CA2302808C

CA2302808C - 50 human secreted proteins

Info

Publication number: CA2302808C
Application number: CA2302808A
Authority: CA
Inventors: Paul A. Moore; Steven M. Ruben; David W. Lafleur; Yanggu Shi; Craig A. Rosen; Henrik S. Olsen; Reinhard Ebner; Laurie A. Brewer
Original assignee: Human Genome Sciences Inc
Current assignee: Human Genome Sciences Inc
Priority date: 1997-09-05
Filing date: 1998-09-03
Publication date: 2010-05-18
Anticipated expiration: 2018-09-03
Also published as: JP2009131263A; EP1019091A4; CA2302808A1; JP2001514024A; EP1019091A1; WO1999011293A1; AU9130498A

Abstract

The present invention relates to novel human secreted proteins and isolated nucleic acids containing the coding regions of the genes encoding such proteins. Also provided are vectors, host cells, antibodies, and recombinant methods for producing human secreted proteins.
The invention further relates to diagnostic and therapeutic methods useful for diagnosing and treating disorders related to these novel human secreted proteins.

Description

50 Human Secreted Proteins Field of the Invention This invention relates to newly identified polynucleotides and the polypeptides encoded by these polynucleotides, uses of such polynucleotides and polypeptides, and their production.
Background of the Invention Unlike bacterium, which exist as a single compartment surrounded by a membrane, human cells and other eucaryotes are subdivided by membranes into many functionally distinct compartments. Each membrane-bounded compartment, or organelle, contains different proteins essential for the function of the organelle. The cell uses "sorting signals," which are amino acid motifs located within the protein, to target proteins to particular cellular organelles.
One type of sorting signal, called a signal sequence, a signal peptide, or a leader sequence, directs a class of proteins to an organelle called the endoplasmic reticulum (ER). The ER separates the membrane-bounded proteins from all other types of proteins. Once localized to the ER, both groups of proteins can be further directed to another organelle called the Golgi apparatus. Here, the Golgi distributes the proteins to vesicles, including secretory vesicles, the cell membrane, lysosomes, and the other organelles.
Proteins targeted to the ER by a signal sequence can be released into the extracellular space as a secreted protein. For example, vesicles containing secreted proteins can fuse with the cell membrane and release their contents into the extracellular space - a process called exocytosis. Exocytosis can occur constitutively or after receipt of a triggering signal. In the latter case, the proteins are stored in secretory vesicles (or secretory granules) until exocytosis is triggered. Similarly, proteins residing on the cell membrane can also be secreted into the extracellular space by proteolytic cleavage of a "linker" holding the protein to the membrane.
Despite the great progress made in recent years, only a small number of genes encoding human secreted proteins have been identified. These secreted proteins include the com.mercially valuable human insulin, interferon, Factor VIII, human growth hormone, tissue plasminogen activator, and erythropoeitin. Thus, in light of the pervasive role of secreted proteins in human physiology, a need exists for identifying and characterizing novel human secreted proteins and the genes that encode them. This knowledge will allow one to detect, to treat, and to prevent medical disorders by using secreted proteins or the genes that encode them.

Summary of the Invention The present inventidn relates to novel polynucleotides and the encoded polypeptides. Moreover, the present invention relates to vectors, host cells, antibodies, and recombinant methods for producing the polypeptides and polynucleotides.
Also provided are diagnostic methods for detecting disorders related to the polypeptides, and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying binding partners of the polypeptides.

Detailed Description Definitions The following definitions are provided to facilitate understanding of certain terms used throughout this specification.
In the present invention, "isolated" refers to material removed from its original environment (e.g., the natural environment if it is naturally occurring), and thus is altered "by the hand of man" from its natural state. For example, an isolated polynucleotide could be part of a vector or a composition of matter, or could be contained within a cell, and still be "isolated" because that vector, composition of matter, or particular cell is not the original environment of the polynucleotide.
In the present invention, a "secreted" protein refers to those proteins capable of being directed to the ER, secretory vesicles, or the extracellular space as a result of a signal sequence, as well as those proteins released into the extracellular space without necessarily containing a signal sequence. If the secreted protein is released into the extracellular space, the secreted protein can undergo extracellular processing to produce a "mature" protein. Release into the extracellular space can occur by many mechanisms, including exocytosis and proteolytic cleavage.
As used herein , a "polynucleotide" refers to a molecule having a nucleic acid sequence contained in SEQ ID NO:X or the cDNA contained within the clone deposited with the ATCC. For example, the polynucleotide can contain the nucleotide sequence of the full length cDNA sequence, including the 5' and 3' untranslated sequences, the coding region, with or without the signal sequence, the secreted protein coding region, as well as fragments, epitopes, domains, and variants of the nucleic acid sequence.
Moreover, as used herein, a "polypeptide" refers to a molecule having the translated amino acid sequence generated from the polynucleotide as broadly defined.
In the present invention, the full length sequence identified as SEQ ID NO:X
was often generated by overlapping sequences contained in multiple clones (contig analysis). A representative clone containing all or most of the sequence for SEQ ID
NO:X was deposited with the American Type Culture Collection ("ATCC"). As shown in Table 1, each clone is identified by a cDNA Clone ID (Identifier) and the ATCC Deposit Number. The ATCC is located at 10801 University Boulevard, Manassas, Virginia 20110-2209, USA. The ATCC deposit was made pursuant to the terms of the Budapest Treaty on the international recognition of the deposit of microorganisms for purposes of patent procedure.
A "polynucleotide" of the present invention also includes those polynucleotides capable of hybridizing, under stringent hybridization conditions, to sequences contained in SEQ ID NO:X, the complement thereof, or the cDNA within the clone deposited with the ATCC. "Stringent hybridization conditions" refers to an overnight incubation at 42 C in a solution comprising 50% formamide, 5x SSC (750 mM NaCI, 75 mM sodium citrate), 50 mM sodium phosphate (pH 7.6), 5x Denhardt's solution, 10% dextran sulfate, and 20 g/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1 x SSC at about 65 C.

Also contemplated are nucleic acid molecules that hybridize to the polynucleotides of the present invention at lower stringency hybridization conditions.
Changes in the stringency of hybridization and signal detection are primarily accomplished through the manipulation of formamide concentration (lower percentages of formamide result in lowered stringency); salt conditions, or temperature.
For example, lower stringency conditions include an overnight incubation at 37 C
in a solution comprising 6X SSPE (20X SSPE = 3M NaCI; 0.2M NaHZPO4; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 ug/mi salmon sperm blocking DNA;
followed by washes at 50 C with 1XSSPE, 0.1% SDS. In addition, to achieve even lower stringency, washes performed following stringent hybridization can be done at higher salt concentrations (e.g. 5X SSC).
Note that variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due=
to problems with compatibility.
Of course, a polynucleotide which hybridizes only to polyA+ sequences (such as any 3' terminal polyA+ tract of a cDNA shown in the sequence listing), or to a complementary stretch of T (or U) residues, would not be included in the definition of "polynucleotide," since such a polynucleotide would hybridize to any nucleic acid molecule containing a poly (A) stretch or the complement thereof (e.g., practically any double-stranded cDNA clone).
The polynucleotide of the present invention can be composed of any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA
or modified RNA or DNA. For example, polynucleotides can be composed of single-and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single-and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single-and double-stranded regions. In addition, the polynucleotide can be composed of triple-stranded regions comprising RNA or DNA or both RNA and DNA. A polynucleotide may also contain one or more modified bases or DNA or RNA backbones modified for stability or for other reasons. "Modified" bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications can be made to DNA
and RNA; thus, "polynucleotide" embraces chemically, enzymatically, or metabolically modified forms.
The polypeptide of the present invention can be composed of amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino acids other than the 20 gene-encoded amino acids. The polypeptides may be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art.
Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched , for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods.
Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI
anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins 5 such as arginylation, and ubiquitination. (See, for instance, PROTEINS -STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W.
H. Freeman and Company, New York (1993); POSTTRANSLATIONAL
COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, pgs. 1-12 (1983); Seifter et al., Meth Enzymol 182:626-646 (1990);
Rattan et al., Ann NY Acad Sci 663:48-62 (1992).) "SEQ ID NO:X" refers to a polynucleotide sequence while "SEQ ID NO:Y"
refers to a polypeptide sequence, both sequences identified by an integer specified in Table 1.
"A polypeptide having biological activity" refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a polypeptide of the present invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. In the case where dose dependency does exist, it need not be identical to that of the polypeptide, but rather substantially similar to the dose-dependence in a given activity as compared to the polypeptide of the present invention (i.e., the candidate polypeptide will exhibit greater activity or not more than about 25-fold less and, preferably, not more than about tenfold less activity, and most preferably, not more than about three-fold less activity relative to the polypeptide of the present invention.) Polynucleotides and Polvpeptides of the Invention FEATURES OF PROTEIN ENCODED BY GENE NO: 1 This gene is expressed primarily in neutrophils.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune disorders, particularly infection and inflammatory disorders.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.immune, hematopoietic, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution in the neutrophils indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and intervention of infection of pathogens, immune disorders, and host-to-graft response control in the tissue or organ transplantation. Additionally, the gene product can be used as the therapeutic target screening.Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ
ID NO: I 1 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome.
Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1096 of SEQ ID NO: 11, b is an integer of 15 to 1110, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:11, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 2 This gene is expressed primarily in dermatofibrosarcoma protuberance, and to a lesser extent, in Synovial Fibroblasts, osteoclastoma, dendritic cells, lung, monocyte and human embryo.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, integumentary, proliferating, or muscle disorders, particularly dermatofibrosarcoma protuberance. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing inununological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the connective tissues, expression of this gene at WO 99/11293 PCTlUS98/18360 significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.integumentary, developming, muscle, skeletal, immune, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, amniotic fluid, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis or intervention of dermatofibrosarcoma. Similarly, the tissue distribution in integumentary tissues indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment, diagnosis, and/or prevention of various skin disorders including congenital disorders (i.e. nevi, moles, freckles, Mongolian spots, hemangiomas, port-wine syndrome), integumentary tumors (i.e. keratoses, Bowenis disease, basal cell carcinoma, squamous cell carcinoma, malignant melanoma, Pagetis disease, mycosis fungoides, and Kaposifs sarcoma), injuries and inflammation of the skin (i.e.wounds, rashes, prickly heat disorder, psoriasis, dermatitis), atherosclerosis, uticaria, eczema, photosensitivity, autoimmune disorders (i.e. lupus erythematosus, vitiligo, dermatomyositis, morphea, scleroderma, pemphigoid, and pemphigus), keloids, striae, erythema, petechiae, purpura, and xanthelasma. Moreover, such disorders may predispose increased susceptibility to viral and bacterial infections of the skin (i.e. cold sores, warts, chickenpox, molluscum contagiosum, herpes zoster, boils, cellulitis, erysipelas, impetigo, tinea, althletes foot, and ringworm). In addition, the protein may also show utility in the detection or treatment of disorders afflicting connective tissues (e.g. arthritis, trauma, tendonitis, chrondomalacia and inflammation), such as in the diagnosis or treatment of various autoimmune disorders such as rheumatoid arthritis, lupus, scleroderma, and dermatomyositis as well as dwarfism, spinal deformation, and specific joint abnormalities as well as chondrodysplasias (ie.
spondyloepiphyseal dysplasia congenita, familial osteoarthritis, Atelosteogenesis type II, metaphyseal chondrodysplasia type Schmid). Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or inununotherapy targets for the above listed tissues. . Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO: 12 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome.
Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 922 of SEQ ID NO: 12, b is an integer of 15 to 936, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO: 12, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 3 The translation product of this gene shares sequence homology with phenylakylamine binding protein (also known as emopamil-binding protein, (EBP)) which is thought to be important in sterol isomerization and neuroprotective agent binding. EBP is known to be the one of the primary receptors for antiischemic drug, and thus serves as a common target for therapeutics of this family (See Genbank Accession No.gi1780263). By comparison of homology, this gene may also play a similar role in either the same or other tissues or cell types. In specific embodiments, polypeptides of the invention comprise the following amino acid sequence:
MNQIFLFGQN V IHS SLHFVFV LLLLNNLFQIGFKATS FRCI V V QLNGDIGKREQI
(SEQ ID NO: 122). Polynucleotides encoding these polypeptides are also encompassed by the invention.
This gene is expressed primarily in cyclohexamide treated supt cells, Alzheimer spongy forms, fetal epithelium, smooth muscle, CD34 depleted buffy coat cord blood and to a lesser extent in activated T-cells, endothelial cells, melanocytes, B-cell lymphoma, and human cerebellum.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neural, immune, or developmental disorders, particularly neurodegenerative disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.neural, integumentary, developmental, fetal, immune, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, anmiotic fluid, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO:68 as residues:
Gly-33 to Ala-38, Glu-123 to His-128, Trp-150 to Asn-161, His-195 to Ser-201.
The tissue distribution in various neural tissues combined with the homology to the EBP protein indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatment of neurodegenerative disease states, behavioural disorders, or inflamatory conditions such as Alzheimers Disease, Parkinsons Disease, Huntingtons Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, ALS, psychoses , autism, and altered bahaviors, including disorders in feeding, sleep patterns, balance, and preception. In addition, based upon the tissue distribution in fetal tissues, indicates that the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, sexually-linked disorders, or disorders of the cardiovascular system. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO: 13 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 907 of SEQ ID NO: 13, b is an integer of 15 to 921, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO: 13, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 4 This gene is expressed primarily in hemangiopericytoma, and to a lesser extent, in hypothalamus, smooth muscle, liver, spleen, brain, bone, adipose and number of other tissues and cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neural disorders, particularly hemangiopericytoma. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing inununological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the blood vessels, expression of this gene at significantly higher or lower levels may be routinely detected 5 in certain tissues or cell types (e.g.neural, hepatic, musculoskeletal, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, bile, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred 10 epitopes include those comprising a sequence shown in SEQ ID NO:69 as residues:
Lys-14 to Glu-19, Glu-74 to Lys-84, Pro-100 to Thr-105, Gly-119 to Ala-129, Gln-135 to Asn-143, Pro-145 to Glu-150, Glu-162 to Glu-167, Glu-207 to Pro-215.
The tissue distribution in hemangiopericytoma and other highly vascularized tissues and organs indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and intervention of disorders of blood vesseles, especially hemangiopericytoma and angiogenesis. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO: 14 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically' excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2527 of SEQ ID NO: 14, b is an integer of 15 to 2541, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO: 14, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 5 This gene is expressed primarily in both normal ovary and ovarian cancer, and to a lesser extent in Merkel cells and synovial fibroblasts.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, endocrine disorders or reproductive disorders, particularly ovarian cancer. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the endocrine and reproductive systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.reproductive, endocrine, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and intervention of disorders of endocrine or reproductive systems. A protein product secreted by ovary may present an hormone that has either systemic or local effects related to reproductive function.
Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO: 15 and may have been publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between I to 1032 of SEQ ID NO: 15, b is an integer of 15 to 1046, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO: 15, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 6 This gene is expressed primarily in Hodgkins lymphoma and testes.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not Iimited to, disorders of immune or reproductive system, particularly Hodkin's lymphoma. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune, endocrine and reproductive systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.immune, reproductive, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:71 as residues: Pro-16 to Cys-32, Thr-46 to Ser-5 1, Gly-59 to Gly-64.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and intervention of disorders of immune system, including immunodeficiency, immune dysfunction, allergy, autoimmune diseases, organ/tissue transplantation, or disorders of endocrine system, or reproductive problems like infertility. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:16 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome.
Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 968 of SEQ ID NO: 16, b is an integer of 15 to 982, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:16, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 7 This gene is expressed primarily in brain tissues, especially that of brain amygdala depression, striatum depression and Alzheimers spongy form, and to a lesser extent in bladder and melanocytes.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurological and psychological disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the central nerve system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.neural, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:72 as residues: Pro-29 to Lys-37.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and intervention of neurological and psychological disorders, including depression, Alzheimers disease, Parkinsons Disease, Huntingtons Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, ALS, psychoses , autism, and altered bahaviors, including disorders in feeding, sleep patterns, balance, and preception. In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, sexually-linked disorders, or disorders of the cardiovascular system. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. . Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO: 17 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 3077 of SEQ ID NO:
17, b is an integer of 15 to 3091, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO: 17, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 8 The translation product of this gene shares sequence homology with G-protein coupled receptors which are thought to be important in signal transduction for ligands of physiological importance.

This gene is expressed primarily in brain tissues such as striatum depression and to a lesser extent in synovial fibroblasts, osteoclastoma, fetal kidney, dendritic cells, hypothalmus, and adipose tissue.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the nervous system. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the central nervous system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types ((e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:73 as residues: Asn-67 to Asn-72.
The tissue distribution and homology to G-protein coupled receptor indicates that polynucleotides and polypeptides corresponding to this gene are useful as a target for screening therapeutic compounds. These compounds may be used for disorders in many bodily systems, including those with central nervous system, connective tissues, bone, urinary, metabolic, immune implications. Additionally, the gene product can be expressed as therapeutic protein in whole or in part, as an antagonist, for example where the disease state results from an overexpression of the same gene..
Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO: 18 and may have been publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 782 of SEQ ID NO: 18, b is an integer of 15 to 796, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO: 18, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 9 This gene is expressed only in fetal lung.
5 Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample atrid for diagnosis of diseases and conditions which include, but are not limited to, pulmonary or developmental disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes 10 for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the pulmonary system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.pulmonary, developmental, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, amniotic fluid, serum, plasma, urine, synovial fluid and 15 spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution of this gene only in fetal lung indicates that it plays a key role in development of the pulmonary system. This would suggest that misregulation of the expression of this protein product in the adult could lead to lymphoma or sarcoma formation, particularly in the lung. It may also be involved in predisposition to certain pulmonary defects such as pulmonary edema and embolism, bronchitis and cystic fibrosis.Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:
19 and may have been publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 808 of SEQ ID NO:19, b is an integer of 15 to 822, where both a and b correspond to the positions of nucleotide residues shown in SEQ
ID
NO: 19, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 10 This gene is expressed primarily in bone, and to a lesser extent, in T-cells, neutrophils, and endothelial cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, skeletal, immune, or hematopoietic disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing inununological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune systems and hematopoetic system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.skeletal, immune, hematopoietic, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:75 as residues: Thr-33 to Glu-44, Tyr-63 to Arg-68.
The tissue distribution of this gene predominantly in hematopoietic cell types indicates that the gene could be important for the treatment or detection of immune or hematopoietic disorders including arthritis, asthma and immunodeficiency diseases. The expression of this gene in bone indicates a potential role in the treatmeent and/or detection of bone developmental defects, bone repair, bone diseases, and bone deformities. Alternatively, the tissue distribution within various hematopoietic tissues indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of hematopoetic related disorders such as anemia, pancytopenia, leukopenia, thrombocytopenia or leukemia since stromal cells are important in the production of cells of hematopoietic lineages. The uses include bone marrow cell ex vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia. The gene product may also be involved in lymphopoiesis, therefore, it can be used in immune disorders such as infection, inflammation, allergy, immunodeficiency etc. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types.
Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:20 and may have been publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between I to 643 of SEQ ID NO:20, b is an integer of 15 to 657, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:20, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 11 This gene is expressed primarily in fetal liver and spleen, and to a lesser extent in smooth muscle, synovial sarcoma and brain.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, developmental, hepatic and hematopoetic disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the hepatic and hematopoetic systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types(e.g. immune, cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO:76 as residues:
Pro-61 to Ala-67.
The tissue distribution of this gene primarily in fetal liver indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment/detection of hepatic disorders including hepatoma, and hepatitis;
developmental disorders and hematopoetic disorders including arthritis, asthma, immunodeficiency diseases and leukemia. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:21 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 618 of SEQ ID
NO:21, b is an integer of 15 to 632, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:21, and where the b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 12 This gene is expressed primarily in cord blood. Any frame shifts in this sequence can easily be clarified using known molecular biology techniques.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, hematopoetic disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the hematopoetic system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g. immune, cancerous and wounded tissues) or bodily fluids (e.g.
lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution in cord blood indicates that the gene could be important for the treatment or detection of immune or hematopoietic disorders including arthritis, asthma, immunodeficiency diseases and leukemia. Expression of this gene product in cord blood cells indicates a role in the regulation of the proliferation;
survival;
differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses). Since the gene is expressed in cells of lymphoid origin, the natural gene product may be involved in immune functions. Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:22 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 851.of SEQ ID
NO:22, b is an integer of 15 to 865, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:22, and where the b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 13 The nucleotide sequence of this gene shows homology with a T-cell surface protein tactile precursor which is thought to be involved in the adhesive interactions of activated T and NK cells during the late phase of the immune response, when these cells are actively engaging diseased cells and moving within areas of inflamation.
This gene is expressed primarily in cord blood.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, hematopoetic disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the hematopoetic and immune systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g. immune, cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.

