp Gln Pro Thr Ala Gly Gln Ala Asp Ala Glu Lys225234s Ser Thr Lys Asn Gln Arg Lys Thr Lys Gly Ala Lys Gly Thr 245 25e His Cys Asp Val Cys MetPhe Thr Ser Ser Arg Met Ser Ser Phe 267g His Met Lys Thr His Thr Ser Glu Lys Pro His Leu Cys His275 28u Cys Leu Lys Thr Phe Arg Thr Val Thr Leu Leu Arg Asn His Val 29hr His Thr Gly Thr ArgPro Tyr Lys Cys Asn Asp Cys Asn Met33la Phe Val Thr Ser Gly Glu Leu Val Arg His Arg Arg TyrLys His 325

33r His Glu Lys Pro Phe Lys Cys Ser Met Cys Lys Tyr Ala Ser Val 345a Ser Lys Leu Lys Arg His ValArg Ser His Thr Gly Glu Arg 355 36o Phe Gln Cys Cys Gln Cys Ser Tyr Ala Ser Arg Asp Thr TyrLys 378s Arg His Met Arg Thr His Ser Gly Glu Lys Pro Tyr Glu Cys385 39le Cys His Thr Arg PheThr Gln Ser Gly Thr Met Lys Ile His 44eu Gln Lys His Gly Glu Asn Val Pro Lys Tyr Gln Cys Pro His423a Thr Ile Ile Ala Arg Lys Ser Asp Leu Arg Val His Met Arg 435 44n Leu His Ala Tyr Ser Ala AlaGlu Leu Lys Cys Arg Tyr Cys Ser 456l Phe His Glu Arg Tyr Ala Leu Ile Gln His Gln Lys Thr His465478n Glu Lys Arg Phe Lys Cys Lys His Cys Ser Tyr Ala Cys Lys 485 49n Glu Arg His Met Thr AlaHis Ile Arg Thr His Thr Gly Glu Lys 55he Thr Cys Leu Ser Cys Asn Lys Cys Phe Arg Gln Lys GlnLeu 5525Leu Asn Ala His Phe Arg Lys Tyr His Asp Ala Asn Phe Ile Pro Thr 534r Lys Cys Ser LysCys Gly Lys Gly Phe Ser Arg Trp Ile Thr545 556s Trp Ser Gly Leu Lys Pro Gln Thr Phe Ile Thr 56557RTHomo sapiens 34Met Ser Gly Asp Glu Arg Ser Asp Glu Ile Val Leu Thr Val Ser Asnsn Val GluGlu Gln Glu Asp Gln Pro Thr Ala Gly Gln Ala Asp 2Ala Glu Lys Ala Lys Ser Thr Lys Asn Gln ArgLys Thr Lys Gly Ala 35 4 Gly Thr Phe His Cys Asp Val Cys Met Phe Thr Ser Ser Arg Met 5Ser SerPhe Asn Arg His Met Lys Thr His Thr Ser Glu Lys Pro His65 7Leu Cys His Leu Cys Leu Lys Thr PheArg Thr Val Thr Leu Leu Arg 85 9 His Val Asn Thr His Thr Gly Thr Arg Pro Tyr Lys Cys Asn AspAsn Met Ala Phe Val Thr Ser Gly Glu Leu Val Arg His Arg Arg Lys His Thr His Glu Lys Pro Phe LysCys Ser Met Cys Lys Tyr Ser Val Glu Ala Ser Lys Leu Lys Arg His Val Arg Ser His Thr Gly Glu ArgPro Phe Gln Cys Cys Gln Cys Ser Tyr Ala Ser Arg Asp Tyr Lys Leu Lys Arg His Met Arg Thr His SerGly Glu Lys Pro Glu Cys His Ile Cys His Thr Arg Phe Thr Gln Ser Gly Thr Met 2le His Ile Leu GlnLys His Gly Glu Asn Val Pro Lys Tyr Gln 222o His Cys Ala Thr Ile Ile Ala Arg Lys Ser Asp Leu ArgVal225 234t Arg Asn Leu His Ala Tyr Ser Ala Ala Glu Leu Lys Cys Arg 245 25r Cys Ser Ala Val PheHis Glu Arg Tyr Ala Leu Ile Gln His Gln 267r His Lys Asn Glu Lys Arg Phe Lys Cys Lys His Cys SerTyr 275 28a Cys Lys Gln Glu Arg His