The tissue distribution of this gene in hematopoietic cell types, and its homology to T-cell surface protein precursor tactile, indicates that the gene could be important for the treatment or detection of immune, or hematopoietic disorders including arthritis, asthma, immunodeficiency diseases and leukemia. Many polynucleotide sequences, 5 such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:23 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the 10 present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between I to 1208 of SEQ ID NO:23, b is an integer of 15 to 1222, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:23, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 14 This gene is expressed primarily in brain, and to a lesser extent in thymus and spleen.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurological and immune disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing inununological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the neurological and immune systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.immune, neural, cancerous and wounded tissues) or bodily fluids (e.g.lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:79 as residues: Asp-48 to Ser-54.
The tissue distribution of this gene product predoniinantly in brain, indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatment of neurodegenerative disease states and behavioural disorders such as Alzheimers Disease, Parkinsons Disease, Huntingtons Disease, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder and panic disorder.
In addition the expression of this gene in the thymus and spleen indicates a possible role in the detection and treatment of immune disorders such as arthritis, asthma, immunodeficiency diseases and leukemia. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:24 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1407 of SEQ ID
NO:24, b is an integer of 15 to 1421, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:24, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 15 This gene is expressed primarily in six-week old embryo.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, developmental disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the fetus, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.developmental, differentiating, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, amniotic fluid, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:80 as residues: Thr-36 to Met-43.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of developmental and degenerative disorders, as well as cancer. Similarly, expression within embryonic tissue and other cellular sources marked by proliferating cells indicates that this protein may play a role in the regulation of cellular division, and may show utility in the diagnosis and treatment of cancer and other proliferative disorders.
Similarly, embryonic development also involves decisions involving cell differentiation and/or apoptosis in pattern formation. Thus this protein may also be involved in apoptosis or tissue differentiation and could again be useful in cancer therapy. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:25 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 624 of SEQ ID NO:25, b is an integer of 15 to 638, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:25, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 16 This gene is expressed primarily in fetal brain.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, brain tumors, developmental and neurodegenerative diseases of the brain. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the brain, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.neural, developmental, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO:81 as residues:
His-41 to Glu-49.

The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of developmental and neurodegenerative diseases of the brain and nervous system. Examples would include; behavioral or nervous system disorders, such as depression, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, mania, dementia, paranoia, and addictive behavior, sleep disorders. Alternatively, expression within fetal tissues indicates that this protein may play a role in the regulation of cellular division, and may show utility in the diagnosis and treatment of cancer and other proliferative disorders. Similarly, embryonic development also involves decisions involving cell differentiation and/or apoptosis in pattern formation. Thus this protein may also be involved in apoptosis or tissue differentiation and could again be useful in cancer therapy. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID
NO:26 and may have been publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between I to 735 of SEQ ID NO:26, b is an integer of 15 to 749, where both a and b correspond to the positions of nucleotide residues shown in SEQ
ID
NO:26, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 17 This gene is expressed primarily in fetal tissue.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, developmental disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the fetus, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.developmental, differentiating, and cancerous and wounded tissues) or bodily fluids (e.g.amniotic fluid, lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of developmental and degenerative disorders, as well as cancer. Similarly, expression within fetal tissues indicates that this protein may play a role in the regulation of cellular division, and may show utility in the diagnosis and treatment of cancer and other proliferative disorders.
Similarly, embryonic development also involves decisions involving cell differentiation and/or apoptosis in pattern formation. Thus this protein may also be involved in apoptosis or tissue differentiation and could again be useful in cancer therapy. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:27 and may have been publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 774 of SEQ ID NO:27, b is an integer of 15 to 788, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:27, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 18 When tested against Reh cell lines, supernatants removed from cells containing this gene activated the GAS (gamma activation site) promoter element. Thus, it is likely that this gene activates B-cells through the Jaks-STAT signal transduction pathway.
GAS is a promoter element found upstream in many genes which are involved in the Jaks-STAT pathway. The Jaks-STAT pathway is a large, signal transduction pathway involved in the differentiation and proliferation of cells. Therefore, activation of the Jaks-STATs pathway, reflected by the binding of the GAS element, can be used to indicate proteins involved in the proliferation and differentiation of cells.
This gene is expressed primarily in brain.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, brain tumors, developmental and neurodegenerative diseases of the brain. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell 5 type(s). For a number of disorders of the above tissues or cells, particularly of the brain, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.neural, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to 10 the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:83 as residues: Met- I to Arg-8.
The tissue distribution in brain indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of developmental 15 and neurodegenerative diseases of the brain and nervous system. Examples would include; behavioral or nervous system disorders, such as depression, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, mania, dementia, paranoia, and addictive behavior, sleep disorders. Alternatively, the detected GAS
biological activity within B-cells indicates a role in the regulation of the proliferation;

20 survival; differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the natural gene product may be involved 25 in immune functions. Therefore it may be also used as an agent for inununological disorders including arthritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheumatoid arthritis, granulomatous disease, inflammatory bowel disease, sepsis, acne, neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cytotoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases, or autoimmunity disorders, such as autoimmune infertility, lense tissue injury, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's disease, scleroderma and tissues. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:28 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 927 of SEQ ID NO:28, b is an integer of 15 to 941, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:28, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 19 This gene is expressed primarily in fetal heart.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, cardiac, skeletal or developmental disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the cardiovascular system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.muscle, cardiac, developmental, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, amniotic fluid, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO:84 as residues:
Pro-42 to Asn-49, Arg-54 to Gly-59, Ile-73 to Glu-81.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of cadiovascular and disorders, particularly those relating to the heart and its development.
Conditions relating to heart disease, such as restenosis, atherosclerosis, stoke, angina, thrombosis, and wound healing, are all potential areas of applicability for the protein product of this gene. Similarly, expression within fetal tissues and other cellular sources marked by proliferating cells indicates that this protein may play a role in the regulation of cellular division, and may show utility in the diagnosis and treatment of cancer and other proliferative disorders. Similarly, embryonic development also involves decisions involving cell differentiation and/or apoptosis in pattern formation. Thus this protein may also be involved in apoptosis or tissue differentiation and could again be useful in cancer therapy. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID
NO:29 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome.
Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 821 of SEQ ID NO:29, b is an integer of 15 to 835, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:29, and where the b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 20 This gene is expressed primarily in placenta.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, fetal deficiencies and pre-natal disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.developmental, proliferating, and cancerous and wounded tissues) or bodily fluids (e.g.lymph, amniotic fluid, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO:85 as residues:
Val-54 to Asp-59.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of developmental anomalies, fetal deficiencies, reproductive disfunction or pre-natal disorders.Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:30 and may have been publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 539 of SEQ ID NO:30, b is an integer of 15 to 553, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:30, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 21 The translation product of this gene shares sequence homology with drosophila peroxidasin which is thought to be important in extracellular matrix architecture. When tested against Jurkat T-cell lines, supernatants removed from cells containing this gene activated the GAS pathway. Thus, it is likely that this gene activates T-cells through the Jaks-STAT signal transduction pathway. GAS is a promoter element found upstream in many genes which are involved in the Jaks-STAT pathway. The Jaks-STAT pathway is a large, signal transduction pathway involved in the differentiation and proliferation of cells. Therefore, activation of the Jaks-STAT pathway, reflected by the binding of the GAS element, can be used to indicate proteins involved in the proliferation and differentiation of cells.
This gene is expressed primarily in umbilical vein and to a lesser extent in endothelial and brain cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune, developmental and growth disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of fetal tissues, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g. immune, hematopoietic, neural, cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid) or WO 99/11293 PCTlUS98/18360 another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.Preferred epitopes include those comprising a sequence shown in SEQ ID NO:86 as residues: Ala-55 to Thr-62, His-164 to Gly-175, Ala-197 to Glu-202.
The tissue distribution and homology to peroxidasin indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study, diagnosis, and treatment of various fetal developmental and growth disorders involving the formation of extracellular matrix. Alternatively, the tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of a variety of immune system disorders. Activation of the GAS pathway by the gene product of this gene indicates a role in the regulation of the proliferation; survival; differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses). Since the gene product demonstrates activity with regard to the GAS
pathway, the natural gene product may be involved in immune functions.
Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. and tissues. In addition, this gene product may have commercial utility in the expansion of stem cells and conunitted progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID
NO:31 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome.
Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1332 of SEQ ID NO:31, b is an integer of 15 to 1346, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:31, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 22 The translation product of this gene was shown to have homology to the Human 5 M97-2 secreted protein, which is thought to be involved in immune regulation (see PCT
publication number W09740151). Based upon the similar structure, it is believed that these proteins share similar biological activity. Preferred polypeptides comprise the following amino acid sequence :
LSAYRTLDNTHIHTHKNAHEPNPEKV PAGPPPS PPPPTSPLDSEDRRGTRGHLG

QKKNENEKRGIP (SEQ ID NO:123), LSAYRTLDNTHIHTHKNAHEPNPEKVPA
G (SEQ ID NO: 124), LDSEDRRGTRGHL (SEQ ID NO: 125), IITLYITQSFWFS
RTRLPKYHLQKVTLA (SEQ ID NO:126), or VIILFICSLC (SEQ ID NO:127) This gene is expressed primarily in kidney medulla and to a lesser extent in 15 brain (amygdala-depression and infant brain).
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, renal, endocrine and CNS disorders. Similarly, polypeptides and 20 antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the renal, endocrine and central nervous system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types(e.g. renal, cerebral, immune, hematopoietic, 25 cancerous and wounded tissues) or bodily fluids (e.g, lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ
ID
30 NO:87 as residues: Pro-5 to Gln-11, Thr-29 to Ala-38.
The tissue distribution indicates that the protein products of this gene is useful for the study, treatment and diagnosis of various endocrine, renal, developmental and central nervous system disorders. The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection and treatment of liver disorders and cancers (e.g. hepatoblastoma, jaundice, hepatitis, liver metabolic diseases and conditions that are attributable to the differentiation of hepatocyte progenitor cells). In addition the expression in fetus would suggest a useful role for the protein product in developmental abnormalities, fetal deficiencies, pre-natal disorders and various would-healing models and/or tissue trauma. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:32 and may have been publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between I to 612 of SEQ ID NO:32, b is an integer of 15 to 626, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:32, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 23 This gene is expressed primarily in meningima and to a lesser extent in infant brain.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the brain and CNS, particularly neuro-degenerative disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the CNS and developmental systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.
immune, hematopoietic, neural, developing, cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study, diagnosis and treatment of disorders and diseases involving the CNS and developmental pathway. The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatment of neurodegenerative disease states and behavioural disorders such as Alzheimers Disease, Parkinsons Disease, Huntingtons Disease, Tourette Syndrome, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, ALS, psychoses, autism, and altered bahaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, sexually-linked disorders, or disorders of the cardiovascular system. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:33 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1004 of SEQ ID
NO:33, b is an integer of 15 to 1018, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:33, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 24 This gene is expressed primarily in breast lymph node.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, metabolic, hematopoietic, and immune disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the metabolic and immune systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g. immune, hematopoietic, cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO:89 as residues:
Lys-27 to Ser-33.

The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study, diagnosis and treatment of metabolic and immune disorders. The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of a variety of immune system disorders. Expression of this gene product in breast lymph nodes indicates a role in the regulation of the proliferation; survival;
differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting inunune responses). Since the gene is expressed in cells of lymphoid origin, the natural gene product may be involved in immune functions. Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion of stem cells and conunitted progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:34 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 753 of SEQ ID
NO:34, b is an integer of 15 to 767, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:34, and where the b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 25 This gene is expressed primarily in breast lymph node, and to a lesser extent in bone marrow.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, metabolic and immune disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the metabolic and immune systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types(e.g. immune, cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study, diagnosis and treatment of various metabolic and immune disorders. The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of a variety of immune system disorders. Expression of this gene product in breast lymph nodes and bone marrow indicates a role in the regulation of the proliferation;
survival; differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the natural gene product may be involved in immune functions. Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. and tissues. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:35 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 826 of SEQ ID
NO:35, b is an integer of 15 to 840, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:35, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 26 The gene sequence shows significant homology to a sequence of the human 5 chromosome X.
This gene is expressed primarily in placenta and to a lesser extent in fetal liver and spleen.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a 10 biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the immune, metabolic, and developing systems.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the metabolic and 15 immune systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g. renal, cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue 20 or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:91 as residues: Ile-98 to Pro-106, Pro-118 to Leu-124, Ser-136 to Arg-148.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study, diagnosis and treatment of disorders 25 involving the immune, developmental and metabolic systems. The nucleotide sequence of this gene shows homology to regions of the human chromosome X, and given its tissue distribution, this gene may function in developmental pathways or the regulation thereof. In addition the expression in fetus would suggest a useful role for the protein product in developmental abnormalities, fetal deficiencies, and pre-natal disorders.
30 Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID
NO:36 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome.
35 Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1134 of SEQ ID NO:36, b is an integer of 15 to 1148, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:36, and where the b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 27 The translation product of this gene shares sequence homology with an estrogen receptor variant which is thought to be important in reproductive, endocrine and metabolic disorders.
This gene is expressed primarily in cancerous meningima tissue.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, cancer and brain disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the brain and cerebrospinal fluids, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g. developmental, cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution and homology to estrogen receptor variant indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study, diagnosis and treatment of brain, endocrine, reproductive and metabolic disorders.
Alternatively, the, tissue distribution to cancerous meningima tissue may suggest that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and intervention of these tumors. Protein, as well as, antibodies directed against the protein may show utility as a tissue-specific marker and/or immunotherapy target for the above listed tissues. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:37 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1353 of SEQ ID
NO:37, b is an integer of 15 to 1367, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:37, and where the b is greater than or equal toa+14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 28 This gene is expressed primarily in human neutrophils.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, inflammatory and immune disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the inflammatory and immune systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g. immune, cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:93 as residues: Asn-20 to Cys-27.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for study, diagnosis and treatment of immune and inflammatory disorders. Expression of this gene product in neutrophils indicates a role in the regulation of the proliferation; survival; differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g.
by boosting immune responses). Since the gene is expressed in cells of lymphoid origin, the natural gene product may be involved in immune functions. Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types.
Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:38 and may have been publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 907 of SEQ ID NO:38, b is an integer of 15 to 921, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:38, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 29 This gene is expressed primarily in T cells and to a lesser extent in pituitary tissue.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune and endocrine disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the endocrine and immune systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g. immune, cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:94 as residues: Lys-23 to Ser-30, Ala-52 to Leu-57, Pro-96 to Ser-105.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study, diagnosis and treatment of various immune and endocrine disorders. Expression of this gene product in T-cells indicates a role in the regulation of the proliferation; survival; differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g.
by boosting inunune responses). Since the gene is expressed in cells of lymphoid origin, the natural gene product may be involved in immune functions. Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types.
Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:39 and may have been publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 618 of SEQ ID NO:39, b is an integer of 15 to 632, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:39, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 30 The translation product of this gene shares sequence homology with Mlrq mouse protein which is thought to be important in MHC recognition by T cells.
The translation product of this gene also shares homology with human platelet factors, which could suggest that this gene is important in the aggregation of immune cells, such as neutrophils.
This gene is expressed primarily in synovial fibroblasts and to a lesser extent in T cells and Hodgkin's lymphoma.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune/autoimmune disorders and cancer. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune and metabolic systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g. lypmh, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an 5 individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:95 as residues: Asp-43 to Val-54, Asn-66 to Glu-74.
The tissue distribution and homology to Mlrq mouse protein indicates that polynucleotides and polypeptides corresponding to this gene are useful for study, diagnosis and treatment of immune, autoimmune diseases and cancers. Expression of 10 this gene product in immune cells indicates a role in the regulation of the proliferation;
survival; differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the 15 gene is expressed in cells of lymphoid origin, the natural gene product may be involved in immune functions. Therefore it may be also used as an agent for inununological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion 20 of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of 25 these sequences are related to SEQ ID NO:40 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the 30 general formula of a-b, where a is any integer between 1 to 594 of SEQ ID
NO:40, b is an integer of 15 to 608, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:40, and where the b is greater than or equal to a + 14.
35 FEATURES OF PROTEIN ENCODED BY GENE NO: 31 This gene is expressed primarily in neutrophils, and to a lesser extent in kidney medulla.

Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not Iimited to, immune and inflammatory disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune or renal systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cells types (e.g. immune, renal, cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:96 as residues: Glu-21 to Gly-30, Glu-to Thr-47.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study, diagnosis and treatment of inflammatory and immune disorders. Expression of this gene product in neutrophils indicates a role in the regulation of the proliferation; survival;
differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses). Since the gene is expressed in cells of lymphoid origin, the natural gene product may be involved in immune functions.
Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Alternatively, the tissue distribution in kidney indicates that this gene or gene product could be used in the treatment and/or detection of kidney diseases including renal failure, nephritus, renal tubular acidosis, proteinuria, pyuria, edema, pyelonephritis, hydronephritis, nephrotic syndrome, crush syndrome, glomerulonephritis, hematuria, renal colic and kidney stones, in addition to Wilms Tumor Disease, and congenital kidney abnormalities such as horseshoe kidney, polycystic kidney, and Falconi's syndrome. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID
NO:41 and may have been publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 863 of SEQ ID NO:41, b is an integer of 15 to 877, where both a and b correspond to the positions of nucleotide residues shown in SEQ
ID
NO:41, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 32 This gene is expressed primarily in uterus and epididymus tissue.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, reproductive and hormonal disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for study and treatment of developmental, reproductive, and endocrine disorders. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:42 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 964 of SEQ ID
NO:42, b is an integer of 15 to 978, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:42, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 33 This gene is expressed primarily in LPS induced neutrophils.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, inflammation and immune defects. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study and treatment of inflammatory and general immune disorders. Expression of this gene product in induced neutrophils indicates a role in the regulation of the proliferation; survival;
differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses). Since the gene is expressed in cells of lymphoid origin, the natural gene product may be involved in immune functions.
Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.

Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID
NO:43 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome.
Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 985 of SEQ ID NO:43, b is an integer of 15 to 999, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:43, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 34 This gene is expressed primarily in LPS induced neutrophils.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, inflammation and immune defects. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g. immune, cancerous and wounded tissues) or bodily fluids (e.g.
lypmh, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:99 as residues: Pro-9 to Cys-14.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for study and treatment of inflammatory and general immune disorders. Expression of this gene product in induced neutrophils indicates a role in the regulation of the proliferation; survival;
differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses). Since the gene is expressed in cells of lymphoid origin, the natural gene product may be involved in immune functions.

Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion of stem cells and committed 5 progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID
10 NO:44 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome.
Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of 15 a-b, where a is any integer between 1 to 496 of SEQ ID NO:44, b is an integer of 15 to 510, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:44, and where the b is greater than or equal to a + 14.

20 FEATURES OF PROTEIN ENCODED BY GENE NO: 35 This gene is expressed primarily in infant brain and several normal and transformed cell types.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a 25 biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurological diseases and cancer. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous and lymphatic systems, 30 expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g. brain, cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an 35 individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study and treatment of cancer and/or developmental, nervous system and lymphoid disorders such as Alzheimers Disease, Parkinsons Disease, Huntingtons Disease, Tourette Syndrome, and schizophrenia.
In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, sexually-linked disorders, or disorders of the cardiovascular system. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:45 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 972 of SEQ ID
NO:45, b is an integer of 15 to 986, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:45, and where the b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 36 The translation product of this gene shares sequence homology with type II
collagen which is thought to be important in marix integrity and tissue homeostasis.
One embodiment of this gene comprises polypeptides of the following amino acid sequence: PEGECCPVCP (SEQ ID NO:128). An additional embodiment is the polynucleotides encoding these polypeptides.
This gene is expressed primarily in osteoblasts.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not liniited to, skeletal and other mesenchymal diseases. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the musculoskeletal system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO: 101 as residues: Asp- 18 to Arg-3 1, Leu-38 to Leu-53.
The tissue distribution and homology to collagens indicates that polynucleotides and polypeptides corresponding to this gene are useful for study and treatment of osteoporosis, arthritic and other skeletal disorders. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed disorders. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:46 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 646 of SEQ ID
NO:46, b is an integer of 15 to 660, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:46, and where the b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 37 The sequence shares homology with a sequence which has been mapped to the human chromosome 17.
This gene is expressed primarily in pineal gland and infant brain.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neuroendocrine diseases. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous and endocrine systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g. brain, cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO: 102 as residues: Ala-38 to Lys-62.

The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for study and treatment of nervous system and hormonal disorders such as Alzheimers Disease, Parkinsons Disease, Huntingtons Disease, Tourette Syndrome, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, ALS, psychoses , autism, and altered bahaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, sexually-linked disorders, or disorders of the cardiovascular system. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:47 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 326 of SEQ ID NO:47, b is an integer of 15 to 340, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:47, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 38 The sequence shows significant homology to human uroplakin protein, which is thought to play a significant role as a component of the asymmetric unit membrane, which is a highly specialized biomembrane composed of tetminally differentiated urothelial cells. This protein may play an important role in the regulation of the assembly of the asymmetric unit membrane. The asymmetric unit membrane forms the apical plaques of mammalian urothelium and is believed to play a role in strengthening the urothelial apical surface, thus preventing the cells from rupturing during bladder distention. One embodiment of this gene comprises polypeptides of the following amino acid sequence:
ISYLVKKGTATESSREIPMSTLPRRNMESIGLGMARTGGM V VITVLLS VAMFLL
VLGFIIALALGSRK (SEQ ID NO: 129), MARTGGMVVITVLLSVAMFLLVLG (SEQ
ID NO:i30), orNMESIGLGMARTGGMVVITVLLSVA (SEQ ID NO:131). An additional embodiment is the polynucleotides encoding these polypeptides.

This gene is expressed primarily in bone marrow and synovial sarcoma.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, hematopoietic and joint diseases. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune and skeletal systems, as well as cells involved in membrane structure expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred epitopes include those comprising a sequence shown in SEQ ID NO: 103 as residues:
Gln-29 to Ser-49.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for study and treatment of immune and skeletal disorders and cancers. Alternatively, given the tissue distribution and homology, it is likely that this gene and its corresponding translation product may play an important role in the regulation of the assembly of the asymmetric unit membrane, which forms the apical plaques of mammalian urothelium, thus strengthening those cells and preventing them from rupturing during bladder distention. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:48 and may have been publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 553 of SEQ ID NO:48, b is an integer of 15 to 567, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:48, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 39 The amino acid sequence is weakly homologous to a collagen-like protein thought to function in collagen or membrane development and/or structure.
This gene is expressed primarily in lung, brain, and spinal cord.
Therefore, polynucleotides and polypeptides of the invention are useful as 5 reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, nervous system and respiratory diseases. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders 10 of the above tissues or cells, particularly of the CNS and developmental tissues, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene 15 expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO: 104 as residues: Pro-38 to His-47, Ala-59 to Thr-66.
The tissue distribution and homology to collagen-like proteins indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study 20 and treatment of nervous system and respiratory disorders. The translation product of this gene may also function in the regulation of the development and/or structure of collagen or membranes within the body. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:49 and may have been publicly available 25 prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between I to 1343 of SEQ ID
NO:49, b 30 is an integer of 15 to 1357, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:49, and where the b is greater than or equal toa+14.

35 FEATURES OF PROTEIN ENCODED BY GENE NO: 40 This gene is expressed primarily in testes, breast and developing tissue, and to a lesser extent in several other tissues and organs.

Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of endocrine, reproductive and developing organs.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the endocrine and reproductive systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO: 105 as residues: Met-1 to Thr-6, Gly-to Asn-74.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of disorders of the endocrine, reproductive and developing organs. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:50 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1024 of SEQ ID NO:50, b is an integer of 15 to 1038, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:50, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 41 The translation product of this gene shares sequence homology with [insert name of closest homolog] which is thought to be important in [insert physiological role(s) of the homologous gene product].
This gene is expressed primarily in [insert tissue or cell line where strongest expression is seen] and to a lesser extent in [insert other tissue(s) and cell line(s) where gene is expressed].

Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, [insert disease condition]. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the [insert system where a related disease state is likely, e.g., immune], expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO: 106 as residues: Val- 10 to Lys- 17, Ser-24 to Lys-29.
The tissue distribution and homology to [gene or gene family] indicates that polynucleotides and polypeptides corresponding to this gene are useful for [take best guess(es) and explain rationale]. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:51 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 995 of SEQ ID
NO:51, b is an integer of 15 to 1009, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:51, and where the b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 42 The gene encoding the disclosed cDNA is thought to reside on chromosome 11.
Accordingly, polynucleotides related to this invention are useful as a marker in linkage analysis of chromosome 11.
This gene is expressed primarily in melanocytes and fetal lung and to a lesser extent in several other tissues and organs.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, diseases of the fetal, pulmonary system and skin. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the developing, pulmonary and dermal system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of diseases of the epidermal, pulmonary and developing systems. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:52 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 894 of SEQ ID NO:52, b is an integer of 15 to 908, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:52, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 43 This gene is expressed primarily in tracheal tumor and retina.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, cancer, diseases of the eye and pulmonary system. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the ocular and pulmonary system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of disorders of the eye, pulmonary system, and cancer. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:53 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome.
Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between I to 1241 of SEQ ID NO:53, b is an integer of 15 to 1255, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:53, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 44 The translation product of this gene shows homology to cell growth regulatory proteins which are under the control of the wild-type p53 gene, the mutation of which is thought to be a contributing factor to many cases of cancer. The gene encoding the disclosed cDNA is thought to reside on chromosome 11. Accordingly, polynucleotides related to this invention are useful as a marker in linkage analysis of chromosome 11.
This gene is expressed primarily in breast and breast cancer and to a lesser extent in haemopoietic and immune tissue and several other tissues and organs.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the reproductive, endocrine and haemopoietic system, and cancer. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive, endocrine and haemopoietic system, and cancerous tissue, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an 5 individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:109 as residues: Cys-42 to Gly-48, Gly-52 to Ile-61.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of disorders of the reproductive, endocrine and haemopoietic organs including cancer. Given the tissue 10 distribution and homology to cell growth regulatory proteins, it is also plausible that the translation product of this gene may play a role in the regulation of cancerous cells, or be useful as a diagnostic tool to determine tumorous growths. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, 15 such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:54 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the 20 present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1128 of SEQ ID NO:54, b is an integer of 15 to 1142, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:54, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 45 The translation product of this gene shares sequence homology with proteins which are involved in G-coupled receptor signalling which is thought to be important in various diseases including cancer, aquired immunodeficiency, diabetes, cardiovascular disease and neurological disorders.
This gene is expressed primarily in adrenal gland tumor, endothelial cells and the central nervous system and to a lesser extent in several other tissue and organs.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the endothelium, CNS and cancers . Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the endothelium and central nervous system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO: 110 as residues: Thr-41 to Ala-50.
The tissue distribution and homology to proteins which are involved in G-coupled receptor signalling indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of disorders of the CNS, endothelium and cancer. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:55 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome.
Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1909 of SEQ ID NO:55, b is an integer of 15 to 1923, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:55, and where the b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 46 This gene is expressed primarily in activated T-cells and adrenal gland tumor.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the immune and endocrine system. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune and endocrine systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.immune, cancerous and wounded tissues) or bodily fluids (e.g.lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Prefen:ed epitopes include those comprising a sequence shown in SEQ ID NO: 111 as residues: Asn-52 to Asn-60, Gly-72 to Pro-88, Pro-94 to Ile-99, Gln-127 to Lys-132, Glu-138 to Gly-144.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of disorders of the immune and endocrine system. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:56 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1214 of SEQ ID
NO:56, b is an integer of 15 to 1228, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:56, and where the b is greater than or equal toa+l4.

FEATURES OF PROTEIN ENCODED BY GENE NO: 47 This gene is expressed primarily in prostate and brain.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, diseases of the reproductive and central nervous system.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the CNS and reproductive system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO: 112 as residues: Ser-22 to Lys-27.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of disorders of the CNS and reproductive system. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:57 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1024 of SEQ ID
NO:57, b is an integer of 15 to 1038, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:57, and where the b is greater than or equal to a + 14.

FEATURES OF PROTEIN ENCODED BY GENE NO: 48 This gene is expressed primarily in bone marrow.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, diseases of the bone marrow. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune and haemopoietic systems, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g.immune, cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. Preferred epitopes include those comprising a sequence shown in SEQ ID NO:113 as residues: Ser-39 to Ala-47, Phe-55 to Leu-64.
The tissue distribution and homology to indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of diseases of the immune and haemopoietic systems. Expression of this gene product in marrow cells indicates a role in the regulation of the proliferation;
survival;
differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses). Since the gene is expressed in cells of lymphoid origin, the natural gene product may be involved in immune functions. Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:58 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 976 of SEQ ID
NO:58, b is an integer of 15 to 990, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:58, and where the b is greater than or equal to a + 14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 49 The gene encoding the disclosed cDNA is thought to reside on chromosome X.
Accordingly, polynucleotides related to this invention are useful as a marker in linkage analysis of chromosome X.
This gene is expressed primarily in melanocytes, fetal tissues and endothelial cells and to a lesser extent in several other tissues including cancers.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, diseases of the skin and developing organs. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing inununological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the epidermal and fetal system, expression of this gene at significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample 5 taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for tretment and diagnosis of diseases of the 10 epidermis and developing tissues including cancers. Proteins, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST
sequences, are publicly available and accessible through sequence databases.
Some of these sequences are related to SEQ ID NO:59 and may have been publicly available 15 prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1753 of SEQ ID
NO:59, b 20 is an integer of 15 to 1767, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:59, and where the b is greater than or equal to a + 14.

25 FEATURES OF PROTEIN ENCODED BY GENE NO: 50 This gene is expressed primarily in tonsils and to a lesser extent in several other tissues including dendritic cells, bone marrow, brain and pulmonary cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue(s) or cell type(s) present in a 30 biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune system disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue(s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at 35 significantly higher or lower levels may be routinely detected in certain tissues or cell types (e.g. immune, cancerous and wounded tissues) or bodily fluids (e.g.
lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of disorders of the immune system and several other systems including the bone and pulmonary system.
Expression of this gene product in immune cells indicates a role in the regulation of the proliferation; survival; differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product may be involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses). Since the gene is expressed in cells of lymphoid origin, the natural gene product may be involved in immune functions. Therefore it may be also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:60 and may have been publicly available prior to conception of the present invention. Preferably, such related-polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1611 of SEQ ID NO:60, b is an integer of 15 to 1625, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:60, and where the b is greater than or equal to a + 14.

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~o 0 SUBSTITUTE SHEET (RULE 26) Table 1 summarizes the information corresponding to each "Gene No."
described above. The nucleotide sequence identified as "NT SEQ ID NO:X" was assembled from partially homologous ("overlapping") sequences obtained from the "cDNA clone ID" identified in Table 1 and, in some cases, from additional related DNA
clones. The overlapping sequences were assembled into a single contiguous sequence of high redundancy (usually three to five overlapping sequences at each nucleotide position), resulting in a final sequence identified as SEQ ID NO:X.
The cDNA Clone ID was deposited on the date and given the corresponding deposit number listed in "ATCC Deposit No:Z and Date." Some of the deposits contain multiple different clones corresponding to the same gene. "Vector" refers to the type of vector contained in the cDNA Clone ID.
"Total NT Seq." refers to the total number of nucleotides in the contig identified by "Gene No." The deposited clone may contain all or most of these sequences, reflected by the nucleotide position indicated as "5' NT of Clone Seq." and the "3' NT
of Clone Seq." of SEQ ID NO:X. The nucleotide position of SEQ ID NO:X of the putative start codon (methionine) is identified as "5' NT of Start Codon."
Similarly , the nucleotide position of SEQ ID NO:X of the predicted signal sequence is identified as "5' NT of First AA of Signal Pep."
The translated amino acid sequence, beginning with the methionine, is identified as "AA SEQ ID NO:Y," although other reading frames can also be easily translated using known molecular biology techniques. The polypeptides produced by these alternative open reading frames are specifically contemplated by the present invention.
The first and last amino acid position of SEQ ID NO:Y of the predicted signal peptide is identified as "First AA of Sig Pep" and "Last AA of Sig Pep." The predicted first amino acid position of SEQ ID NO:Y of the secreted portion is identified as "Predicted First AA of Secreted Portion." Finally, the amino acid position of SEQ ID
NO:Y of the last amino acid in the open reading frame is identified as "Last AA of ORF."
SEQ ID NO:X and the translated SEQ ID NO:Y are sufficiently accurate and otherwise suitable for a variety of uses well known in the art and described further below. For instance, SEQ ID NO:X is useful for designing nucleic acid hybridization probes that will detect nucleic acid sequences contained in SEQ ID NO:X or the cDNA
contained in the deposited clone. These probes will also hybridize to nucleic acid molecules in biological samples, thereby enabling a variety of forensic and diagnostic methods of the invention. Similarly, polypeptides identified from SEQ ID NO:Y
may be used to generate antibodies which bind specifically to the secreted proteins encoded by the cDNA clones identified in Table 1.

Nevertheless, DNA sequences generated by sequencing reactions can contain sequencing errors. The errors exist as misidentified nucleotides, or as insertions or deletions of nucleotides in the generated DNA sequence. The erroneously inserted or deleted nucleotides cause frame shifts in the reading frames of the predicted amino acid 5 sequence. In these cases, the predicted amino acid sequence diverges from the actual amino acid sequence, even though the generated DNA sequence may be greater than 99.9% identical to the actual DNA sequence (for example, one base insertion or deletion in an open reading frame of over 1000 bases).
Accordingly, for those applications requiring precision in the nucleotide 10 sequence or the amino acid sequence, the present invention provides not only the generated nucleotide sequence identified as SEQ ID NO:X and the predicted translated amino acid sequence identified as SEQ ID NO:Y, but also a sample of plasmid DNA
containing a human cDNA of the invention deposited with the ATCC, as set forth in Table 1. The nucleotide sequence of each deposited clone can readily be determined by 15 sequencing the deposited clone in accordance with known methods. The predicted arnino acid sequence can then be verified from such deposits. Moreover, the amino acid sequence of the protein encoded by a particular clone can also be directly deten;nined by peptide sequencing or by expressing the protein in a suitable host cell containing the deposited human cDNA, collecting the protein, and determining its 20 sequence.
The present invention also relates to the genes corresponding to SEQ ID NO:X, SEQ ID NO:Y, or the deposited clone. The corresponding gene can be isolated in accordance with known methods using the sequence information disclosed herein.
Such methods include preparing probes or primers from the disclosed sequence and 25 identifying or amplifying the corresponding gene from appropriate sources of genomic material.
Also provided in the present invention are species homologs. Species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source for the desired 30 homologue.
The polypeptides of the invention can be prepared in any suitable manner. Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well 35 understood in the art.
The polypeptides may be in the form of the secreted protein, including the mature form, or may be a part of a larger protein, such as a fusion protein (see below).

It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification , such as multiple histidine residues, or an additional sequence for stability during recombinant production.
The polypeptides of the present invention are preferably provided in an isolated form, and preferably are substantially purified. A recombinantly produced version of a polypeptide, including the secreted polypeptide, can be substantially purified by the one-step method described in Smith and Johnson, Gene 67:31-40 (1988).
Polypeptides of the invention also can be purified from natural or recombinant sources using antibodies of the invention raised against the secreted protein in methods which are well known in the art.

Signal Secluences Methods for predicting whether a protein has a signal sequence, as well as the cleavage point for that sequence, are available. For instance, the method of McGeoch, Virus Res. 3:271-286 (1985), uses the information from a short N-terminal charged region and a subsequent uncharged region of the complete (uncleaved) protein.
The method of von Heinje, Nucleic Acids Res. 14:4683-4690 (1986) uses the information from the residues surrounding the cleavage site, typically residues -13 to +2, where +1 indicates the amino terminus of the secreted protein. The accuracy of predicting the cleavage points of known mammalian secretory proteins for each of these methods is in the range of 75-80%. (von Heinje, supra.) However, the two methods do not always produce the same predicted cleavage point(s) for a given protein.
In the present case, the deduced amino acid sequence of the secreted polypeptide was analyzed by a computer program called SignalP (Henrik Nielsen et al., Protein Engineering 10:1-6 (1997)), which predicts the cellular location of a protein based on the amino acid sequence. As part of this computational prediction of localization, the methods of McGeoch and von Heinje are incorporated. The analysis of the amino acid sequences of the secreted proteins described herein by this program provided the results shown in Table 1.
As one of ordinary skill would appreciate, however, cleavage sites sometimes vary from organism to organism and cannot be predicted with absolute certainty.
Accordingly, the present invention provides secreted polypeptides having a sequence shown in SEQ ID NO:Y which have an N-terminus beginning within 5 residues (i.e., +
or - 5 residues) of the predicted cleavage point. Similarly, it is also recognized that in some cases, cleavage of the signal sequence from a secreted protein is not entirely uniform, resulting in more than one secreted species. These polypeptides, and the polynucleotides encoding such polypeptides, are contemplated by the present invention.
Moreover, the signal sequence identified by the above analysis may not necessarily predict the naturally occurring signal sequence. For example, the naturally occurring signal sequence may be further upstream from the predicted signal sequence.
However, it is likely that the predicted signal sequence will be capable of directing the secreted protein to the ER. These polypeptides, and the polynucleotides encoding such polypeptides, are contemplated by the present invention.

Polynucleotide and Polypeptide Variants "Variant" refers to a polynucleotide or polypeptide differing from the polynucleotide or polypeptide of the present invention, but retaining essential properties thereof. Generally, variants are overall closely similar, and, in many regions, identical to the polynucleotide or polypeptide of the present invention.
By a polynucleotide having a nucleotide sequence at least, for example, 95%
"identical" to a reference nucleotide sequence of the present invention, it is intended that the nucleotide sequence of the polynucleotide is identical to the reference sequence except that the polynucleotide sequence may include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence encoding the polypeptide.
In other words, to obtain a polynucleotide having a nucleotide sequence at least 95%
identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence may be inserted into the reference sequence. The query sequence may be an entire sequence shown inTable 1, the ORF
(open reading frame), or any fragement specified as described herein.
As a practical matter, whether any particular nucleic acid molecule or polypeptide is at least 90%, 95%, 96%, 97%, 98% or 99% identical to a nucleotide sequence of the presence invention can be determined conventionally using known computer programs. A preferred method for determing the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB
computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci.
(1990) 6:237-245). In a sequence alignment the query and subject sequences are both DNA
sequences. An RNA sequence can be compared by converting U's to T's. The result of said global sequence alignment is in percent identity. Preferred parameters used in a FASTDB alignment of DNA sequences to calculate percent identiy are:
Matrix=Unitary, k-tuple=4, Mismatch Penalty= 1, Joining Penalty=30, Randomization Group Length=0, Cutoff Score=1, Gap Penalty=5, Gap Size Penalty 0.05, Window Size=500 or the lenght of the subject nucleotide sequence, whichever is shorter.
If the subject sequence is shorter than the query sequence because of 5' or 3' deletions, not because of internal deletions, a manual correction must be made to the results. This is becuase the FASTDB program does not account for 5' and 3' truncations of the subject sequence when calculating percent identity. For subject sequences truncated at the 5' or 3' ends, relative to the the query sequence, the percent identity is corrected by calculating the number of bases of the query sequence that are 5' and 3' of the subject sequence, which are not matched/aligned, as a percent of the total bases of the query sequence. Whether a nucleotide is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This corrected score is what is used for the purposes of the present invention. Only bases outside the 5' and 3' bases of the subject sequence, as displayed by the FASTDB alignment, which are not matched/aligned with the query sequence, are calculated for the purposes of manually adjusting the percent identity score.
For example, a 90 base subject sequence is aligned to a 100 base query sequence to determine percent identity. The deletions occur at the 5' end of the subject sequence and therefore, the FASTDB alignment does not show a matched/alignement of the first 10 bases at 5' end. The 10 unpaired bases represent 10% of the sequence (number of bases at the 5' and 3' ends not matched/total number of bases in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 bases were perfectly matched the final percent identity would be 90%. In another example, a 90 base subject sequence is compared with a 100 base query sequence. This time the deletions are internal deletions so that there are no bases on the 5' or 3' of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only bases 5' and 3' of the subject sequence which are not matched/aligned with the query sequnce are manually corrected for. No other manual corrections are to made for the purposes of the present invention.
By a polypeptide having an amino acid sequence at least, for example, 95%
"identical" to a query amino acid sequence of the present invention, it is intended that the amino acid sequence of the subject polypeptide is identical to the query sequence except that the subject polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence. In other words, to obtain a polypeptide having an amino acid sequence at least 95% identical to a query aniino acid sequence, up to 5% of the amino acid residues in the subject sequence may be inserted, deleted, (indels) or substituted with another amino acid. These alterations of the reference sequence may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence.
As a practical matter, whether any particular polypeptide is at least 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance, the amino acid sequences shown in Table 1 or to the amino acid sequence encoded by deposited DNA clone can be determined conventionally using known computer programs. A preferred method for determing the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci. (1990) 6:237-245). In a sequence alignment the query and subject sequences are either both nucleotide sequences or both amino acid sequences.
The result of said global sequence alignment is in percent identity. Preferred parameters used in a FASTDB amino acid alignment are: Matrix=PAM 0, k-tuple=2, Mismatch Penalty= 1, Joining Penalty=20, Randomization Group Length=0, Cutoff Score= 1, Window Size=sequence length, Gap Penalty=5, Gap Size Penalty=0.05, Window Size=500 or the length of the subject amino acid sequence, whichever is shorter.
If the subject sequence is shorter than the query sequence due to N- or C-terminal deletions, not because of internal deletions, a manual correction must be made to the results. This is becuase the FASTDB program does not account for N- and C-terminal truncations of the subject sequence when calculating global percent identity.
For subject sequences truncated at the N- and C-termini, relative to the the query sequence, the percent identity is corrected by calculating the number of residues of the query sequence that are N- and C-terminal of the subject sequence, which are not matched/aligned with a corresponding subject residue, as a percent of the total bases of the query sequence. Whether a residue is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This final percent identity score is what is used for the purposes of the present invention. Only residues to the N- and C-termini of the subject sequence, which are not matched/aligned with the query sequence, are considered for the purposes of manually adjusting the percent identity score.
That is, only query residue positions outside the farthest N- and C-terminal residues of the subject sequence.