Met Thr Ala His Ile Arg Thr His Thr 29lu Lys Pro Phe Thr CysLeu Ser Cys Asn Lys Cys Phe Arg Gln33ys Gln Leu Leu Asn Ala His Phe Arg Lys Tyr His Asp AlaAsn Phe 325 33e Pro Thr Val Tyr Lys Cys Ser Lys Cys Gly Lys Gly Phe Ser Arg 345e Leu Trp ValGly Asn Ser Glu Val Ala Glu Leu Gly Gly Pro 355 36y Ser Gly Pro Leu Leu Arg Leu Gln Ser GlyCys Pro Pro Gly Leu 378s Pro Lys Ala Gly Leu Gly Pro Glu Asp Pro Leu Pro Gly Gln385 39rg HisThr Thr Ala Gly Thr Gly Leu Ser Ser Leu Leu Gln Gly 44eu Cys Arg Ala Ala 42RTHomo sapiens


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35Met Phe Thr Ser Ser Arg Met Ser Ser Phe Asn Arg His Met Lys Thrhr Ser Glu Lys Pro His LeuCys His Leu Cys Leu Lys Thr Phe 2Arg Thr Val Thr Leu Leu Arg Asn His Val Asn Thr His Thr GlyThr 35 4 Pro Tyr Lys Cys Asn Asp Cys Asn Met Ala Phe Val Thr Ser Gly 5Glu Leu Val Arg His ArgArg Tyr Lys His Thr His Glu Lys Pro Phe65 7Lys Cys Ser Met Cys Lys Tyr Ala Ser Val Glu Ala SerLys Leu Lys 85 9 His Val Arg Ser His Thr Gly Glu Arg Pro Phe Gln Cys Cys Gln Ser Tyr Ala Ser ArgAsp Thr Tyr Lys Leu Lys Arg His Met Arg His Ser Gly Glu Lys Pro Tyr Glu Cys His Ile Cys His ThrArg Thr Gln Ser Gly Thr Met Lys Ile His Ile Leu Gln Lys His Gly Glu Asn Val Pro Lys Tyr Gln CysPro His Cys Ala Thr Ile Ile Ala Lys Ser Asp Leu Arg Val His Met Arg Asn Leu His Ala Tyr Ser AlaGlu Leu Lys Cys Arg Tyr Cys Ser Ala Val Phe His Glu Arg 2la Leu Ile Gln His Gln Lys Thr His LysAsn Glu Lys Arg Phe 222s Lys His Cys Ser Tyr Ala Cys Lys Gln Glu Arg His Met Thr225 234s IleArg Thr His Thr Gly Glu Lys Pro Phe Thr Cys Leu Ser 245 25s Asn Lys Cys Phe Arg Gln Lys GlnLeu Leu Asn Ala His Phe Arg 267r His Asp Ala Asn Phe Ile Pro Thr Val Tyr Lys Cys Ser Lys 275 28sGly Lys Gly Phe Ser Arg Trp Val Leu Tyr 29275PRTHomo sapiens 36Met Ala Ala Thr Glu Ile SerVal Leu Ser Glu Gln Phe Thr Lys Ilelu Leu Glu Leu Met Pro Glu Lys Gly Leu Lys Glu Glu Glu Lys2Asp Gly Val Cys Arg Glu Lys Asp His Arg Ser Pro Ser Glu Leu Glu 35 4 Glu Arg Thr Ser Gly AlaPhe Gln Asp Ser Val Leu Glu Glu Glu 5Val Glu Leu Val Leu Ala Pro Ser Glu Glu Ser Glu Lys Tyr IleLeu65 7Thr Leu Gln Thr Val His Phe Thr Ser Glu Ala Val Glu Leu Gln Asp 85 9 Ser Leu Leu Ser IleGln Gln Gln Glu Gly Val Gln Val Val Val Gln Pro Gly Pro Gly Leu Leu Trp Leu Glu Glu Gly Pro ArgGln Leu Gln Gln Cys Val Ala Ile Ser Ile Gln Gln Glu Leu Tyr Ser Gln Glu Met Glu Val Leu Gln PheHis Ala Leu Glu Glu Asn Val Met Val Ala Ser Glu Asp Ser Lys Leu Ala Val Ser Leu Ala Glu Thr GlyLeu Ile Lys Leu Glu Glu Glu Gln Glu Lys Asn Gln Leu Leu Glu Arg Thr Lys Glu Gln Leu