For example, a 90 amino acid residue subject sequence is aligned with a 100 residue query sequence to determine percent identity. The deletion occurs at the N-terminus of the subject sequence and therefore, the FASTDB alignment does not show a matching/alignment of the first 10 residues at the N-terminus. The 10 unpaired 5 residues represent 10% of the sequence (number of residues at the N- and C-termini not matched/total number of residues in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining residues were perfectly matched the final percent identity would be 90%. In another example, a 90 residue subject sequence is compared with a 100 residue query sequence.
10 This time the deletions are internal deletions so there are no residues at the N- or C-termini of the subject sequence which are not matched/aligned with the query.
In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only residue positions outside the N- and C-terminal ends of the subject sequence, as displayed in the FASTDB alignment, which are not matched/aligned with the query 15 sequnce are manually corrected for. No other manual corrections are to made for the purposes of the present invention.
The variants may contain alterations in the coding regions, non-coding regions, or both. Especially preferred are polynucleotide variants containing alterations which produce silent substitutions, additions, or deletions, but do not alter the properties or 20 activities of the encoded polypeptide. Nucleotide variants produced by silent substitutions due to the degeneracy of the genetic code are preferred.
Moreover, variants in which 5-10, 1-5, or 1-2 amino acids are substituted, deleted, or added in any combination are also preferred. Polynucleotide variants can be produced for a variety of reasons, e.g., to optimize codon expression for a particular host (change codons in 25 the human mRNA to those preferred by a bacterial host such as E. coli).
Naturally occurring variants are called "allelic variants," and refer to one of several alternate forms of a gene occupying a given locus on a chromosome of an organism. (Genes II, Lewin, B., ed., John Wiley & Sons, New York (1985).) These allelic variants can vary at either the polynucleotide and/or polypeptide level.
30 Alternatively, non-naturally occurring variants may be produced by mutagenesis techniques or by direct synthesis.
Using known methods of protein engineering and recombinant DNA
technology, variants may be generated to improve or alter the characteristics of the polypeptides of the present invention. For instance, one or more amino acids can be 35 deleted from the N-terminus or C-terminus of the secreted protein without substantial loss of biological function. The authors of Ron et al., J. Biol. Chem. 268:

(1993), reported variant KGF proteins having heparin binding activity even after deleting 3, 8, or 27 amino-terminal amino acid residues. Similarly, Interferon gamma exhibited up to ten times higher activity after deleting 8-10 amino acid residues from the carboxy terminus of this protein. (Dobeli et al., J. Biotechnology 7:199-216 (1988).) Moreover, ample evidence demonstrates that variants often retain a biological activity similar to that of the naturally occurring protein. For example, Gayle and coworkers (J. Biol. Chem 268:22105-22111 (1993)) conducted extensive mutational analysis of human cytokine IL-1 a. They used random mutagenesis to generate over 3,500 individual IL-1 a mutants that averaged 2.5 amino acid changes per variant over the entire length of the molecule. Multiple mutations were examined at every possible amino acid position. The investigators found that "[m]ost of the molecule could be altered with little effect on either [binding or biological activity]." (See, Abstract.) In fact, only 23 unique amino acid sequences, out of more than 3,500 nucleotide sequences examined, produced a protein that significantly differed in activity from wild-type.
Furthermore, even if deleting one or more amino acids from the N-terminus or C-terminus of a polypeptide results in modification or loss of one or more biological functions, other biological activities may still be retained. For example, the ability of a deletion variant to induce and/or to bind antibodies which recognize the secreted form will likely be retained when less than the majority of the residues of the secreted form are removed from the N-terminus or C-terminus. Whether a particular polypeptide lacking N- or C-terminal residues of a protein retains such immunogenic activities can readily be determined by routine methods described herein and otherwise known in the art.
Thus, the invention further includes polypeptide variants which show substantial biological activity. Such variants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art so as have little effect on activity. For example, guidance concerning how to make phenotypically silent amino acid substitutions is provided in Bowie, J. U. et al., Science 247:1306-1310 (1990), wherein the authors indicate that there are two main strategies for studying the tolerance of an amino acid sequence to change.
The first strategy exploits the tolerance of amino acid substitutions by natural selection during the process of evolution. By comparing amino acid sequences in different species, conserved amino acids can be identified. These conserved amino acids are likely important for protein function. In contrast, the amino acid positions where substitutions have been tolerated by natural selection indicates that these positions are not critical for protein function. Thus, positions tolerating amino acid substitution could be modified while still maintaining biological activity of the protein.

The second strategy uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene to identify regions critical for protein function. For example, site directed mutagenesis or alanine-scanning mutagenesis (introduction of single alanine mutations at every residue in the molecule) can be used.
(Cunningham and Wells, Science 244:1081-1085 (1989).) The resulting mutant molecules can then be tested for biological activity.
As the authors state, these two strategies have revealed that proteins are surprisingly tolerant of amino acid substitutions. The authors further indicate which amino acid changes are likely to be permissive at certain amino acid positions in the protein. For example, most buried (within the tertiary structure of the protein) amino acid residues require nonpolar side chains, whereas few features of surface side chains are generally conserved. Moreover, tolerated conservative amino acid substitutions involve replacement of the aliphatic or hydrophobic amino acids Ala, Val, Leu and Ile;
replacement of the hydroxyl residues Ser and Thr; replacement of the acidic residues Asp and Glu; replacement of the amide residues Asn and Gln, replacement of the basic residues Lys, Arg, and His; replacement of the aromatic residues Phe, Tyr, and Trp, and replacement of the small-sized amino acids Ala, Ser, Thr, Met, and Gly.
Besides conservative amino acid substitution, variants of the present invention include (i) substitutions with one or more of the non-conserved amino acid residues, where the substituted amino acid residues may or may not be one encoded by the genetic code, or (ii) substitution with one or more of amino acid residues having a substituent group, or (iii) fusion of the mature polypeptide with another compound, such as a compound to increase the stability and/or solubility of the polypeptide (for example, polyethylene glycol), or (iv) fusion of the polypeptide with additional amino acids, such as an IgG Fc fusion region peptide, or leader or secretory sequence, or a sequence facilitating purification. Such variant polypeptides are deemed to be within the scope of those skilled in the art from the teachings herein.
For example, polypeptide variants containing amino acid substitutions of charged amino acids with other charged or neutral amino acids may produce proteins with improved characteristics, such as less aggregation. Aggregation of pharmaceutical formulations both reduces activity and increases clearance due to the aggregate's immunogenic activity. (Pinckard et al., Clin. Exp. Immunol. 2:331-340 (1967);
Robbins et al., Diabetes 36: 838-845 (1987); Cleland et al., Crit. Rev.
Therapeutic Drug Carrier Systems 10:307-377 (1993).) Polynucleotide and Polypeptide Fragments In the present invention, a "polynucleotide fragment" refers to a short polynucleotide having a nucleic acid sequence contained in the deposited clone or shown in SEQ ID NO:X. The short nucleotide fragments are preferably at least about 15 nt, and more preferably at least about 20 nt, still more preferably at least about 30 nt, and even more preferably, at least about 40 nt in length. A fragment "at least 20 nt in length," for example, is intended to include 20 or more contiguous bases from the cDNA sequence contained in the deposited clone or the nucleotide sequence shown in SEQ ID NO:X. These nucleotide fragments are useful as diagnostic probes and primers as discussed herein. Of course, larger fragments (e.g., 50, 150, 500, 600, nucleotides) are preferred.
Moreover, representative examples of polynucleotide fragments of the invention, include, for example, fragments having a sequence from about nucleotide number 1-50, 51-100, 101-150, 151-200, 201-250, 251-300, 301-350, 351-400, 401-450, 451-500, 501-550, 551-600, 651-700, 701-750, 751-800, 800-850, 851-900, 901-950, 951-1000, 1001-1050, 1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-1300, 1301-1350, 1351-1400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650, 1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950, 1951-2000, or 2001 to the end of SEQ ID NO:X or the cDNA contained in the deposited clone. In this context "about" includes the particularly recited ranges, larger or smaller by several (5, 4, 3, 2, or 1) nucleotides, at either terminus or at both termini.
Preferably, these fragments encode a polypeptide which has biological activity. More preferably, these polynucleotides can be used as probes or primers as discussed herein.
In the present invention, a "polypeptide fragment" refers to a short amino acid sequence contained in SEQ ID NO:Y or encoded by the cDNA contained in the deposited clone. Protein fragments may be "free-standing," or comprised within a larger polypeptide of which the fragment forms a part or region, most preferably as a single continuous region. Representative examples of polypeptide fragments of the invention, include, for example, fragments from about amino acid number 1-20, 21-40, 41-60, 61-80, 81-100, 102-120, 121-140, 141-160, or 161 to the end of the coding region. Moreover, polypeptide fragments can be about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 amino acids in length. In this context "about"
includes the particularly recited ranges, larger or smaller by several (5, 4, 3, 2, or 1) amino acids, at either extreme or at both extremes.
Preferred polypeptide fragments include the secreted protein as well as the mature form. Further preferred polypeptide fragments include the secreted protein or the mature form having a continuous series of deleted residues from the amino or the carboxy terminus, or both. For example, any number of amino acids, ranging from 1-60, can be deleted from the amino terminus of either the secreted polypeptide or the mature form. Similarly, any number of amino acids, ranging from 1-30, can be deleted from the carboxy terminus of the secreted protein or mature form. Furthermore, any combination of the above amino and carboxy terminus deletions are preferred.
Similarly, polynucleotide fragments encoding these polypeptide fragments are also preferred.
Also preferred are polypeptide and polynucleotide fragments characterized by structural or functional domains, such as fragments that comprise alpha-helix and alpha-helix forming regions, beta-sheet and beta-sheet-forming regions, turn and turn-forming regions, coil and coil-forming regions, hydrophilic regions, hydrophobic regions, alpha amphipathic regions, beta amphipathic regions, flexible regions, surface-forming regions, substrate binding region, and high antigenic index regions.
Polypeptide fragments of SEQ ID NO:Y falling within conserved domains are specifically contemplated by the present invention. Moreover, polynucleotide fragments encoding these domains are also contemplated.
Other preferred fragments are biologically active fragments. Biologically active fragments are those exhibiting activity similar, but not necessarily identical, to an activity of the polypeptide of the present invention. The biological activity of the fragments may include an improved desired activity, or a decreased undesirable activity.
Epitopes & Antibodies In the present invention, "epitopes" refer to polypeptide fragments having antigenic or immunogenic activity in an animal, especially in a human. A
preferred embodiment of the present invention relates to a polypeptide fragment comprising an epitope, as well as the polynucleotide encoding this fragment. A region of a protein molecule to which an antibody can bind is defined as an "antigenic epitope."
In contrast, an "immunogenic epitope" is defined as a part of a protein that elicits an antibody response. (See, for instance, Geysen et al., Proc. Natl. Acad. Sci.
USA
81:3998- 4002 (1983).) Fragments which function as epitopes may be produced by any conventional means. (See, e.g., Houghten, R. A., Proc. Natl. Acad. Sci. USA 82:5131-5135 (1985) further described in U.S. Patent No. 4,631,211.) In the present invention, antigenic epitopes preferably contain a sequence of at least seven, more preferably at least nine, and most preferably between about 15 to about 30 amino acids. Antigenic epitopes are useful to raise antibodies, including monoclonal antibodies, that specifically bind the epitope. (See, for instance, Wilson et al., Cell 37:767-778 (1984); Sutcliffe, J. G. et al., Science 219:660-666 (1983).) Similarly, immunogenic epitopes can be used to induce antibodies according to methods well known in the art. (See, for instance, Sutcliffe et al., supra;
Wilson et al., supra; Chow, M. et al., Proc. Natl. Acad. Sci. USA 82:910-914; and Bittle, F.
J. et al., J. Gen. Virol. 66:2347-2354 (1985).) A preferred immunogenic epitope includes 5 the secreted protein. The immunogenic epitopes may be presented together with a carrier protein, such as an albumin, to an animal system (such as rabbit or mouse) or, if it is long enough (at least about 25 amino acids), without a carrier. However, immunogenic epitopes comprising as few as 8 to 10 amino acids have been shown to be sufficient to raise antibodies capable of binding to, at the very least, linear epitopes in a 10 denatured polypeptide (e.g., in Western blotting.) As used herein, the term "antibody" (Ab) or "monoclonal antibody" (Mab) is meant to include intact molecules as well as antibody fragments (such as, for example, Fab and F(ab')2 fragments) which are capable of specifically binding to protein. Fab and F(ab')2 fragments lack the Fc fragment of intact antibody, clear more rapidly from 15 the circulation, and may have less non-specific tissue binding than an intact antibody.
(Wahl et al., J. Nucl. Med. 24:316-325 (1983).) Thus, these fragments are preferred, as well as the products of a FAB or other immunoglobulin expression library.
Moreover, antibodies of the present invention include chimeric, single chain, and humanized antibodies.
Fusion Proteins Any polypeptide of the present invention can be used to generate fusion proteins. For example, the polypeptide of the present invention, when fused to a second protein, can be used as an antigenic tag. Antibodies raised against the polypeptide of the present invention can be used to indirectly detect the second protein by binding to the polypeptide. Moreover, because secreted proteins target cellular locations based on trafficking signals, the polypeptides of the present invention can be used as targeting molecules once fused to other proteins.
Examples of domains that can be fused to polypeptides of the present invention include not only heterologous signal sequences, but also other heterologous functional regions. The fusion does not necessarily need to be direct, but may occur through linker sequences.
Moreover, fusion proteins may also be engineered to improve characteristics of the polypeptide of the present invention. For instance, a region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the polypeptide to improve stability and persistence during purification from the host cell or subsequent handling and storage. Also, peptide moieties may be added to the polypeptide to facilitate purification. Such regions may be removed prior to final preparation of the polypeptide. The addition of peptide moieties to facilitate handling of polypeptides are familiar and routine techniques in the art.
Moreover, polypeptides of the present invention, including fragments, and specifically epitopes, can be combined with parts of the constant domain of immunoglobulins (IgG), resulting in chimeric polypeptides. These fusion proteins facilitate purification and show an increased half-life in vivo. One reported example describes chimeric proteins consisting of the first two domains of the human polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. (EP A 394,827; Traunecker et al., Nature 331:84-86 (1988).) Fusion proteins having disulfide-linked dimeric structures (due to the IgG) can also be more efficient in binding and neutralizing other molecules, than the monomeric secreted protein or protein fragment alone. (Fountoulakis et al., J.
Biochem. 270:3958-3964 (1995).) Similarly, EP-A-O 464 533 (Canadian counterpart 2045869) discloses fusion proteins comprising various portions of constant region of immunoglobulin molecules together with another human protein or part thereof. In many cases, the Fc part in a fusion protein is beneficial in therapy and diagnosis, and thus can result in, for example, improved pharmacokinetic properties. (EP-A 0232 262.) Alternatively, deleting the Fc part after the fusion protein has been expressed, detected, and purified, would be desired. For example, the Fc portion may hinder therapy and diagnosis if the fusion protein is used as an antigen for immunizations. In drug discovery, for example, human proteins, such as hIL-5, have been fused with Fc portions for the purpose of high-throughput screening assays to identify antagonists of hIL-5.
(See, D.
Bennett et al., J. Molecular Recognition 8:52-58 (1995); K. Johanson et al., J. Biol.
Chem. 270:9459-9471 (1995).) Moreover, the polypeptides of the present invention can be fused to marker sequences, such as a peptide which facilitates purification of the fused polypeptide. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311), among others, many of which are conunercially available.
As described in Gentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein.
Another peptide tag useful for purification, the "HA" tag, corresponds to an epitope derived from the influenza hemagglutinin protein. (Wilson et al., Cell 37:767 (1984).) Thus, any of these above fusions can be engineered using the polynucleotides or the polypeptides of the present invention.

VectorsL Host Cells, and Protein Production The present invention also relates to vectors containing the polynucleotide of the present invention, host cells, and the production of polypeptides by recombinant techniques. The vector may be, for example, a phage, piasmid, viral, or retroviral vector. Retroviral vectors may be replication competent or replication defective. In the latter case, viral propagation generally will occur only in complementing host cells.
The polynucleotides may be joined to a vector containing a selectable marker for propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it may be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.
The polynucleotide insert should be operatively linked to an appropriate promoter, such as the phage lambda PL promoter, the E. coli lac, trp, phoA and tac promoters, the SV40 early and late promoters and promoters of retroviral LTRs, to name a few. Other suitable promoters will be known to the skilled artisan. The expression constructs will further contain sites for transcription initiation, ternvnation, and, in the transcribed region, a ribosome binding site for translation. The coding portion of the transcripts expressed by the constructs will preferably include a translation initiating codon at the beginning and a termination codon (UAA, UGA or UAG) appropriately positioned at the end of the polypeptide to be translated.
As indicated, the expression vectors will preferably include at least one selectable marker. Such markers include dihydrofolate reductase, G418 or neomycin resistance for eukaryotic cell culture and tetracycline, kanamycin or ampicillin resistance genes for culturing in E. coli and other bacteria. Representative examples of appropriate hosts include, but are not limited to, bacterial cells, such as E.
coli, Streptomyces and Salmonella typhimurium cells; fungal cells, such as yeast cells; insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, 293, and Bowes melanoma cells; and plant cells. Appropriate culture mediums and conditions for the above-described host cells are known in the art.
Among vectors preferred for use in bacteria include pQE70, pQE60 and pQE-9, available from QIAGEN, Inc.; pBluescript vectors, Phagescript vectors, pNH8A, pNH 16a, pNH18A, pNH46A, available from Stratagene Cloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 available from Pharmacia Biotech, Inc. Among preferred eukaryotic vectors are pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia. Other suitable vectors will be readily apparent to the skilled artisan.

Introduction of the construct into the host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other methods. Such methods are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology (1986). It is specifically contemplated that the polypeptides of the present invention may in fact be expressed by a host cell lacking a recombinant vector.
A polypeptide of this invention can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography ("HPLC") is employed for purification.
Polypeptides of the present invention, and preferably the secreted form, can also be recovered from: products purified from natural sources, including bodily fluids, tissues and cells, whether directly isolated or cultured; products of chemical synthetic procedures; and products produced by recombinant techniques from a prokaryotic or eukaryotic host, including, for example, bacterial, yeast, higher plant, insect, and mammalian cells. Depending upon the host employed in a recombinant production procedure, the polypeptides of the present invention may be glycosylated or may be non-glycosylated. In addition, polypeptides of the invention may also include an initial modified methionine residue, in some cases as a result of host-mediated processes.
Thus, it is well known in the art that the N-terminal methionine encoded by the translation initiation codon generally is removed with high efficiency from any protein after translation in all eukaryotic cells. While the N-terminal methionine on most proteins also is efficiently removed in most prokaryotes, for some proteins, this prokaryotic removal process is inefficient, depending on the nature of the amino acid to which the N-terminal methionine is covalently linked.

Uses of the Polynucleotides Each of the polynucleotides identified herein can be used in numerous ways as reagents. The following description should be considered exemplary and utilizes known techniques.
The polynucleotides of the present invention are useful for chromosome identification. There exists an ongoing need to identify new chromosome markers, since few chromosome marking reagents, based on actual sequence data (repeat polymorphisms), are presently available. Each polynucleotide of the present invention can be used as a chromosome marker.
Briefly, sequences can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp) from the sequences shown in SEQ ID NO:X. Primers can be selected using computer analysis so that primers do not span more than one predicted exon in the genomic DNA. These primers are then used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the SEQ ID NO:X will yield an amplified fragment.
Similarly, somatic hybrids provide a rapid method of PCR mapping the polynucleotides to particular chromosomes. Three or more clones can be assigned per day using a single thermal cycler. Moreover, sublocalization of the polynucleotides can be achieved with panels of specific chromosome fragments. Other gene mapping strategies that can be used include in situ hybridization, prescreening with labeled flow-sorted chromosomes, and preselection by hybridization to construct chromosome specific-cDNA libraries.
Precise chromosomal location of the polynucleotides can also be achieved using fluorescence in situ hybridization (FISH) of a metaphase chromosomal spread.
This technique uses polynucleotides as short as 500 or 600 bases; however, polynucleotides 2,000-4,000 bp are preferred. For a review of this technique, see Verma et al., "Human Chromosomes: a Manual of Basic Techniques," Pergamon Press, New York (1988).
For chromosome mapping, the polynucleotides can be used individually (to mark a single chromosome or a single site on that chromosome) or in panels (for marking multiple sites and/or multiple chromosomes). Preferred polynucleotides correspond to the noncoding regions of the cDNAs because the coding sequences are more likely conserved within gene families, thus increasing the chance of cross hybridization during chromosomal mapping.
Once a polynucleotide has been mapped to a precise chromosomal location, the physical position of the polynucleotide can be used in linkage analysis.
Linkage analysis establishes coinheritance between a chromosomal location and presentation of a particular disease. (Disease mapping data are found, for example, in V.
McKusick, Mendelian Inheritance in Man (available on line through Johns Hopkins University Welch Medical Library) .) Assuming 1 megabase mapping resolution and one gene per 20 kb, a cDNA precisely localized to a chromosomal region associated with the disease could be one of 50-500 potential causative genes.
Thus, once coinheritance is established, differences in the polynucleotide and the corresponding gene between affected and unaffected individuals can be examined.

First, visible structural alterations in the chromosomes, such as deletions or translocations, are examined in chromosome spreads or by PCR. If no structural alterations exist, the presence of point mutations are ascertained. Mutations observed in some or all affected individuals, but not in normal individuals, indicates that the 5 mutation may cause the disease. However, complete sequencing of the polypeptide and the corresponding gene from several normal individuals is required to distinguish the mutation from a polymorphism. If a new polymorphism is identified, this polymorphic polypeptide can be used for further linkage analysis.
Furthermore, increased or decreased expression of the gene in affected 10 individuals as compared to unaffected individuals can be assessed using polynucleotides of the present invention. Any of these alterations (altered expression, chromosomal rearrangement, or mutation) can be used as a diagnostic or prognostic marker.
In addition to the foregoing, a polynucleotide can be used to control gene 15 expression through triple helix formation or antisense DNA or RNA. Both methods rely on binding of the polynucleotide to DNA or RNA. For these techniques, preferred polynucleotides are usually 20 to 40 bases in length and complementary to either the region of the gene involved in transcription (triple helix - see Lee et al., Nucl. Acids Res. 6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 20 251:1360 (1991) ) or to the mRNA itself (antisense - Okano, J. Neurochem.
56:560 (1991); Oligodeoxy-nucleotides as Antisense Inhibitors of Gene Expression, CRC
Press, Boca Raton, FL (1988).) Triple helix formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide. Both techniques are effective in model 25 systems, and the information disclosed herein can be used to design antisense or triple helix polynucleotides in an effort to treat disease.
Polynucleotides of the present invention are also useful in gene therapy. One goal of gene therapy is to insert a normal gene into an organism having a defective gene, in an effort to correct the genetic defect. The polynucleotides disclosed in the 30 present invention offer a means of targeting such genetic defects in a highly accurate manner. Another goal is to insert a new gene that was not present in the host genome, thereby producing a new trait in the host cell.
The polynucleotides are also useful for identifying individuals from minute biological samples. The United States military, for example, is considering the use of 35 restriction fragment length polymorphism (RFLP) for identification of its personnel. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identifying personnel. This method does not suffer from the current limitations of "Dog Tags"
which can be lost, switched, or stolen, making positive identification difficult. The polynucleotides of the present invention can be used as additional DNA markers for RFLP.
The polynucleotides of the present invention can also be used as an alternative to RFLP, by determining the actual base-by-base DNA sequence of selected portions of an individual's genome. These sequences can be used to prepare PCR primers for amplifying and isolating such selected DNA, which can then be sequenced. Using this technique, individuals can be identified because each individual will have a unique set of DNA sequences. Once an unique ID database is established for an individual, positive identification of that individual, living or dead, can be made from extremely small tissue samples.
Forensic biology also benefits from using DNA-based identification techniques as disclosed herein. DNA sequences taken from very small biological samples such as tissues, e.g., hair or skin, or body fluids, e.g., blood, saliva, semen, etc., can be amplified using PCR. In one prior art technique, gene sequences amplified from polymorphic loci, such as DQa class II HLA gene, are used in forensic biology to identify individuals. (Erlich, H., PCR Technology, Freeman and Co. (1992).) Once these specific polymorphic loci are amplified, they are digested with one or more restriction enzymes, yielding an identifying set of bands on a Southern blot probed with DNA corresponding to the DQa class II HLA gene. Similarly, polynucleotides of the present invention can be used as polymorphic markers for forensic purposes.
There is also a need for reagents capable of identifying the source of a particular tissue. Such need arises, for example, in forensics when presented with tissue of unknown origin. Appropriate reagents can comprise, for example, DNA probes or primers specific to particular tissue prepared from the sequences of the present invention. Panels of such reagents can identify tissue by species and/or by organ type.
In a similar fashion, these reagents can be used to screen tissue cultures for contamination.
In the very least, the polynucleotides of the present invention can be used as molecular weight markers on Southern gels, as diagnostic probes for the presence of a specific mRNA in a particular cell type, as a probe to "subtract-out" known sequences in the process of discovering novel polynucleotides, for selecting and making oligomers for attachment to a "gene chip" or other support, to raise anti-DNA antibodies using DNA immunization techniques, and as an antigen to elicit an immune response.

Uses of the Polypeptides Each of the polypeptides identified herein can be used in numerous ways. The following description should be considered exemplary and utilizes known techniques.
A polypeptide of the present invention can be used to assay protein levels in a biological sample using antibody-based techniques. For example, protein expression in tissues can be studied with classical immunohistological methods. (Jalkanen, M., et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, M., et al., J. Cell . Biol.
105:3087-3096 (1987).) Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked inununosorbent assay (ELISA) and the radioinununoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase, and radioisotopes, such as iodine (125I, 1211), carbon (14C), sulfur (35S), tritium (3H), indium (112In), and technetium (99mTc), and fluorescent labels, such as fluorescein and rhodamine, and biotin.
In addition to assaying secreted protein levels in a biological sample, proteins can also be detected in vivo by imaging. Antibody labels or markers for in vivo imaging of protein include those detectable by X-radiography, NMR or ESR. For X-radiography, suitable labels include radioisotopes such as barium or cesium, which emit detectable radiation but are not overtly harmful to the subject. Suitable markers for NMR and ESR include those with a detectable characteristic spin, such as deuterium, which may be incorporated into the antibody by labeling of nutrients for the relevant hybridoma.
A protein-specific antibody or antibody fragment which has been labeled with an appropriate detectable imaging moiety, such as a radioisotope (for example, 13 11, 112In, 99mTc), a radio-opaque substance, or a material detectable by nuclear magnetic resonance, is introduced (for example, parenterally, subcutaneously, or intraperitoneally) into the mammal. It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of 99mTc. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which contain the specific protein. In vivo tumor imaging is described in S.W. Burchiel et al., "Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments." (Chapter 13 in Tumor Imaging:
The Radiochemical Detection of Cancer, S.W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982).) Thus, the invention provides a diagnostic method of a disorder, which involves (a) assaying the expression of a polypeptide of the present invention in cells or body fluid of an individual; (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed polypeptide gene expression level compared to the standard expression level is indicative of a disorder.
Moreover, polypeptides of the present invention can be used to treat disease.
For example, patients can be administered a polypeptide of the present invention in an effort to replace absent or decreased levels of the polypeptide (e.g., insulin), to supplement absent or decreased levels of a different polypeptide (e.g., hemoglobin S
for hemoglobin B), to inhibit the activity of a polypeptide (e.g., an oncogene), to activate the activity of a polypeptide (e.g., by binding to a receptor), to reduce the activity of a membrane bound receptor by competing with it for free ligand (e.g., soluble TNF receptors used in reducing inflammation), or to bring about a desired response (e.g., blood vessel growth).
Similarly, antibodies directed to a polypeptide of the present invention can also be used to treat disease. For example, administration of an antibody directed to a polypeptide of the present invention can bind and reduce overproduction of the polypeptide. Similarly, administration of an antibody can activate the polypeptide, such as by binding to a polypeptide bound to a membrane (receptor).
At the very least, the polypeptides of the present invention can be used as molecular weight markers on SDS-PAGE gels or on molecular sieve gel filtration columns using methods well known to those of skill in the art. Polypeptides can also be used to raise antibodies, which in turn are used to measure protein expression from a recombinant cell, as a way of assessing transformation of the host cell.
Moreover, the polypeptides of the present invention can be used to test the following biological activities.

Biological Activities The polynucleotides and polypeptides of the present invention can be used in assays to test for one or more biological activities. If these polynucleotides and polypeptides do exhibit activity in a particular assay, it is likely that these molecules may be involved in the diseases associated with the biological activity. Thus, the polynucleotides and polypeptides could be used to treat the associated disease.

Immune Activity A polypeptide or polynucleotide of the present invention may be useful in treating deficiencies or disorders of the immune system, by activating or inhibiting the proliferation, differentiation, or mobilization (chemotaxis) of immune cells.
Immune cells develop through a process called hematopoiesis, producing myeloid (platelets, red blood cells, neutrophils, and macrophages) and lymphoid (B and T lymphocytes) cells from pluripotent stem cells. The etiology of these immune deficiencies or disorders may be genetic, somatic, such as cancer or some autoimmune disorders, acquired (e.g., by chemotherapy or toxins), or infectious. Moreover, a polynucleotide or polypeptide of the present invention can be used as a marker or detector of a particular immune system disease or disorder.
A polynucleotide or polypeptide of the present invention may be useful in treating or detecting deficiencies or disorders of hematopoietic cells. A
polypeptide or polynucleotide of the present invention could be used to increase differentiation and proliferation of hematopoietic cells, including the pluripotent stem cells, in an effort to treat those disorders associated with a decrease in certain (or many) types hematopoietic cells. Examples of immunologic deficiency syndromes include, but are not limited to:
blood protein disorders (e.g. agammaglobulinemia, dysgammaglobulinemia), ataxia telangiectasia, common variable immunodeficiency, Digeorge Syndrome, HIV
infection, HTLV-BLV infection, leukocyte adhesion deficiency syndrome, lymphopenia, phagocyte bactericidal dysfunction, severe combined immunodeficiency (SCIDs), Wiskott-Aldrich Disorder, anemia, thrombocytopenia, or hemoglobinuria.
Moreover, a polypeptide or polynucleotide of the present invention could also be used to modulate hemostatic (the stopping of bleeding) or thrombolytic activity (clot formation). For example, by increasing hemostatic or thrombolytic activity, a polynucleotide or polypeptide of the present invention could be used to treat blood coagulation disorders (e.g., afibrinogenemia, factor deficiencies), blood platelet disorders (e.g. thrombocytopenia), or wounds resulting from trauma, surgery, or other causes. Alternatively, a polynucleotide or polypeptide of the present invention that can decrease hemostatic or thrombolytic activity could be used to inhibit or dissolve clotting. These molecules could be important in the treatment of heart attacks (infarction), strokes, or scarring.
A polynucleotide or polypeptide of the present invention may also be useful in treating or detecting autoimmune disorders. Many autoinunune disorders result from inappropriate recognition of self as foreign material by immune cells. This inappropriate recognition results in an immune response leading to the destruction of the host tissue. Therefore, the administration of a polypeptide or polynucleotide of the present invention that inhibits an immune response, particularly the proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing autoimmune disorders.

Examples of autoimmune disorders that can be treated or detected by the present invention include, but are not limited to: Addison's Disease, hemolytic anemia, antiphospholipid syndrome, rheumatoid arthritis, dermatitis, allergic encephalomyelitis, glomerulonephritis, Goodpasture's Syndrome, Graves' Disease, Multiple Sclerosis, 5 Myasthenia Gravis, Neuritis, Ophthalmia, Bullous Pemphigoid, Pemphigus, Polyendocrinopathies, Purpura, Reiter's Disease, Stiff-Man Syndrome, Autoimmune Thyroiditis, Systemic Lupus Erythematosus, Autoimmune Pulmonary Inflammation, Guillain-Barre Syndrome, insulin dependent diabetes mellitis, and autoimmune inflammatory eye disease.
10 Similarly, allergic reactions and conditions, such as asthma (particularly allergic asthma) or other respiratory problems, may also be treated by a polypeptide or polynucleotide of the present invention. Moreover, these molecules can be used to treat anaphylaxis, hypersensitivity to an antigenic molecule, or blood group incompatibility.
A polynucleotide or polypeptide of the present invention may also be used to 15 treat and/or prevent organ rejection or graft-versus-host disease (GVHD).
Organ rejection occurs by host immune cell destruction of the transplanted tissue through an immune response. Similarly, an immune response is also involved in GVHD, but, in this case, the foreign transplanted immune cells destroy the host tissues. The administration of a polypeptide or polynucleotide of the present invention that inhibits 20 an immune response, particularly the proliferation. differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing organ rejection or GVHD.
Similarly, a polypeptide or polynucleotide of the present invention may also be used to modulate inflammation. For example, the polypeptide or polynucleotide may inhibit the proliferation and differentiation of cells involved in an inflammatory 25 response. These molecules can be used to treat inflammatory conditions, both chronic and acute conditions, including inflammation associated with infection (e.g., septic shock, sepsis, or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine induced lung injury, inflammatory bowel 30 disease, Crohn's disease, or resulting from over production of cytokines (e.g., TNF or IL-1.) Hyperproliferative Disorders A polypeptide or polynucleotide can be used to treat or detect hyperproliferative 35 disorders, including neoplasms. A polypeptide or polynucleotide of the present invention may inhibit the proliferation of the disorder through direct or indirect interactions. Alternatively, a polypeptide or polynucleotide of the present invention may proliferate other cells which can inhibit the hyperproliferative disorder.
For example, by increasing an immune response, particularly increasing antigenic qualities of the hyperproliferative disorder or by proliferating, differentiating, or mobilizing T-cells, hyperproliferative disorders can be treated. This immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, decreasing an immune response may also be a method of treating hyperproliferative disorders, such as a chemotherapeutic agent.
Examples of hyperproliferative disorders that can be treated or detected by a polynucleotide or polypeptide of the present invention include, but are not limited to neoplasms located in the: abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous (central and peripheral), lymphatic system, pelvic, skin, soft tissue, spleen, thoracic, and urogenital.
Similarly, other hyperproliferative disorders can also be treated or detected by a polynucleotide or polypeptide of the present invention. Examples of such hyperproliferative disorders include, but are not limited to:
hypergammaglobulinemia, lymphoproliferative disorders, paraproteinemias, purpura, sarcoidosis, Sezary Syndrome, Waldenstron's Macroglobulinemia, Gaucher's Disease, histiocytosis, and any other hyperproliferative disease, besides neoplasia, located in an organ system listed above.

Infectious Disease A polypeptide or polynucleotide of the present invention can be used to treat or detect infectious agents. For example, by increasing the immune response, particularly increasing the proliferation and differentiation of B and/or T cells, infectious diseases may be treated. The immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, the polypeptide or polynucleotide of the present invention may also directly inhibit the infectious agent, without necessarily eliciting an immune response.
Viruses are one example of an infectious agent that can cause disease or symptoms that can be treated or detected by a polynucleotide or polypeptide of the present invention. Examples of viruses, include, but are not limited to the following DNA and RNA viral families: Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Birnaviridae,-Bunyaviridae, Caliciviridae, Circoviridae, Coronaviridae, Flaviviridae, Hepadnaviridae (Hepatitis), Herpesviridae (such as, Cytomegalovirus, Herpes Simplex, Herpes Zoster), Mononegavirus (e.g., Paramyxoviridae, Morbillivirus, Rhabdoviridae), Orthomyxoviridae (e.g., Influenza), Papovaviridae, Parvoviridae, Picornaviridae, Poxviridae (such as Smallpox or Vaccinia), Reoviridae (e.g., Rotavirus), Retroviridae (HTLV-I, HTLV-II, Lentivirus), and Togaviridae (e.g., Rubivirus). Viruses falling within these families can cause a variety of diseases or symptoms, including, but not limited to: arthritis, bronchiollitis, encephalitis, eye infections (e.g., conjunctivitis, keratitis), chronic fatigue syndrome, hepatitis (A, B, C, E, Chronic Active, Delta), meningitis, opportunistic infections (e.g., AIDS), pneumonia, Burkitt's Lymphoma, chickenpox, hemorrhagic fever, Measles, Mumps, Parainfluenza, Rabies, the common cold, Polio, leukemia, Rubella, sexually transmitted diseases, skin diseases (e.g., Kaposi's, warts), and viremia. A
polypeptide or polynucleotide of the present invention can be used to treat or detect any of these symptoms or diseases.
Siniilarly, bacterial or fungal agents that can cause disease or symptoms and that can be treated or detected by a polynucleotide or polypeptide of the present invention include, but not limited to, the following Gram-Negative and Gram-positive bacterial families and fungi: Actinomycetales (e.g., Corynebacterium, Mycobacterium, Norcardia), Aspergillosis, Bacillaceae (e.g., Anthrax, Clostridium), Bacteroidaceae, Blastomycosis, Bordetella, Borrelia, Brucellosis, Candidiasis, Campylobacter, Coccidioidomycosis, Cryptococcosis, Dermatocycoses, Enterobacteriaceae (Klebsiella, Salmonella, Serratia, Yersinia), Erysipelothrix, Helicobacter, Legionellosis, Leptospirosis, Listeria, Mycoplasmatales, Neisseriaceae (e.g., Acinetobacter, Gonorrhea, Menigococcal), Pasteurellacea Infections (e.g., Actinobacillus, Heamophilus, Pasteurella), Pseudomonas, Rickettsiaceae, Chlamydiaceae, Syphilis, and Staphylococcal. These bacterial or fungal families can cause the following diseases or symptoms, including, but not limited to: bacteremia, endocarditis, eye infections (conjunctivitis, tuberculosis, uveitis), gingivitis, opportunistic infections (e.g., AIDS
related infections), paronychia, prosthesis-related infections, Reiter's Disease, respiratory tract infections, such as Whooping Cough or Empyema, sepsis, Lyme Disease, Cat-Scratch Disease, Dysentery, Paratyphoid Fever, food poisoning, Typhoid, pneumonia, Gonorrhea, meningitis, Chlamydia, Syphilis, Diphtheria, Leprosy, Paratuberculosis, Tuberculosis, Lupus, Botulism, gangrene, tetanus, impetigo, Rheumatic Fever, Scarlet Fever, sexually transmitted diseases, skin diseases (e.g., cellulitis, dermatocycoses), toxemia, urinary tract infections, wound infections.
A polypeptide or polynucleotide of the present invention can be used to treat or detect any of these symptoms or diseases.