Phe PheVal Glu Thr Met Ser Gly 2lu Arg Ser Asp Glu Ile Val Leu Thr Val Ser Asn Ser Asn Val 222u Gln GluAsp Gln Pro Thr Ala Gly Gln Ala Asp Ala Glu Lys225 234s Ser Thr Lys Asn Gln Arg Lys Thr LysGly Ala Lys Glu Pro 245 25r Thr Val Met Ser Ala Cys Ser Pro Leu Leu Glu Cys Gln Val Leu 267l Ile27537omo sapiens 37Met Phe Thr Ser Ser Arg Met Ser Ser Phe Asn Arg His Met Lys Thrhr Ser GluLys Pro His Leu Cys His Leu Cys Leu Lys Thr Phe 2Arg Thr Val Thr Leu Leu Arg Asn His Val AsnThr His Thr Gly Thr 35 4 Pro Tyr Lys Cys Asn Asp Cys Asn Met Ala Phe Val Thr Ser Gly 5Glu LeuVal Arg His Arg Arg Tyr Lys His Thr His Glu Lys Pro Phe65 7Lys Cys Ser Met Cys Lys Tyr Ala SerVal Glu Ala Ser Lys Leu Lys 85 9 His Val Arg Ser His Thr Gly Glu Arg Pro Phe Gln Cys Cys Gln SerTyr Ala Ser Arg Asp Thr Tyr Lys Leu Lys Arg His Met Arg His Ser Gly Lys Gly Ser Gly Ala Glu GlyLeu Ile Pro Thr Val Thr Leu Lys Ala Ser Phe Lys Lys Leu Leu Phe Ile Gly Thr Ile Lys Val GlnArg38426PRTHomo sapiens 38Met Ala Ala Thr Glu Ile Ser Val Leu Ser Glu Gln Phe Thr Lys IleluLeu Glu Leu Met Pro Glu Lys Gly Leu Lys Glu Glu Glu Lys 2Asp Gly Val Cys Arg Glu Lys Asp HisArg Ser Pro Ser Glu Leu Glu 35 4 Glu Arg Thr Ser Gly Ala Phe Gln Asp Ser Val Leu Glu Glu Glu5Val Glu Leu Val Leu Ala Pro Ser Glu Glu Ser Glu Lys Tyr Ile Leu65 7Thr Leu Gln Thr Val His PheThr Ser Glu Ala Val Glu Leu Gln Asp 85 9 Ser Leu Leu Ser Ile Gln Gln Gln Glu Gly Val Gln Val ValVal Gln Pro Gly Pro Gly Leu Leu Trp Leu Glu Glu Gly Pro Arg Gln Leu Gln Gln Cys Val Ala Ile SerIle Gln Gln Glu Leu Tyr Ser Gln Glu Met Glu Val Leu Gln Phe His Ala Leu Glu Glu Asn Val Met ValAla Ser Glu Asp Ser Lys Leu Ala Val Ser Leu Ala Glu Thr Gly Leu Ile Lys Leu Glu Glu Glu Gln GluLys Asn Gln Leu Leu Glu Arg Thr Lys Glu Gln Leu Phe Phe Val Glu Thr Met Ser Gly 2lu Arg SerAsp Glu Ile Val Leu Thr Val Ser Asn Ser Asn Val 222u Gln Glu Asp Gln Pro Thr Ala Gly Gln AlaAsp Ala Glu Lys225 234s Ser Thr Lys Asn Gln Arg Lys Thr Lys Gly Ala Lys Gly Thr 245 25e HisCys Asp Val Cys Met Phe Thr Ser Ser Arg Met Ser Ser Phe 267g His Met Lys Thr His Thr Ser GluLys Pro His Leu Cys His 275 28u Cys Leu Lys Thr Phe Arg Thr Val Thr Leu Leu Arg Asn His Val29hr His Thr Gly Thr Arg Pro Tyr Lys Cys Asn Asp Cys Asn Met33la Phe Val Thr Ser Gly Glu Leu