Moreover, parasitic agents causing disease or symptoms that can be treated or detected by a polynucleotide or polypeptide of the present invention include, but not limited to, the following families: Amebiasis, Babesiosis, Coccidiosis, Cryptosporidiosis, Dientamoebiasis, Dourine, Ectoparasitic, Giardiasis, Helminthiasis, Leishmaniasis, Theileriasis, Toxoplasmosis, Trypanosomiasis, and Trichomonas.
These parasites can cause a variety of diseases or symptoms, including, but not limited to: Scabies, Trombiculiasis, eye infections, intestinal disease (e.g., dysentery, giardiasis), liver disease, lung disease, opportunistic infections (e.g., AIDS
related), Malaria, pregnancy complications, and toxoplasmosis. A polypeptide or polynucleotide of the present invention can be used to treat or detect any of these symptoms or diseases.
Preferably, treatment using a polypeptide or polynucleotide of the present invention could either be by administering an effective amount of a polypeptide to the patient, or by removing cells from the patient, supplying the cells with a polynucleotide of the present invention, and returning the engineered cells to the patient (ex vivo therapy). Moreover, the polypeptide or polynucleotide of the present invention can be used as an antigen in a vaccine to raise an immune response against infectious disease.
Regeneration A polynucleotide or polypeptide of the present invention can be used to differentiate, proliferate, and attract cells, leading to the regeneration of tissues. (See, Science 276:59-87 (1997).) The regeneration of tissues could be used to repair, replace, or protect tissue damaged by congenital defects, trauma (wounds, burns, incisions, or ulcers), age, disease (e.g. osteoporosis, osteocarthritis, periodontal disease, liver failure), surgery, including cosmetic plastic surgery, fibrosis, reperfusion injury, or systemic cytokine damage.
Tissues that could be regenerated using the present invention include organs (e.g., pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac), vascular (including vascular endothelium), nervous, hematopoietic, and skeletal (bone, cartilage, tendon, and ligament) tissue. Preferably, regeneration occurs without or decreased scarring. Regeneration also may include angiogenesis.
Moreover, a polynucleotide or polypeptide of the present invention may increase regeneration of tissues difficult to heal. For example, increased tendon/ligament regeneration would quicken recovery time after damage. A polynucleotide or polypeptide of the present invention could also be used prophylactically in an effort to avoid damage. Specific diseases that could be treated include of tendinitis, carpal tunnel syndrome, and other tendon or ligament defects. A further example of tissue regeneration of non-healing wounds includes pressure ulcers, ulcers associated with vascular insufficiency, surgical, and traumatic wounds.
Similarly, nerve and brain tissue could also be regenerated by using a polynucleotide or polypeptide of the present invention to proliferate and differentiate nerve cells. Diseases that could be treated using this method include central and peripheral nervous system diseases, neuropathies, or mechanical and traumatic disorders (e.g., spinal cord disorders, head trauma, cerebrovascular disease, and stoke). Specifically, diseases associated with peripheral nerve injuries, peripheral neuropathy (e.g., resulting from chemotherapy or other medical therapies), localized neuropathies, and central nervous system diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome), could all be treated using the polynucleotide or polypeptide of the present invention.

Chemotaxis A polynucleotide or polypeptide of the present invention may have chemotaxis activity. A chemotaxic molecule attracts or mobilizes cells (e.g., monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells) to a particular site in the body, such as inflammation, infection, or site of hyperproliferation. The mobilized cells can then fight off and/or heal the particular trauma or abnormality.
A polynucleotide or polypeptide of the present invention may increase chemotaxic activity of particular cells. These chemotactic molecules can then be used to treat inflammation, infection, hyperproliferative disorders, or any immune system disorder by increasing the number of cells targeted to a particular location in the body.
For example, chemotaxic molecules can be used to treat wounds and other trauma to tissues by attracting immune cells to the injured location. Chemotactic molecules of the present invention can also attract fibroblasts, which can be used to treat wounds.
It is also contemplated that a polynucleotide or polypeptide of the present invention may inhibit chemotactic activity. These molecules could also be used to treat disorders. Thus, a polynucleotide or polypeptide of the present invention could be used as an inhibitor of chemotaxis.

Binding Activity A polypeptide of the present invention may be used to screen for molecules that bind to the polypeptide or for molecules to which the polypeptide binds. The binding of the polypeptide and the molecule may activate (agonist), increase, inhibit (antagonist), or decrease activity of the polypeptide or the molecule bound.
Examples of such molecules include antibodies, oligonucleotides, proteins (e.g., receptors),or small molecules.
Preferably, the molecule is closely related to the natural ligand of the 5 polypeptide, e.g., a fragment of the ligand, or a natural substrate, a ligand, a structural or functional mimetic. (See, Coligan et al., Current Protocols in Immunology 1(2):Chapter 5 (1991).) Similarly, the molecule can be closely related to the natural receptor to which the polypeptide binds, or at least, a fragment of the receptor capable of being bound by the polypeptide (e.g., active site). In either case, the molecule can 10 be rationally designed using known techniques.
Preferably, the screening for these molecules involves producing appropriate cells which express the polypeptide, either as a secreted protein or on the cell membrane. Preferred cells include cells from mammals, yeast, Drosophila, or E.
coli.
Cells expressing the polypeptide (or cell membrane containing the expressed 15 polypeptide) are then preferably contacted with a test compound potentially containing the molecule to observe binding, stimulation, or inhibition of activity of either the polypeptide or the molecule.
The assay may simply test binding of a candidate compound to the polypeptide, wherein binding is detected by a label, or in an assay involving competition with a 20 labeled competitor. Further, the assay may test whether the candidate compound results in a signal generated by binding to the polypeptide.
Alternatively, the assay can be carried out using cell-free preparations, polypeptide/molecule affixed to a solid support, chemical libraries, or natural product mixtures. The assay may also simply comprise the steps of mixing a candidate 25 compound with a solution containing a polypeptide, measuring polypeptide/molecule activity or binding, and comparing the polypeptide/molecule activity or binding to a standard.
Preferably, an ELISA assay can measure polypeptide level or activity in a sample (e.g., biological sample) using a monoclonal or polyclonal antibody.
The 30 antibody can measure polypeptide level or activity by either binding, directly or indirectly, to the polypeptide or by competing with the polypeptide for a substrate.
All of these above assays can be used as diagnostic or prognostic markers. The molecules discovered using these assays can be used to treat disease or to bring about a particular result in a patient (e.g., blood vessel growth) by activating or inhibiting the 35 polypeptide/molecule. Moreover, the assays can discover agents which may inhibit or enhance the production of the polypeptide from suitably manipulated cells or tissues.

Therefore, the invention includes a method of identifying compounds which bind to a polypeptide of the invention comprising the steps of: (a) incubating a candidate binding compound with a polypeptide of the invention; and (b) determining if binding has occurred. Moreover, the invention includes a method of identifying agonists/antagonists comprising the steps of: (a) incubating a candidate compound with a polypeptide of the invention, (b) assaying a biological activity , and (b) determining if a biological activity of the polypeptide has been altered.

Other Activities A polypeptide or polynucleotide of the present invention may also increase or decrease the differentiation or proliferation of embryonic stem cells, besides, as discussed above, hematopoietic lineage.
A polypeptide or polynucleotide of the present invention may also be used to modulate mammalian characteristics, such as body height, weight, hair color, eye color, skin, percentage of adipose tissue, pigmentation, size, and shape (e.g., cosmetic surgery). Similarly, a polypeptide or polynucleotide of the present invention may be used to modulate mammalian metabolism affecting catabolism, anabolism, processing, utilization, and storage of energy.
A polypeptide or polynucleotide of the present invention may be used to change a mammal's mental state or physical state by influencing biorhythms, caricadic rhythms, depression (including depressive disorders), tendency for violence, tolerance for pain, reproductive capabilities (preferably by Activin or Inhibin-like activity), hormonal or endocrine levels, appetite, libido, memory, stress, or other cognitive qualities.
A polypeptide or polynucleotide of the present invention may also be used as a food additive or preservative, such as to increase or decrease storage capabilities, fat content, lipid, protein, carbohydrate, vitamins, minerals, cofactors or other nutritional components.

Other Preferred Embodiments Other preferred embodiments of the claimed invention include an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95%
identical to a sequence of at least about 50 contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X wherein X is any integer as defined in Table 1.
Also preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is included in the nucleotide sequence of SEQ ID NO:X in the range of positions beginning with the nucleotide at about the position of the 5' Nucleotide of the Clone Sequence and ending with the nucleotide at about the position of the 3' Nucleotide of the Clone Sequence as defined for SEQ ID NO:X in Table 1.
Also preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is included in the nucleotide sequence of SEQ ID NO:X in the range of positions beginning with the nucleotide at about the position of the 5' Nucleotide of the Start Codon and ending with the nucleotide at about the position of the 3' Nucleotide of the Clone Sequence as defined for SEQ ID NO:X in Table 1.
Similarly preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is included in the nucleotide sequence of SEQ ID NO:X
in the range of positions beginning with the nucleotide at about the position of the 5' Nucleotide of the First Amino Acid of the Signal Peptide and ending with the nucleotide at about the position of the 3' Nucleotide of the Clone Sequence as defined for SEQ ID
NO:X in Table 1.
Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 150 contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X.
Further preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 500 contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X.
A further preferred embodiment is a nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the nucleotide sequence of SEQ
ID NO:X beginning with the nucleotide at about the position of the 5' Nucleotide of the First Amino Acid of the Signal Peptide and ending with the nucleotide at about the position of the 3' Nucleotide of the Clone Sequence as defined for SEQ ID NO:X
in Table 1.
A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the complete nucleotide sequence of SEQ ID NO:X.
Also preferred is an isolated nucleic acid molecule which hybridizes under stringent hybridization conditions to a nucleic acid molecule, wherein said nucleic acid molecule which hybridizes does not hybridize under stringent hybridization conditions to a nucleic acid molecule having a nucleotide sequence consisting of only A
residues or of only T residues.
Also preferred is a composition of matter comprising a DNA molecule which comprises a human cDNA clone identified by a cDNA Clone Identifier in Table 1, which DNA molecule is contained in the material deposited with the American Type Culture Collection and given the ATCC Deposit Number shown in Table 1 for said cDNA Clone Identifier.
Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least 50 contiguous nucleotides in the nucleotide sequence of a human cDNA clone identified by a cDNA
Clone Identifier in Table 1, which DNA molecule is contained in the deposit given the ATCC Deposit Number shown in Table 1.
Also preferred is an isolated nucleic acid molecule, wherein said sequence of at least 50 contiguous nucleotides is included in the nucleotide sequence of the complete open reading frame sequence encoded by said human cDNA clone.
Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to sequence of at least 150 contiguous nucleotides in the nucleotide sequence encoded by said human cDNA clone.
A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to sequence of at least contiguous nucleotides in the nucleotide sequence encoded by said human cDNA
clone.
A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the complete nucleotide sequence encoded by said human cDNA clone.
A further preferred embodiment is a rnethod for detecting in a biological sample a nucleic acid molecule comprising a nucleotide sequence which is at least 95%
identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X wherein X is any integer as defined in Table 1; and a nucleotide sequence encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1; which method comprises a step of comparing a nucleotide sequence of at least one nucleic acid molecule in said sample with a sequence selected from said group and determining whether the sequence of said nucleic acid molecule in said sample is at least 95%
identical to said selected sequence.
Also preferred is the above method wherein said step of comparing sequences comprises determining the extent of nucleic acid hybridization between nucleic acid molecules in said sample and a nucleic acid molecule comprising said sequence selected from said group. Similarly, also preferred is the above method wherein said step of comparing sequences is performed by comparing the nucleotide sequence determined from a nucleic acid molecule in said sample with said sequence selected from said group. The nucleic acid molecules can comprise DNA molecules or RNA molecules.

A further preferred embodiment is a method for identifying the species, tissue or cell type of a biological sample which method comprises a step of detecting nucleic acid molecules in said sample, if any, comprising a nucleotide sequence that is at least 95%
identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X wherein X is any integer as defined in Table 1; and a nucleotide sequence encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
The method for identifying the species, tissue or cell type of a biological sample can comprise a step of detecting nucleic acid molecules comprising a nucleotide sequence in a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from said group.
Also preferred is a method for diagnosing in a subject a pathological condition associated with abnormal structure or expression of a gene encoding a secreted protein identified in Table 1, which method comprises a step of detecting in a biological sample obtained from said subject nucleic acid molecules, if any, comprising- a nucleotide sequence that is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X wherein X is any integer as defined in Table 1; and a nucleotide sequence encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table I and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
The method for diagnosing a pathological condition can comprise a step of detecting nucleic acid molecules comprising a nucleotide sequence in a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95%
identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from said group.
Also preferred is a composition of matter comprising isolated nucleic acid molecules wherein the nucleotide sequences of said nucleic acid molecules comprise a panel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X
wherein X is any integer as defined in Table 1; and a nucleotide sequence encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table I and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1. The nucleic acid molecules can comprise DNA molecules or RNA molecules.

Also preferred is an isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence of at least about 10 contiguous amino acids in the amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table 1.
Also preferred is a polypeptide, wherein said sequence of contiguous amino acids is included in the amino acid sequence of SEQ ID NO:Y in the range of positions beginning with the residue at about the position of the First Amino Acid of the Secreted Portion and ending with the residue at about the Last Amino Acid of the Open Reading Frame as set forth for SEQ ID NO:Y in Table 1.
Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 30 contiguous amino acids in the amino acid sequence of SEQ ID NO:Y.
Further preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 100 contiguous amino acids in the amino acid sequence of SEQ ID NO:Y.
Further preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to the complete amino acid sequence of SEQ ID NO:Y.
Further preferred is an isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence of at least about 10 contiguous amino acids in the complete amino acid sequence of a secreted protein encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Also preferred is a polypeptide wherein said sequence of contiguous amino acids is included in the amino acid sequence of a secreted portion of the secreted protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA
clone in Table 1.
Also preferred is an isolated polypeptide comprising an atnino acid sequence at least 95% identical to a sequence of at least about 30 contiguous amino acids in the amino acid sequence of the secreted portion of the protein encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 100 contiguous amino acids in the amino acid sequence of the secreted portion of the protein encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.

Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to the amino acid sequence of the secreted portion of the protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA
clone in Table 1.
Further preferred is an isolated antibody which binds specifically to a polypeptide comprising an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO: Y wherein Y is any integer as defined in Table 1; and a complete amino acid sequence of a protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Further preferred is a method for detecting in a biological sample a polypeptide comprising an anuno acid sequence which is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table 1;
and a complete amino acid sequence of a protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1; which method comprises a step of comparing an amino acid sequence of at least one polypeptide molecule in said sample with a sequence selected from said group and determining whether the sequence of said polypeptide molecule in said sample is at least 90%
identical to said sequence of at least 10 contiguous amino acids.
Also preferred is the above method wherein said step of comparing an amino acid sequence of at least one polypeptide molecule in said sample with a sequence selected from said group comprises determining the extent of specific binding of polypeptides in said sample to an antibody which binds specifically to a polypeptide comprising an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of:
an amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table 1;
and a complete amino acid sequence of a protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Also preferred is the above method wherein said step of comparing sequences is performed by comparing the amino acid sequence determined from a polypeptide molecule in said sample with said sequence selected from said group.

Also preferred is a method for identifying the species, tissue or cell type of a biological sample which method comprises a step of detecting polypeptide molecules in said sample, if any, comprising an amino acid sequence that is at least 90%
identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table 1; and a complete amino acid sequence of a secreted protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table I and contained in the deposit with the ATCC Deposit Number shown for said cDNA. clone in Table 1.
Also preferred is the above method for identifying the species, tissue or cell type of a biological sample, which method comprises a step of detecting polypeptide molecules comprising an amino acid sequence in a panel of at least two amino acid sequences, wherein at least one sequence in said panel is at least 90%
identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the above group.
Also preferred is a method for diagnosing in a subject a pathological condition associated with abnormal structure or expression of a gene encoding a secreted protein identified in Table 1, which method comprises a step of detecting in a biological sample obtained from said subject polypeptide molecules comprising an amino acid sequence in a panel of at least two amino acid sequenceti, wherein at least one sequence in said panel is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ
ID
NO:Y wherein Y is any integer as defined in Table I; and a complete amino acid sequence of a secreted protein encoded by a human cDNA clone identified by a cDNA
Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
In any of these methods, the step of detecting said polypeptide molecules includes using an antibody.
Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a nucleotide sequence encoding a polypeptide wherein said polypeptide comprises an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y
is any integer as defmed in Table 1; and a complete amino acid sequence of a secreted protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA
clone in Table 1.

Also preferred is an isolated nucleic acid molecule, wherein said nucleotide sequence encoding a polypeptide has been optimized for expression of said polypeptide in a prokaryotic host.
Also preferred is an isolated nucleic acid molecule, wherein said polypeptide comprises an amino acid sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO: Y wherein Y is any integer as defined in Table 1; and a complete amino acid sequence of a secreted protein encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Further preferred is a method of making a recombinant vector comprising inserting any of the above isolated nucleic acid molecule into a vector. Also preferred is the recombinant vector produced by this method. Also preferred is a method of making a recombinant host cell comprising introducing the vector into a host cell, as well as the recombinant host cell produced by this method.
Also preferred is a method of making an isolated polypeptide comprising culturing this recombinant host cell under conditions such that said polypeptide is expressed and recovering said polypeptide. Also preferred is this method of making an isolated polypeptide, wherein said recombinant host cell is a eukaryotic cell and said polypeptide is a secreted portion of a human secreted protein comprising an amino acid sequence selected from the group consisting of: an amino acid sequence of SEQ
ID
NO:Y beginning with the residue at the position of the First Amino Acid of the Secreted Portion of SEQ ID NO:Y wherein Y is an integer set forth in Table 1 and said position of the First Amino Acid of the Secreted Portion of SEQ ID NO: Y is defined in Table 1;
and an amino acid sequence of a secreted portion of a protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1. The isolated polypeptide produced by this method is also preferred.
Also preferred is a method of treatment of an individual in need of an increased level of a secreted protein activity, which method comprises administering to such an individual a pharmaceutical composition comprising an amount of an isolated polypeptide, polynucleotide, or antibody of the claimed invention effective to increase the level of said protein activity in said individual.
Having generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended as limiting.

Examples Example 1: Isolation of a Selected cDNA Clone From the Deposited Sample Each cDNA clone in a cited ATCC deposit is contained in a plasmid vector.
Table 1 identifies the vectors used to construct the cDNA library from which each clone was isolated. In many cases, the vector used to construct the library is a phage vector from which a plasmid has been excised. The table immediately below correlates the related plasmid for each phage vector used in constructing the cDNA library.
For example, where a particular clone is identified in Table I as being isolated in the vector "Lambda Zap," the corresponding deposited clone is in "pBluescript."
Vector Used to Construct Library Corresponding Deposited Plasmid Lambda Zap pBluescript (pBS) Uni-Zap XR pBluescript (pBS) Zap Express pBK
lafmid BA plafmid BA
pSport l pSport l pCMVSport 2.0 pCMVSport 2.0 pCMVSport 3.0 pCMVSport 3.0 pCR 2.1 pCR 2.1 Vectors Lambda Zap (U.S. Patent Nos. 5,128,256 and 5,286,636), Uni-Zap XR (U.S. Patent Nos. 5,128, 256 and 5,286,636), Zap Express (U.S. Patent Nos.
5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res.
16:7583-7600 (1988); Alting-Mees, M. A. and Short, J. M., Nucleic Acids Res.
17:9494 (1989)) and pBK (Alting-Mees, M. A. et al., Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla, CA, 92037. pBS contains an ampicillin resistance gene and pBK
contains a neomycin resistance gene. Both can be transformed into E. coli strain XL-1 Blue, also available from Stratagene. pBS comes in 4 forms SK+, SK-, KS+ and KS.
The S and K refers to the orientation of the polylinker to the T7 and T3 primer sequences which flank the polylinker region ("S" is for SacI and "K" is for KpnI which are the first sites on each respective end of the linker). "+" or "-" refer to the orientation of the fl origin of replication ("ori"), such that in one orientation, single stranded rescue initiated from the f i ori generates sense strand DNA and in the other, antisense.
Vectors pSport l, pCMVSport 2.0 and pCMVSport 3.0, were obtained from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, MD 20897. All Sport vectors contain an ampicillin resistance gene and may be transformed into E. coli strain DHIOB, also available from Life Technologies. (See, for instance, Gruber, C.
E., et al., Focus 15:59 (1993).) Vector lafmid BA (Bento Soares, Columbia University, NY) contains an ampicillin resistance gene and can be transformed into E. coli strain XL-1 Blue. Vector pCR 2.1, which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an ampicillin resistance gene and may be transformed into E. coli strain DH10B, available from Life Technologies. (See, for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al., Bio/Technology 9:
(1991).) Preferably, a polynucleotide of the present invention does not comprise the phage vector sequences identified for the particular clone in Table 1, as well as the corresponding plasmid vector sequences designated above.
The deposited material in the sample assigned the ATCC Deposit Number cited in Table 1 for any given cDNA clone also may contain one or more additional plasmids, each comprising a cDNA clone different from that given clone. Thus, deposits sharing the same ATCC Deposit Number contain at least a plasmid for each cDNA clone identified in Table 1. Typically, each ATCC deposit sample cited in Table 1 comprises a mixture of approximately equal amounts (by weight) of about 50 plasmid DNAs, each containing a different cDNA clone; but such a deposit sample may include plasmids for more or less than 50 cDNA clones, up to about 500 cDNA clones.
Two approaches can be used to isolate a particular clone from the deposited sample of plasmid DNAs cited for that clone in Table 1. First, a plasmid is directly isolated by screening the clones using a polynucleotide probe corresponding to SEQ ID
NO:X.
Particularly, a specific polynucleotide with 30-40 nucleotides is synthesized using an Applied Biosystems DNA synthesizer according to the sequence reported.
The oligonucleotide is labeled, for instance, with 32 P-y-ATP using T4 polynucleotide kinase and purified according to routine methods. (E.g., Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring, NY
(1982).) The plasmid mixture is transformed into a suitable host, as indicated above (such as XL-1 Blue (Stratagene)) using techniques known to those of skill in the art, such as those provided by the vector supplier or in related publications or patents cited above.
The transformants are plated on 1.5% agar plates (containing the appropriate selection agent, e.g., ampicillin) to a density of about 150 transformants (colonies) per plate.
These plates are screened using Nylon membranes according to routine methods for bacterial colony screening (e.g., Sambrook et al., Molecular Cloning: A
Laboratory Manual, 2nd Edit., (1989), Cold Spring Harbor Laboratory Press, pages 1.93 to 1.104), or other techniques known to those of skill in the art.

Alternatively, two primers of 17-20 nucleotides derived from both ends of the SEQ ID NO:X (i.e., within the region of SEQ ID NO:X bounded by the 5' NT and the 3' NT of the clone defined in Table 1) are synthesized and used to amplify the desired cDNA using the deposited cDNA plasmid as a template. The polymerase chain reaction is carried out under routine conditions, for instance, in 25 l of reaction nrnixture with 0.5 ug of the above cDNA template. A convenient reaction mixture is 1.5-5 mM
MgC121 0.01 % (w/v) gelatin, 20 M each of dATP, dCTP, dGTP, dTTP, 25 pmol of each primer and 0.25 Unit of Taq polymerase. Thirty five cycles of PCR
(denaturation at 94 C for I min; annealing at 55 C for 1 min; elongation at 72 C for 1 min) are performed with a Perkin-Elmer Cetus automated thermal cycler. The amplified product is analyzed by agarose gel electrophoresis and the DNA band with expected molecular weight is excised and purified. The PCR product is verified to be the selected sequence by subcloning and sequencing the DNA product.
Several methods are available for the identification of the 5' or 3' non-coding portions of a gene which may not be present in the deposited clone. These methods include but are not limited to, filter probing, clone enrichment using specific probes, and protocols similar or identical to 5' and 3' "RACE" protocols which are well known in the art. For instance, a method similar to 5' RACE is available for generating the missing 5' end of a desired full-length transcript. (Fromont-Racine et al., Nucleic Acids Res. 21(7):1683-1684 (1993).) Briefly, a specific RNA oligonucleotide is ligated to the 5' ends of a population of RNA presumably containing full-length gene RNA transcripts. A primer set containing a primer specific to the ligated RNA oligonucleotide and a primer specific to a known sequence of the gene of interest is used to PCR amplify the 5' portion of the desired full-length gene. This amplified product may then be sequenced and used to generate the full length gene.
This above method starts with total RNA isolated from the desired source, although poly-A+ RNA can be used. The RNA preparation can then be treated with phosphatase if necessary to eliminate 5' phosphate groups on degraded or damaged RNA which may interfere with the later RNA ligase step. The phosphatase should then be inactivated and the RNA treated with tobacco acid pyrophosphatase in order to remove the cap structure present at the 5' ends of messenger RNAs. This reaction leaves a 5' phosphate group at the 5' end of the cap cleaved RNA which can then be ligated to an RNA oligonucleotide using T4 RNA ligase.
This modified RNA preparation is used as a template for first strand cDNA
synthesis using a gene specific oligonucleotide. The first strand synthesis reaction is used as a template for PCR amplification of the desired 5' end using a primer specific to the ligated RNA oligonucleotide and a primer specific to the known sequence of the gene of interest. The resultant product is then sequenced and analyzed to confirm that the 5' end sequence belongs to the desired gene.
Example 2: Isolation of Genomic Clones Corresponding to a PolXnucleotide A human genomic P1 library (Genomic Systems, Inc.) is screened by PCR
using primers selected for the cDNA sequence corresponding to SEQ ID NO:X., according to the method described in Example 1. (See also, Sambrook.) Example 3: Tissue Distribution of Polypeptide Tissue distribution of mRNA expression of polynucleotides of the present invention is determined using protocols for Northern blot analysis, described by, among others, Sambrook et al. For example, a cDNA probe produced by the method described in Example 1 is labeled with P32 using the rediprimeTM DNA labeling system (Amersham Life Science), according to manufacturer's instructions. After labeling, the probe is purified using CHROMA SPIN-100TM column (Clontech Laboratories, Inc.), according to manufacturer's protocol number PT 1200-1. The purified labeled probe is then used to examine various human tissues for mRNA expression.
Multiple Tissue Northern (MTN) blots containing various human tissues (H) or human immune system tissues (IM) (Clontech) are examined with the labeled probe using ExpressHybTM hybridization solution (Clontech) according to manufacturer's protocol number PT1190-1. Following hybridization and washing, the blots are mounted and exposed to film at -70 C overnight, and the films developed according to standard procedures.

Example 4: Chromosomal Mapping of the Polynucleotides An oligonucleotide primer set is designed according to the sequence at the 5' end of SEQ ID NO:X. This primer preferably spans about 100 nucleotides. This primer set is then used in a polymerase chain reaction under the following set of conditions : 30 seconds, 95 C; 1 minute, 56 C; 1 minute, 70 C. This cycle is repeated 32 times followed by one 5 minute cycle at 70 C. Human, mouse, and hamster DNA
is used as template in addition to a somatic cell hybrid panel containing individual chromosomes or chromosome fragments (Bios, Inc). The reactions is analyzed on either 8% polyacrylamide gels or 3.5 % agarose gels. Chromosome mapping is determined by the presence of an approximately 100 bp PCR fragment in the particular somatic cell hybrid.

Example 5: Bacterial Expression of a Polypeptide A polynucleotide encoding a polypeptide of the present invention is amplified using PCR oligonucleotide primers corresponding to the 5' and 3' ends of the DNA
sequence, as outlined in Example 1, to synthesize insertion fragments. The primers used to amplify the cDNA insert should preferably contain restriction sites, such as BamHI and Xbal, at the 5' end of the primers in order to clone the amplified product into the expression vector. For example, BamHI and Xbal correspond to the restriction enzyme sites on the bacterial expression vector pQE-9. (Qiagen, Inc., Chatsworth, CA). This plasmid vector encodes antibiotic resistance (Ampr), a bacterial origin of replication (ori), an IPTG-regulatable promoter/operator (P/O), a ribosome binding site (RBS), a 6-histidine tag (6-His), and restriction enzyme cloning sites.
The pQE-9 vector is digested with BamHI and Xbal and the amplified fragment is ligated into the pQE-9 vector maintaining the reading frame initiated at the bacterial RBS. The ligation mixture is then used to transform the E. coli strain M
15/rep4 (Qiagen, Inc.) which contains multiple copies of the plasmid pREP4, which expresses the lacI repressor and also confers kanamycin resistance (Kanr). Transformants are identified by their ability to grow on LB plates and ampicillin/kanamycin resistant colonies are selected. Plasmid DNA is isolated and confirmed by restriction analysis.
Clones containing the desired constructs are grown overnight (O/N) in liquid culture in LB media supplemented with both Amp (100 ug/ml) and Kan (25 ug/ml).
The O/N culture is used to inoculate a large culture at a ratio of 1:100 to 1:250. The cells are grown to an optical density 600 (O.D.600) of between 0.4 and 0.6.
IPTG
(Isopropyl-B-D-thiogalacto pyranoside) is then added to a final concentration of 1 mM.
IPTG induces by inactivating the lacl repressor, clearing the P/O leading to increased gene expression.
Cells are grown for an extra 3 to 4 hours. Cells are then harvested by centrifugation (20 mins at 6000Xg). The cell pellet is solubilized in the chaotropic agent 6 Molar Guanidine HCI by stirring for 3-4 hours at 4 C. The cell debris is removed by centrifugation, and the supernatant containing the polypeptide is loaded onto a nickel-nitrilo-tri-acetic acid ("Ni-NTA") affinity resin column (available from QIAGEN, Inc., supra). Proteins with a 6 x His tag bind to the Ni-NTA resin with high affinity and can be purified in a simple one-step procedure (for details see:
The QIAexpressionist (1995) QIAGEN, Inc., supra).
Briefly, the supernatant is loaded onto the column in 6 M guanidine-HC1, pH 8, the colunm is first washed with 10 volumes of 6 M guanidine-HCI, pH 8, then washed with 10 volumes of 6 M guanidine-HCI pH 6, and finally the polypeptide is eluted with 6 M guanidine-HCI, pH 5.
The purified protein is then renatured by dialyzing it against phosphate-buffered saline (PBS) or 50 mM Na-acetate, pH 6 buffer plus 200 mM NaCI. Alternatively, the protein can be successfully refolded while immobilized on the Ni-NTA column.
The recommended conditions are as follows: renature using a linear 6M-1M urea gradient in 500 mM NaCI, 20% glycerol, 20 mM Tris/HCl pH 7.4, containing protease inhibitors.
The renaturation should be performed over a period of 1.5 hours or more. After renaturation the proteins are eluted by the addition of 250 m1VI immidazole.
Immidazole is removed by a final dialyzing step against PBS or 50 mM sodium acetate pH 6 buffer plus 200 mM NaC1. The purified protein is stored at 4" C or frozen at -80 C.
In addition to the above expression vector, the present invention further includes an expression vector comprising phage operator and promoter elements operatively linked to a polynucleotide of the present invention, called pHE4a. (ATCC
Accession Number 209645, deposited on February 25, 1998.) This vector contains: 1) a neomycinphosphotransferase gene as a selection marker, 2) an E. coli origin of replication, 3) a T5 phage promoter sequence, 4) two lac operator sequences, 5) a Shine-Delgarno sequence, and 6) the lactose operon repressor gene (laclq). The origin of replication (oriC) is derived from pUC 19 (LTI, Gaithersburg, MD). The promoter sequence and operator sequences are made synthetically.
DNA can be inserted into the pHEa by restricting the vector with NdeI and Xbal, BamHI, Xho1, or Asp718, running the restricted product on a gel, and isolating the larger fragment (the stuffer fragment should be about 310 base pairs). The DNA
insert is generated according to the PCR protocol described in Example 1, using PCR
primers having restriction sites for Nde1(5' primer) and Xbal, BamHI, Xho1, or Asp718 (3' primer). The PCR insert is gel purified and restricted with compatible enzymes. The insert and vector are ligated according to standard protocols.
The engineered vector could easily be substituted in the above protocol to express protein in a bacterial system.

Examnle 6: Purification of a Polypeptide from an Inclusion Body The following altemative method can be used to purify a polypeptide expressed in E coli when it is present in the form of inclusion bodies. Unless otherwise specified, all of the following steps are conducted at 4-10 C.

Upon completion of the production phase of the E. coli fermentation, the cell culture is cooled to 4-10 C and the cells harvested by continuous centrifugation at 15,000 rpm (Heraeus Sepatech). On the basis of the expected yield of protein per unit weight of cell paste and the amount of purified protein required, an appropriate amount of cell paste, by weight, is suspended in a buffer solution containing 100 mM
Tris, 50 mM EDTA, pH 7.4. The cells are dispersed to a homogeneous suspension using a high shear mixer.
The cells are then lysed by passing the solution through a microfluidizer (Microfuidics, Corp. or APV Gaulin, Inc.) twice at 4000-6000 psi. The homogenate is then mixed with NaCI solution to a final concentration of 0.5 M NaCI, followed by centrifugation at 7000 xg for 15 min. The resultant pellet is washed again using 0.5M
NaCl, 100 mM Tris, 50 mM EDTA, pH 7.4.
The resulting washed inclusion bodies are solubilized with 1.5 M guanidine hydrochloride (GuHCI) for 2-4 hours. After 7000 xg centrifugation for 15 min., the pellet is discarded and the polypeptide containinc, supernatant is incubated at 4 C
overnight to allow further GuHCI extraction.
Following high speed centrifugation (30.000 xg) to remove insoluble particles, the GuHCI solubilized protein is refolded by quickly mixing the GuHCI extract with 20 volumes of buffer containing 50 mM sodium, pH 4.5, 150 mM NaCI, 2 mM EDTA by vigorous stirring. The refolded diluted protein solution is kept at 4 C
without mixing for 12 hours prior to further purification steps.
To clarify the refolded polypeptide solution, a previously prepared tangential filtration unit equipped with 0.16 m membrane filter with appropriate surface area (e.g., Filtron), equilibrated with 40 mM sodium acetate, pH 6.0 is employed.
The filtered sample is loaded onto a cation exchange resin (e.g., Poros HS-50, Perseptive Biosystems). The column is washed with 40 mM sodium acetate, pH 6.0 and eluted with 250 mM, 500 mM, 1000 mM, and 1500 mM NaCI in the same buffer, in a stepwise manner. The absorbance at 280 nm of the effluent is continuously monitored.
Fractions are collected and further analyzed by SDS-PAGE.
Fractions containing the polypeptide are then pooled and mixed with 4 volumes of water. The diluted sample is then loaded onto a previously prepared set of tandem columns of strong anion (Poros HQ-50, Perseptive Biosystems) and weak anion (Poros CM-20, Perseptive Biosystems) exchange resins. The columns are equilibrated with 40 mM sodium acetate, pH 6Ø Both columns are washed with 40 mM sodium acetate, pH 6.0, 200 mM NaC1. The CM-20 column is then eluted using a 10 column volume linear gradient ranging from 0.2 M NaCl, 50 mM sodium acetate, pH 6.0 to 1.0 M NaC1, 50 mM sodium acetate, pH 6.5. Fractions are collected under constant A28, monitoring of the effluent. Fractions containing the polypeptide (determined, for instance, by 16% SDS-PAGE) are then pooled.
The resultant polypeptide should exhibit greater than 95% purity after the above refolding and purification steps. No major contaminant bands should be observed from Commassie blue stained 16% SDS-PAGE gel when 5 g of purified protein is loaded.
The purified protein can also be tested for endotoxin/LPS contamination, and typically the LPS content is less than 0.1 ng/ml according to LAL assays.

Example 7: Cloning and Expression of a Polypeptide in a Baculovirus Expression System In this example, the plasmid shuttle vector pA2 is used to insert a polynucleotide into a baculovirus to express a polypeptide. This expression vector contains the strong polyhedrin promoter of the Autographa californica nuclear polyhedrosis virus (AcMNPV) followed by convenient restriction sites such as BamHI, Xba I and Asp718. The polyadenylation site of the simian virus 40 ("SV40") is used for efficient polyadenylation. For easy selection of recombinant virus, the plasmid contains the beta-galactosidase gene from E. coli under control of a weak Drosophila promoter in the same orientation, followed by the polyadenylation signal of the polyhedrin gene. The inserted genes are flanked on both sides by viral sequences for cell-mediated homologous recombination with wild-type viral DNA to generate a viable virus that express the cloned polynucleotide.
Many other baculovirus vectors can be used in place of the vector above, such as pAc373, pVL941, and pAcIM 1, as one skilled in the art would readily appreciate, as long as the construct provides appropriately located signals for transcription, translation, secretion and the like, including a signal peptide and an in-frame AUG as required. Such vectors are described, for instance, in Luckow et al., Virology 170:31-39 (1989).
Specifically, the cDNA sequence contained in the deposited clone, including the AUG initiation codon and the naturally associated leader sequence identified in Table 1, is amplified using the PCR protocol described in Example 1. If the naturally occurring signal sequence is used to produce the secreted protein, the pA2 vector does not need a second signal peptide. Alternatively, the vector can be modified (pA2 GP) to include a baculovirus leader sequence, using the standard methods described in Summers et al., "A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures,"
Texas Agricultural Experimental Station Bulletin No. 1555 (1987).
The amplified fragment is isolated from a 1% agarose gel using a commercially available kit ("Geneclean," BIO 101 Inc., La Jolla, Ca.). The fragment then is digested with appropriate restriction enzymes and again purified on a 1% agarose gel.
The plasmid is digested with the corresponding restriction enzymes and optionally, can be dephosphorylated using calf intestinal phosphatase, using routine procedures known in the art. The DNA is then isolated from a 1% agarose gel using a commercially available kit ("Geneclean" BIO 101 Inc., La Jolla, Ca.).
The fragment and the dephosphorylated plasmid are ligated together with T4 DNA ligase. E. coli HB 101 or other suitable E. coli hosts such as XL-1 Blue (Stratagene Cloning Systems, La Jolla, CA) cells are transformed with the ligation mixture and spread on culture plates. Bacteria containing the plasmid are identified by digesting DNA from individual colonies and analyzing the digestion product by gel electrophoresis. The sequence of the cloned fragment is confirmed by DNA
sequencing.
Five g of a plasmid containing the polynucleotide is co-transfected with 1.0 g of a commercially available linearized baculovirus DNA ("BaculoGoldTM
baculovirus DNA", Pharmingen, San Diego, CA), using the lipofection method described by Felgner et al., Proc. Natl. Acad. Sci. USA 84:7413-7417 (1987). One g of BaculoGoldTM virus DNA and 5 g of the plasmid are mixed in a sterile well of a microtiter plate containing 50 l of serum-free Grace's medium (Life Technologies Inc., Gaithersburg, MD). Afterwards, 10 l Lipofectin plus 90 l Grace's medium are added, mixed and incubated for 15 minutes at room temperature. Then the transfection mixture is added drop-wise to Sf9 insect cells (ATCC CRL 1711) seeded in a 35 mm tissue culture plate with 1 ml Grace's medium without serum. The plate is then incubated for 5 hours at 27 C. The transfection solution is then removed from the plate and 1 rnl of Grace's insect medium supplemented with 10% fetal calf serum is added.
Cultivation is then continued at 27 C for four days.
After four days the supernatant is collected and a plaque assay is performed, as described by Summers and Smith, supra. An agarose gel with "Blue Gal" (Life Technologies Inc., Gaithersburg) is used to allow easy identification and isolation of gal-expressing clones, which produce blue-stained plaques. (A detailed description of a "plaque assay" of this type can also be found in the user's guide for insect cell culture and baculovirology distributed by Life Technologies Inc., Gaithersburg, page 9-10.) After appropriate incubation, blue stained plaques are picked with the tip of a micropipettor (e.g., Eppendorf). The agar containing the recombinant viruses is then resuspended in a microcentrifuge tube containing 200 l of Grace's medium and the suspension containing the recombinant baculovirus is used to infect Sf9 cells seeded in 35 mm dishes. Four days later the supernatants of these culture dishes are harvested and then they are stored at 4 C.
To verify the expression of the polypeptide, Sf9 cells are grown in Grace's medium supplemented with 10% heat-inactivated FBS. The cells are infected with the recombinant baculovirus containing the polynucleotide at a multiplicity of infection ("MOI") of about 2. If radiolabeled proteins are desired, 6 hours later the medium is removed and is replaced with SF900 II medium minus methionine and cysteine (available from Life Technologies Inc., Rockville, MD). After 42 hours, 5 Ci of ;`S-methionine and 5 Ci 35S-cysteine (available from Amersham) are added. The cells are further incubated for 16 hours and then are harvested by centrifugation. The proteins in the supernatant as well as the intracellular proteins are analyzed by SDS-PAGE
followed by autoradiography (if radiolabeled).
Microsequencing of the amino acid sequence of the amino terminus of purified protein may be used to determine the amino terminal sequence of the produced protein.
Example 8: Expression of a Polypeptide in Mammalian Cells The polypeptide of the present invention can be expressed in a mammalian cell.
A typical mammalian expression vector contains a promoter element, which mediates the initiation of transcription of mRNA, a protein coding sequence, and signals required for the termination of transcription and polyadenylation of the transcript.
Additional elements include enhancers, Kozak sequences and intervening sequences flanked by donor and acceptor sites for RNA splicing. Highly efficient transcription is achieved with the early and late promoters from SV40, the long terminal repeats (LTRs) from Retroviruses, e.g., RSV, HTLVI, HIVI and the early promoter of the cytomegalovirus (CMV). However, cellular elements can also be used (e.g., the human actin promoter).
Suitable expression vectors for use in practicing the present invention include, for example, vectors such as pSVL and pMSG (Pharmacia, Uppsala, Sweden), pRSVcat (ATCC 37152), pSV2dhfr (ATCC 37146), pBC12MI (ATCC 67109), pCMVSport 2.0, and pCMVSport 3Ø Mammalian host cells that could be used include, human Hela, 293, H9 and Jurkat cells, mouse NIH3T3 and C127 cells, Cos 1, Cos 7 and CV 1, quail QC1-3 cells, mouse L cells and Chinese hamster ovary (CHO) cells.