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Val Arg His Arg Arg Tyr Lys His 325 33r His Glu Lys Pro Phe Lys Cys Ser Met Cys Lys Tyr Ala SerVal 345a Ser Lys Leu Lys Arg His Val Arg Ser His Thr Gly Glu Arg 355 36o Phe Gln Cys Cys GlnCys Ser Tyr Ala Ser Arg Asp Thr Tyr Lys 378s Arg His Met Arg Thr His Ser Gly Lys Gly Ser GlyAla Glu385 39eu Ile Pro Thr Val Leu Thr Leu Lys Ala Ser Phe Lys Lys Leu 44he Ile Gly Thr Ile LysVal Gln Arg 4245o sapiens 39Met Ala Ala Thr Glu Ile Ser Val Leu Ser Glu Gln Phe Thr Lys Ilelu LeuGlu Leu Met Pro Glu Lys Gly Leu Lys Glu Glu Glu Lys 2Asp Gly Val Cys Arg Glu Lys Asp His ArgSer Pro Ser Glu Leu Glu 35 4 Glu Arg Thr Ser Gly Ala Phe Gln Asp Ser Val Leu Glu Glu Glu 5ValGlu Leu Val Leu Ala Pro Ser Glu Glu Ser Glu Lys Tyr Ile Leu65 7Thr Leu Gln Thr Val His Phe ThrSer Glu Ala Val Glu Leu Gln Asp 85 9 Ser Leu Leu Ser Ile Gln Gln Gln Glu Gly Val Gln Val Val ValGln Pro Gly Pro Gly Leu Leu Trp Leu Glu Glu Gly Pro Arg Gln Leu Gln Gln Cys Val Ala Ile Ser IleGln Gln Glu Leu Tyr Ser Gln Glu Met Glu Val Leu Gln Phe His Ala Leu Glu Glu Asn Val Met ValAla Ser Glu Asp Ser Lys Leu Ala Val Ser Leu Ala Glu Thr Gly Leu Ile Lys Leu Glu Glu Glu Gln GluLys Asn Gln Leu Leu Glu Arg Thr Lys Glu Gln Leu Phe Phe Val Glu Thr Met Ser Gly 2lu Arg SerAsp Glu Ile Val Leu Thr Val Ser Asn Ser Asn Val 222u Gln Glu Asp Gln Pro Thr Ala Gly Gln AlaAsp Ala Glu Lys225 234s Ser Thr Lys Asn Gln Arg Lys Thr Lys Gly Ala Lys Gly Thr 245 25e HisCys Asp Val Cys Met Phe Thr Ser Ser Arg Met Ser Ser Phe 267g His Met Lys Thr His Thr Ser GluLys Pro His Leu Cys His 275 28u Cys Leu Lys Thr Phe Arg Thr Val Thr Leu Leu Arg Asn His Val29hr His Thr Gly Thr Arg Pro Tyr Lys Cys Asn Asp Cys Asn Met33la Phe Val Thr Ser Gly Glu LeuVal Arg His Arg Arg Tyr Lys His 325 33r His Glu Lys Pro Phe Lys Cys Ser Met Cys Lys Tyr Ala SerVal 345a Ser Lys Leu Lys Arg His Val Arg Ser His Thr Gly Glu Arg 355 36o Phe Gln Cys Cys GlnCys Ser Tyr Ala Ser Arg Asp Thr Tyr Lys 378s Arg His Met Arg Thr His Ser Gly Glu Lys Pro TyrGlu Cys385 39le Cys His Thr Arg Phe Thr Gln Ser Gly Thr Met Lys Ile His 44eu Gln Lys His GlyGlu Asn Val Pro Lys Tyr Gln Cys Pro His 423a Thr Ile Ile Ala Arg Lys Ser Asp Leu Arg Phe Leu GlyLeu 435 44o Phe Pro 45RTHomo sapiens 4s Cys Ser Lys Cys Gly Lys Gly Phe Ser Arg Trp Ile AsnLeurg His Ser Glu Lys Cys Gly Ser Gly Glu Ala Lys Ser Ala Ala 2Ser Gly Lys Gly Arg Arg Thr ArgLys Arg Lys Gln Thr Ile Leu Lys 35 4 Ala Thr Lys Gly Gln Lys Glu Ala Ala Lys Gly Trp Lys Glu Ala5Ala Asn Gly Asp Glu Ala Ala Ala Glu Glu Ala Ser Thr Thr Lys Gly65 7Glu Gln Phe Pro Gly GluMet Phe Pro Val Ala Cys Arg Glu Thr Thr 85 9 Arg Val Lys Glu Glu Val Asp Glu Gly Val Thr CysGlu Met Leu Asn Thr Met Asp Lys His Leu Ala Gln Met Leu Asp Leu Tyr Gln Leu Ser Trp Ile PheLeu Trp Gly Glu Cys Tyr Tyr Lys Ser Tyr 454Homo sapiens 4r Val Tyr Lys Cys Ser Lys Cys Gly LysGly Phe Ser Arg Trpsn Leu His Arg His Ser Glu Lys Cys Gly Ser Gly Glu Ala Lys 2R>3a Ala Ser Gly Lys Gly Arg Arg Thr Arg Lys Arg Lys Gln Thr 35 4 Leu Lys Glu Ala Thr Lys Gly GlnLys Glu Ala Ala Lys Gly Trp 5Lys Glu Ala Ala Asn Gly Asp Asp Ile Leu His Arg Cys Trp Ile Cys657Ile Lys Val Cys His Gly Phe Ser Phe Gly Glu Ser Ala Ile Ile Asn 85 9 Thr Val Ser His Cys Ser ThrLeu Ser Ser Ile Glu Thr Ala Pro Gln Val Arg Ala Val Arg Ala Leu Gly Asp Ser Val Pro Arg3PRTHomo sapiens 42Met Ala Ala Thr Glu Ile Ser Val Leu Ser Glu Gln Phe Thr Lys Ilelu Leu GluLeu Met Pro Glu Lys Gly Leu Lys Glu Glu Glu Lys 2Asp Gly Val Cys Arg Glu Lys Asp His Arg SerPro Ser Glu Leu Glu 35 4 Glu Arg Thr Ser Gly Ala Phe Gln Asp Ser Val Leu Glu Glu Glu 5Val GluLeu Val Leu Ala Pro Ser Glu Glu Ser Glu Lys Tyr Ile Leu65 7Thr Leu Gln Thr Val His Phe Thr SerGlu Ala Val Glu Leu Gln Asp 85 9 Ser Leu Leu Ser Ile Gln Gln Gln Glu Gly Val Gln Val Val Val GlnPro Gly Pro Gly Leu Leu Trp Leu Glu Glu Gly Pro Arg Gln Leu Gln Gln Cys Val Ala Ile Ser Ile GlnGln Glu Leu Tyr Ser Gln Glu Met Glu Val Leu Gln Phe His Ala Leu Glu Glu Asn Val Met Val AlaSer Glu Asp Ser Lys Leu Ala Val Ser Leu Ala Glu Thr Gly Leu Ile Lys Leu Glu Glu Glu Gln Glu LysAsn Gln Leu Leu Glu Arg Thr Lys Glu Gln Leu Phe Phe Val Glu Thr Met Ser Gly 2lu Arg Ser AspGlu Ile Val Leu Thr Val Ser Asn Ser Asn Val 222u Gln Glu Asp Gln Pro Thr Ala Gly Gln Ala Asp


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Ala Glu Lys225 234s Ser Thr Lys Asn Gln Arg Lys Thr Lys Gly Ala Lys Gly Thr 245 25e His CysAsp Val Cys Met Phe Thr Ser Ser Arg Met Ser Ser Phe 267g His Met Lys Thr His Thr Ser Glu LysPro His Leu Cys His 275 28u Cys Leu Lys Thr Phe Arg Thr Val Thr Leu Leu Arg Asn His Val 29hrHis Thr Gly Thr Arg Pro Tyr Lys Cys Asn Asp Cys Asn Met33la Phe Val Thr Ser Gly Glu Leu ValArg His Arg Arg Tyr Lys His 325 33r His Glu Lys Pro Phe Lys Cys Ser Met Cys Lys Tyr Ala Ser Val345a Ser Lys Leu Lys Arg His Val Arg Ser His Thr Gly Glu Arg 355 36o Phe Gln Cys Cys Gln CysSer Tyr Ala Ser Arg Asp Thr Tyr Lys 378s Arg His Met Arg Thr His Ser Gly Val His Met Arg AsnLeu385 39la Tyr Ser Ala Ala Glu Leu Lys Cys Arg Tyr Cys Ser Ala Val 44is Glu Arg Tyr Ala Leu IleGln His Gln Lys Thr His Lys Asn 423s Arg Phe Lys Cys Lys His Cys Ser Tyr Ala Cys Lys Gln Glu435 44g His Met Thr Ala His Ile Arg Thr His Thr Gly Glu Lys Pro Phe 456s Leu Ser Cys Asn LysCys Phe Arg Gln Lys Gln Leu Leu Asn465 478s Phe Arg Lys Tyr His Asp Ala Asn Phe Ile Pro ThrVal Tyr 485 49s Cys Ser Lys Cys Gly Lys Gly Phe Ser Arg Trp Ile Asn Leu His 55is Ser Glu Lys CysGly Ser Gly Glu Ala Lys Ser Ala Ala Ser 5525Gly Lys Gly Arg Arg Thr Arg Lys Arg Lys Gln Thr IleLeu Lys Glu 534r Lys Gly Gln Lys Glu Ala Ala Lys Gly Trp Lys Glu Ala Ala545 556y Asp Glu AlaAla Ala Glu Glu Ala Ser Thr Thr Lys Gly Glu 565 57n Phe Pro Gly Glu Met Phe Pro Val Ala Cys ArgGlu Thr Thr Ala 589l Lys Glu Glu Val Asp Glu Gly Val Thr Cys Glu Met Leu Leu 595 6sn Thr MetAsp Lys 6PRTHomo sapiens 43Met Ala Ala Thr Glu Ile Ser Val Leu Ser Glu Gln Phe Thr Lys IleluLeu Glu Leu Met Pro Glu Lys Gly Leu Lys Glu Glu Glu Lys 2Asp Gly Val Cys Arg Glu Lys Asp HisArg Ser Pro Ser Glu Leu Glu 35 4 Glu Arg Thr Ser Gly Ala Phe Gln Asp Ser Val Leu Glu Glu Glu5Val Glu Leu Val Leu Ala Pro Ser Glu Glu Ser Glu Lys Tyr Ile Leu65 7Thr Leu Gln Thr Val His PheThr Ser Glu Ala Val Glu Leu Gln Asp 85 9 Ser Leu Leu Ser Ile Gln Gln Gln Glu Gly Val Gln Val ValVal Gln Pro Gly Pro Gly Leu Leu Trp Leu Glu Glu Gly Pro Arg Gln Leu Gln Gln Cys Val Ala Ile SerIle Gln Gln Glu Leu Tyr Ser Gln Glu Met Glu Val Leu Gln Phe His Ala Leu Glu Glu Asn Val Met ValAla Ser Glu Asp Ser Lys Leu Ala Val Ser Leu Ala Glu Thr Gly Leu Ile Lys Leu Glu Glu Glu Gln GluLys Asn Gln Leu Leu Glu Arg Thr Lys Glu Gln Leu Phe Phe Val Glu Thr Met Ser Gly 2lu Arg SerAsp Glu Ile Val Leu Thr Val Ser Asn Ser Asn Val 222u Gln Glu Asp Gln Pro Thr Ala Gly Gln AlaAsp Ala Glu Lys225 234s Ser Thr Lys Asn Gln Arg Lys Thr Lys Gly Ala Lys Gly Thr 245 25e HisCys Asp Val Cys Met Phe Thr Ser Ser Arg Met Ser Ser Phe 267g His Met Lys Thr His Thr Ser GluLys Pro His Leu Cys His 275 28u Cys Leu Lys Thr Phe Arg Thr Val Thr Leu Leu Arg Asn His Val29hr His Thr Gly Thr Arg Pro Tyr Lys Cys Asn Asp Cys Asn Met33la Phe Val Thr Ser Gly Glu LeuVal Arg His Arg Arg Tyr Lys His 325 33r His Glu Lys Pro Phe Lys Cys Ser Met Cys Lys Tyr Ala SerVal 345a Ser Lys Leu Lys Arg His Val Arg Ser His Thr Gly Glu Arg 355 36o Phe Gln Cys Cys GlnCys Ser Tyr Ala Ser Arg Asp Thr Tyr Lys 378s Arg His Met Arg Thr His Ser Gly Glu Lys Pro TyrGlu Cys385 39le Cys His Thr Arg Phe Thr Gln Ser Gly Thr Met Lys Ile His 44eu Gln Lys His GlyGlu Asn Val Pro Lys Tyr Gln Cys Pro His 423a Thr Ile Ile Ala Arg Lys Ser Asp Leu Arg Val His MetArg 435 44n Leu His Ala Tyr Ser Ala Ala Glu Leu Lys Cys Arg Tyr Cys Ser 456l Phe His Glu ArgTyr Ala Leu Ile Gln His Gln Lys Thr His465 478n Glu Lys Arg Phe Lys Cys Lys His Cys Ser Tyr AlaCys Lys 485 49n Glu Arg His Met Thr Ala His Ile Arg Thr His Thr Gly Glu Lys 55he Thr Cys LeuSer Cys Asn Lys Cys Phe Arg Gln Lys Gln Leu 5525Leu Asn Ala His Phe Arg Lys Tyr His Asp AlaAsn Phe Ile Pro Thr 534r Lys Cys Ser Lys Cys Gly Lys Gly Phe Ser Arg Trp Ile Asn545 556s Arg HisSer Glu Lys Cys Gly Ser Gly Glu Ala Lys Ser Ala 565 57a Ser Gly Lys Gly Arg Arg Thr Arg Lys ArgLys Gln Thr Ile Leu 589u Ala Thr Lys Gly Gln Lys Glu Ala Ala Lys Gly Trp Lys Glu 595 6la Ala AsnGly Asp Glu Ala Ala Ala Glu Glu Ala Ser Thr Thr Lys 662u Gln Phe Pro Gly Glu Met Phe Pro ValAla Cys Arg Glu Thr625 634a Arg Val Lys Glu Glu Val Asp Glu Gly Val Thr Cys Glu Met 645 65uLeu Asn Thr Met Asp Lys 66DNAHomo sapiens 44ggcaccagac gcggtgcacg aggcagagcc acaagccaaa


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gacggagtgg gccgagcatt 6acgc cttccgcggc caagtcatta tggcagccac tgagatctct gtcctttctg attcac caagatcaaagaactcgagt tgatgccgga aaaaggcctg aaggaggagg agacgg agtgtgcaga gagaaagacc atcggagccc tagtgagttggaggccgagc 24ctgg ggccttccag gacagcgtcc tggaggaaga agtggagctg gtgctggccc 3gagga gagcgagaagtacatcctga ccctgcagac ggtgcacttc acttctgaag 36agtt gcaggatatg agcttgctga gcatacagca gcaagaaggggtgcaggtgg 42aaca gcctggccct gggttgctgt ggcttgagga agggccccgg cagagcctgc 48gtgt ggccattagtatccagcaag agctgtactc cccgcaagag atggaggtgt 54tcca cgctctagag gagaatgtga tggtggccag tgaagacagtaagttagcgg 6ctggc tgaaactgct ggactgatca agctcgagga agagcaggag aagaaccagt 66ctga aagaacaaaggagcagctct tttttgtgga aacaatgtca ggagatgaaa 72acga aattgttctc acagtttcaa attcaaatgt ggaagaacaagaggatcaac 78ctgg tcaagcagat gctgaaaagg ccaaatctac aaaaaatcaa agaaagacaa 84caaa aggaaccttccactgtgatg tctgcatgtt cacctcttct agaatgtcaa 9aatcg tcatatgaaa actcacacca gtgagaagcc tcacctgtgtcacctctgcc 96cctt ccgtacggtc actctgctgc ggaaccatgt taacacccac acaggaacca cctacaa gtgtaacgactgcaacatgg catttgtcac cagtggagaa ctcgtccgac ggcgcta taaacatact catgagaaac cctttaaatg ttccatgtgcaagtatgcca tggaggc aagtaaattg aagcgccatg tccgatccca cactggggag cgcccctttc gttgcca gtgcagctatgccagcagag atacctacaa gctgaaacgc cacatgagaa actcagg tgagaagcct tacgaatgcc acatctgcca cacccgcttcacccagagcg ccatgaa aatacatatt ctgcagaaac acggcgaaaa tgtccccaaa taccagtgtc attgtgc caccatcattgcacggaaaa gcgacctacg tgtgcatatg cgcaacttgc cttacag cgctgcagag ctgaaatgcc gctactgttc tgctgtcttccatgaacgct ccctcat tcagcaccag aaaactcata agaatgagaa gaggttcaag tgcaaacact gttatgc ctgcaagcaggaacgtcata tgaccgctca cattcgtacc cacactggag aaccatt cacctgcctt tcttgcaata aatgtttccg acagaagcaacttctaaacg acttcag gaaataccac gatgcaaatt tcatcccgac tgtttacaaa tgctccaagt gcaaagg cttttcccgc tggattaacctgcacagaca ttcggagaag tgtggatcag aagcaaa gtcggctgct tcaggaaagg gaagaagaac aagaaagagg aagcagaccatgaagga agccacaaag ggtcagaagg aagctgcgaa gggatggaag gaagccgcga gagacga agctgctgct gaggaggcttccaccacgaa gggagaacag ttcccaggag tgtttcc tgtcgcctgc agagaaacca cagccagagt caaagaggaa gtggatgaag2gacctg tgaaatgctc ctcaacacga tggataagtg agagggattc gggttgcgtg 2ctgccc ccaattccta aagcaagttagaagttttta gcatttaagg tgtgaaatgc 2caacac gatggataag tgagagagag tcaggttgca tgttcactgc ccctaattcc222aagt tagaaatttt tagcattttc tttgaaacaa ttaagttcat gacaatggat 228agtt tgaggtagtg tctagaattg ttctcctgtttgtagctgga tatttcaaag 234tgca ggtattttat aaaagtttta aaccttgaat gagagggtaa cacctcaaac 24gattc attcacttgatattggcaag gtggcccaca atgagtgagt agtgattttt 246ttca aaatagtcta gaccagctag tgcttccaca gtcaaagctggacattttta 252atta tatacaccca tgatatttct aataatatat ggttttaaac attaaagaca 258ttta tacaaatgaa ttttctacaaaatttaaagc taccataatg cttttaatta 264aatt caaccaaaaa atgttttact cttataaaaa ggaaaactga gtaggaaatg 27ctagattagactaga aaataaggaa taaatcgatt ttactttggt ataggagcaa 276cctt tagatttttg tattctcttt taattatgct ccttggcaggtatgaaattg 282ttac attccattat tgcttattag tatttcactc cataaccctt ttttctgcta 288ctct ttttatattt gtaaaataattggcagagtg agaagaaaca taaaatcaga 294aaat gtgtacctgt aaggaatttg tactttttca taatgcccag tgattagtga 3ttcccttttgccagtt gacaagattt ttccaccctc gagcagcgtg agagatgcct 3aacact tgaaattcat ttctatctgg atacagaggcagatttttct tcattgctta 3agcagt ttgttttgct gccaacctgt ctccacccct gtatttcaag atcattgata 3ctaaat tcaaattcttaagatatgga ccttttattg aaaatatcac aagttcagaa 324taca atgtgaatat gtggaaataa tttcccagca ggaagagcattatattctct 33ccagc aaattaattt aactcaactc acatgagatt taaattctgt gggctgtagt 336tcat tgtgactgaa tttgtgcaatggtttcttaa tttttttact gttatttaaa 342ttac ataattcaat aaaatgaaat gacttaaaat tgcaaaaaaa aaaaaaaaaa 348aaaaaaaaaaaaaa 35RTHomo sapiens 45Cys Lys Tyr Ala Ser Val Glu Val Lys Pro Phe Leu Asp Leu LysLeuly Ile Leu Val Glu Ala Ala Val Gln Val Thr Pro Ser Val Thr 2Asn Ser Arg Ile 354622PRTHomosapiens 46Cys Tyr Lys Gln Ala Phe Tyr Tyr Ser Tyr Lys Ile Tyr Ile Gly Asnet His Ser Leu Leu2THomo sapiens 47Cys Leu Leu Gly Ser Ser Asp Ser His Ala Ser Val Ser Gly Ala Glyhr Asp AlaArg His His Ala 2THomo sapiens 48Cys Ile Thr Asp Ala Arg His His Ala Trp Leu Ile Val Leu LeuGlual Glu Met Gly Phe Tyr His Val Ser His Ser 27PRTHomo sapiens 49Cys Pro Pro Gly Leu His HisPro Lys Ala Gly Leu Gly Pro Glu Aspeu Pro Gly Gln Leu Arg His Thr Ala Gly 2o sapiens 5n LeuArg His Thr Thr Ala Gly Thr Gly Leu Ser Ser Leu Leuly Pro Leu Cys 2BR>


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51 of 51 8/2/13 4:48 PM

Date post:	22-Nov-2023
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