Alternatively, the polypeptide can be expressed in stable cell lines containing the polynucleotide integrated into a chromosome. The co-transfection with a selectable marker such as dhfr, gpt, neomycin, hygromycin allows the identification and isolation of the transfected cells.
The transfected gene can also be amplified to express large amounts of the encoded protein. The DHFR (dihydrofolate reductase) marker is useful in developing cell lines that carry several hundred or even several thousand copies of the gene of interest. (See, e.g., Alt, F. W., et al., J. Biol. Chem. 253:1357-1370 (1978);
Hamlin, J. L. and Ma, C., Biochem. et Biophys. Acta, 1097:107-143 (1990); Page, M. J.
and Sydenham, M. A., Biotechnology 9:64-68 (1991).) Another useful selection marker is the enzyme glutamine synthase (GS) (Murphy et al., Biochem J. 227:277-279 (1991);
Bebbington et al., Bio/Technology 10:169-175 (1992). Using these markers, the mammalian cells are grown in selective medium and the cells with the highest resistance are selected. These cell lines contain the amplified gene(s) integrated into a chromosome. Chinese hamster ovary (CHO) and NSO cells are often used for the production of proteins.
Derivatives of the plasmid pSV2-dhfr (ATCC Accession No. 37146), the expression vectors pC4 (ATCC Accession No. 209646) and pC6 (ATCC Accession No.209647) contain the strong promoter (LTR) of the Rous Sarcoma Virus (Cullen et al., Molecular and Cellular Biology, 438-447 (March, 1985)) plus a fragment of the CMV-enhancer (Boshart et al., Cell 41:521-530 (1985).) Multiple cloning sites, e.g., with the restriction enzyme cleavage sites BamHI, XbaI and Asp718, facilitate the cloning of the gene of interest. The vectors also contain the 3' intron, the polyadenylation and termination signal of the rat preproinsulin gene, and the mouse DHFR gene under control of the S V40 early promoter.
Specifically, the plasmid pC6, for example, is digested with appropriate restriction enzymes and then dephosphorylated using calf intestinal phosphates by procedures known in the art. The vector is then isolated from a 1% agarose gel.
A polynucleotide of the present invention is amplified according to the protocol outlined in Example 1. If the naturally occurring signal sequence is used to produce the secreted protein, the vector does not need a second signal peptide.
Alternatively, if the naturally occurring signal sequence is not used, the vector can be modified to include a heterologous signal sequence. (See, e.g., WO 96/3489 1.) The amplified fragment is isolated from a 1% agarose gel using a commercially available kit ("Geneclean," BIO 101 Inc., La Jolla, Ca.). The fragment then is digested with appropriate restriction enzymes and again purified on a 1% agarose gel.

The amplified fragment is then digested with the same restriction enzyme and purified on a 1% agarose gel. The isolated fragment and the dephosphorylated vector are then ligated with T4 DNA ligase. E. coli HB 101 or XL-1 Blue cells are then transformed and bacteria are identified that contain the fragment inserted into plasmid pC6 using, for instance, restriction enzyme analysis.
Chinese hamster ovary cells lacking an active DHFR gene is used for transfection. Five g of the expression plasmid pC6 is cotransfected with 0.5 gg of the plasmid pSVneo using lipofectin (Felgner et al., supra). The plasmid pSV2-neo contains a dominant selectable marker, the neo gene from Tn5 encoding an enzyme that confers resistance to a group of antibiotics including G418. The cells are seeded in alpha minus MEM supplemented with 1 mg/ml G418. After 2 days, the cells are trypsinized and seeded in hybridoma cloning plates (Greiner, Germany) in alpha minus MEM supplemented with 10, 25, or 50 ng/ml of metothrexate plus 1 mg/ml G418.
After about 10-14 days single clones are trypsinized and then seeded in 6-well petri dishes or 10 ml flasks using different concentrations of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 800 nM). Clones growing at the highest concentrations of methotrexate are then transferred to new 6-well plates containing even higher concentrations of methotrexate (1 M, 2 M, 5 M, 10 mM, 20 m1V1). The same procedure is repeated until clones are obtained which grow at a concentration of 100 -200 M. Expression of the desired gene product is analyzed, for instance, by SDS-PAGE and Western blot or by reversed phase HPLC analysis.

Example 9: Protein Fusions The polypeptides of the present invention are preferably fused to other proteins.
These fusion proteins can be used for a variety of applications. For example, fusion of the present polypeptides to His-tag, HA-tag, protein A, IgG domains, and maltose binding protein facilitates purification. (See Example 5; see also EP A
394,827;
Traunecker, et al., Nature 331:84-86 (1988).) Similarly, fusion to IgG-1, IgG-3, and albumin increases the halflife time in vivo. Nuclear localization signals fused to the polypeptides of the present invention can target the protein to a specific subcellular localization, while covalent heterodimer or homodimers can increase or decrease the activity of a fusion protein. Fusion proteins can also create chimeric molecules having more than one function. Finally, fusion proteins can increase solubility and/or stability of the fused protein compared to the non-fused protein. All of the types of fusion proteins described above can be made by modifying the following protocol, which outlines the fusion of a polypeptide to an IgG molecule, or the protocol described in Example 5.

Briefly, the human Fc portion of the IgG molecule can be PCR amplified, using primers that span the 5' and 3' ends of the sequence described below. These primers also should have convenient restriction enzyme sites that will facilitate cloning into an expression vector, preferably a manunalian expression vector.
For example, if pC4 (Accession No. 209646) is used, the human Fc portion can be ligated into the BamHI cloning site. Note that the 3' BamHI site should be destroyed. Next, the vector containing the human Fc portion is re-restricted with BamHI, linearizing the vector, and a polynucleotide of the present invention, isolated by the PCR protocol described in Example 1, is ligated into this BamHI site.
Note that the polynucleotide is cloned without a stop codon, otherwise a fusion protein will not be produced.
If the naturally occurring signal sequence is used to produce the secreted protein, pC4 does not need a second signal peptide. Alternatively, if the naturally occurring signal sequence is not used, the vector can be modified to include a heterologous signal sequence. (See, e.g., WO 96/34891.) Human IgG Fc region:
GGGATCCGGAGCCCAAATCTTCTGACAAAACTCACACATGCCCACCGTGCC
CAGCACCTGAATTCGAGGGTGCACCGTCAGTCTTCCTCTTCCCCCCAAAACC
CAAGGACACCCTCATGATCTCCCGGACTCCTGAGGTCACATGCGTGGTGGT
GGACGTAAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACG
GCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAAC
AGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTG
AATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAACCCCC
ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT
GTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCT
GACCTGCCTGGTCAAAGGCTTCTATCCAAGCGACATCGCCGTGGAGTGGGA
GAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGG
ACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCA
GGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGC
ACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGAGTGC
GACGGCCGCGACTCTAGAGGAT (SEQ ID NO:1) Example 10: Production of an Antibody from a Polypeptide The antibodies of the present invention can be prepared by a variety of methods.
(See, Current Protocols, Chapter 2.) For example, cells expressing a polypeptide of the present invention is administered to an animal to induce the production of sera containing polyclonal antibodies. In a preferred method, a preparation of the secreted protein is prepared and purified to render it substantially free of natural contaminants.
Such a preparation is then introduced into an animal in order to produce polyclonal antisera of greater specific activity.
In the most preferred method, the antibodies of the present invention are monoclonal antibodies (or protein binding fragments thereof). Such monoclonal antibodies can be prepared using hybridoma technology. (Kohler et al., Nature 256:495 (1975); K6hler et al., Eur. J. Immunol. 6:511 (1976); Kohler et al., Eur. J.
Immunol. 6:292 (1976); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas, Elsevier, N.Y., pp. 563-681 (1981).) In general, such procedures involve immunizing an animal (preferably a mouse) with polypeptide or, more preferably, with a secreted polypeptide-expressing cell. Such cells may be cultured in any suitable tissue culture medium; however, it is preferable to culture cells in Earle's modified Eagle's medium supplemented with 10% fetal bovine serum (inactivated at about 56 C), and supplemented with about 10 g/l of nonessential amino acids, about 1,000 U/ml of penicillin, and about 100 g/ml of streptomycin.
The splenocytes of such mice are extracted and fused with a suitable myeloma cell line. Any suitable myeloma cell line may be employed in accordance with the present invention; however, it is preferable to employ the parent myeloma cell line (SP2O), available from the ATCC. After fusion, the resulting hybridoma cells are selectively maintained in HAT medium, and then cloned by limiting dilution as described by Wands et al. (Gastroenterology 80:225-232 (1981).) The hybridoma cells obtained through such a selection are then assayed to identify clones which secrete antibodies capable of binding the polypeptide.
Alternatively, additional antibodies capable of binding to the polypeptide can be produced in a two-step procedure using anti-idiotypic antibodies. Such a method makes use of the fact that antibodies are themselves antigens, and therefore, it is possible to obtain an antibody which binds to a second antibody. In accordance with this method, protein specific antibodies are used to immunize an animal, preferably a mouse. The splenocytes of such an animal are then used to produce hybridoma cells, and the hybridoma cells are screened to identify clones which produce an antibody whose ability to bind to the protein-specific antibody can be blocked by the polypeptide.
Such antibodies comprise anti-idiotypic antibodies to the protein-specific antibody and can be used to immunize an animal to induce formation of further protein-specific antibodies.

It will be appreciated that Fab and F(ab')2 and other fragments of the antibodies of the present invention may be used according to the methods disclosed herein. Such fragments are typically produced by proteolytic cleavage, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab')2 fragments).
Alternatively, secreted protein-binding fragments can be produced through the application of recombinant DNA technology or through synthetic chemistry.
For in vivo use of antibodies in humans, it may be preferable to use "humanized" chimeric monoclonal antibodies. Such antibodies can be produced using genetic constructs derived from hybridoma cells producing the monoclonal antibodies described above. Methods for producing chimeric antibodies are known in the art.
(See, for review, Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al., U.S. Patent No. 4,816,567; Taniguchi et al., EP
171496;
Morrison et al., EP 173494; Neuberger et al., WO 8601533; Robinson et al., WO
8702671; Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature 314:268 (1985).) Examnle 11: Production Of Secreted Protein For High-Throughput Screening Assays The following protocol produces a supernatant containing a polypeptide to be tested. This supematant can then be used in the Screening Assays described in Examples 13-20.
First, dilute Poly-D-Lysine (644 587 Boehringer-Mannheim) stock solution ( Img/ml in PBS) 1:20 in PBS (w/o calcium or magnesium 17-516F Biowhittaker) for a working solution of 50ug/ml. Add 200 ul of this solution to each well (24 well plates) and incubate at RT for 20 minutes. Be sure to distribute the solution over each well (note: a 12-channel pipetter may be used with tips on every other channel).
Aspirate off the Poly-D-Lysine solution and rinse with lml PBS (Phosphate Buffered Saline).
The PBS should remain in the well until just prior to plating the cells and plates may be poly-lysine coated in advance for up to two weeks.
Plate 293T cells (do not carry cells past P+20) at 2 x 105 cells/well in .5m1 DMEM(Dulbecco's Modified Eagle Medium)(with 4.5 G/L glucose and L-glutamine (12-604F Biowhittaker))/10% heat inactivated FBS(14-503F Biowhittaker)/lx Penstrep(17-602E Biowhittaker). Let the cells grow overnight.
The next day, mix together in a sterile solution basin: 300 ul Lipofectamine (18324-012 GibcoBRL) and 5m1 Optimem I(31985070 Gibco/BRL)/96-well plate.
With a small volume multi-channel pipetter, aliquot approximately 2ug of an expression vector containing a polynucleotide insert, produced by the methods described in Examples 8 or 9, into an appropriately labeled 96-well round bottom plate.
With a multi-channel pipetter, add 50u1 of the Lipofectamine/Optimem I mixture to each well.
Pipette up and down gently to mix. Incubate at RT 15-45 minutes. After about minutes, use a multi-channel pipetter to add 150u1 Optimem I to each well. As a control, one plate of vector DNA lacking an insert should be transfected with each set of transfections.
Preferably, the transfection should be performed by tag-teaming the following tasks. By tag-teaming, hands on time is cut in half, and the cells do not spend too much time on PBS. First, person A aspirates off the media from four 24-well plates of cells, and then person B rinses each well with.5-lml PBS. Person A then aspirates off PBS rinse, and person B, using a12-channel pipetter with tips on every other channel, adds the 200ul of DNA/Lipofectamine/Optimem I complex to the odd wells first, then to the even wells, to each row on the 24-well plates. Incubate at 37 C for 6 hours.

While cells are incubating, prepare appropriate media, either 1%BSA in DMEM
with 1 x penstrep, or CHO-5 media (116.6 mg/L of CaC12 (anhyd); 0.00130 mg/L
CuSO4-5H20; 0.050 mg/L of Fe(NO;)3-9HZ0; 0.417 mg/L of FeSO4-7H20; 311.80 mg/L of Kcl; 28.64 mg/L of MgC12; 48.84 mg/L of MgSO4,; 6995.50 mg/L of NaCI;
2400.0 mg/L of NaHCO;; 62.50 mg/L of NaH2PO4-H,0; 71.02 mg/L of Na,HPO4;
.4320 mg/L of ZnSO4-7H20; .002 mg/L of Arachidonic Acid ; 1.022 mg/L of Cholesterol; .070 mg/L of DL-alpha-Tocopherol-Acetate; 0.0520 mg/L of Linoleic Acid; 0.010 mg/L of Linolenic Acid; 0.010 mg/L of Myristic Acid; 0.010 mg/L of Oleic Acid; 0.010 mg/L of Palmitric Acid; 0.010 mg/L of Palmitic Acid; 100 mg/L of Pluronic F-68; 0.010 mg/L of Stearic Acid; 2.20 mg/L of Tween 80; 4551 mg/L of D-Glucose; 130.85 mg/ml of L- Alanine; 147.50 mg/n-d of L-Arginine-HCL; 7.50 mg/ml of L-Asparagine-H20; 6.65 mg/ml of L-Aspartic Acid; 29.56 mg/ml of L-Cystine-2HCL-H20; 31.29 mg/ml of L-Cystine-2HCL; 7.35 mg/ml of L-Glutamic Acid; 365.0 mg/ml of L-Glutamine; 18.75 mg/ml of Glycine; 52.48 mg/ml of L-Histidine-HCL-H20; 106.97 mg/ml of L-Isoleucine; 111.45 mg/ml of L-Leucine; 163.75 mg/ml of L-Lysine HCL; 32.34 mg/mi of L-Methionine; 68.48 mg/mi of L-Phenylalainine; 40.0 mg/ml of L-Proline; 26.25 mg/ml of L-Serine; 101.05 mg/ml of L-Threonine;
19.22 mg/ml of L-Tryptophan; 91.79 mg/ml of L-Tryrosine-2Na-2H20; 99.65 mg/ml of L-Valine; 0.0035 mg/L of Biotin; 3.24 mg/L of D-Ca Pantothenate; 11.78 mg/L of Choline Chloride; 4.65 mg/L of Folic Acid; 15.60 mg/L of i-Inositol; 3.02 mg/L
of Niacinamide; 3.00 mg/L of Pyridoxal HCL; 0.031 mg/L of Pyridoxine HCL; 0.319 mg/L of Riboflavin; 3.17 mg/L of Thiamine HCL; 0.365 mg/L of Thymidine; and 0.680 mg/L of Vitamin B12; 25 mM of HEPES Buffer; 2.39 rng/L of Na Hypoxanthine;

WO 99/11293 PCr/US98/18360 0.105 mg/L of Lipoic Acid; 0.081 mg/L of Sodium Putrescine-2HCL; 55.0 mg/L of Sodium Pyruvate; 0.0067 mg/L of Sodium Selenite; 20uM of Ethanolamine; 0.122 mg/L of Ferric Citrate; 41.70 mg/L of Methyl-B-Cyclodextrin complexed with Linoleic Acid; 33.33 mg/L of Methyl-B-Cyclodextrin complexed with Oleic Acid; and 10 mg/L
of Methyl-B-Cyclodextrin complexed with Retinal) with 2mm glutamine and lx penstrep. (BSA (81-068-3 Bayer) 100gm dissolved in 1L DMEM for a 10% BSA stock solution). Filter the media and collect 50 ul for endotoxin assay in 15m1 polystyrene conical.
The transfection reaction is terminated, preferably by tag-teaming, at the end of the incubation period. Person A aspirates off the transfection media, while person B
adds 1.5m] appropriate media to each well. Incubate at 37 C for 45 or 72 hours depending on the media used: 1%BSA for 45 hours or CHO-5 for 72 hours.
On day four, using a 300u1 multichannel pipetter, aliquot 600ul in one 1 mi deep well plate and the remaining supernatant into a 2m1 deep well. The supematants from each well can then be used in the assays described in Examples 13-20.
It is specifically understood that when activity is obtained in any of the assays described below using a supernatant, the activity originates from either the polypeptide directly (e.g., as a secreted protein) or by the polypeptide inducing expression of other proteins, which are then secreted into the supematant. Thus, the invention further provides a method of identifying the protein in the supematant characterized by an activity in a particular assay.

Example 12: Construction of GAS Reporter Construct One signal transduction pathway involved in the differentiation and proliferation of cells is called the Jaks-STATs pathway. Activated proteins in the Jaks-STATs pathway bind to gamma activation site "GAS" elements or interferon-sensitive responsive element ("ISRE"), located in the promoter of many genes. The binding of a protein to these elements alter the expression of the associated gene.
GAS and ISRE elements are recognized by a class of transcription factors called Signal Transducers and Activators of Transcription, or "STATs." There are six members of the STATs family. Stat1 and Stat3 are present in many cell types, as is Stat2 (as response to IFN-alpha is widespread). Stat4 is more restricted and is not in many cell types though it has been found in T helper class I, cells after treatment with IL-12. Stat5 was originally called mammary growth factor, but has been found at higher concentrations in other cells including myeloid cells. It can be activated in tissue culture cells by many cytokines.

The STATs are activated to translocate from the cytoplasm to the nucleus upon tyrosine phosphorylation by a set of kinases known as the Janus Kinase ("Jaks") family. Jaks represent a distinct family of soluble tyrosine kinases and include Tyk2, Jak 1, Jak2, and Jak3. These kinases display significant sequence similarity and are generally catalytically inactive in resting cells.
The Jaks are activated by a wide range of receptors summarized in the Table below. (Adapted from review by Schidler and Darnell, Ann. Rev. Biochem. 64:621-(1995).) A cytokine receptor family, capable of activating Jaks, is divided into two groups: (a) Class 1 includes receptors for IL-2, IL-3, IL-4, IL-6, IL-7, IL-9, IL-11, IL-12, IL-15, Epo, PRL, GH, G-CSF, GM-CSF, LIF, CNTF, and thrombopoietin; and (b) Class 2 includes IFN-a, IFN-g, and IL-10. The Class I receptors share a conserved cysteine motif (a set of four conserved cysteines and one tryptophan) and a WSXWS motif (a membrane proxial region encoding Trp-Ser-Xxx-Trp-Ser (SEQ ID
NO:2)).
Thus, on binding of a ligand to a receptor, Jaks are activated, which in turn activate STATs, which then translocate and bind to GAS elements. This entire process is encompassed in the Jaks-STATs signal transduction pathway.
Therefore, activation of the Jaks-STATs pathway, reflected by the binding of the GAS or the ISRE element, can be used to indicate proteins involved in the proliferation and differentiation of cells. For example, growth factors and cytokines are known to activate the Jaks-STATs pathway. (See Table below.) Thus, by using GAS
elements linked to reporter molecules, activators of the Jaks-STATs pathway can be identified.

JAKs STATS GAS(elements) or ISRE
Ligand Mk? Jakl Jak2 Jak3 IFN faniily IFN-a/B + + - - 1,2,3 ISRE
IFN-g + + - 1 GAS (IRF1>Lys6>IFP) ll-10 + ? ? - 1,3 gp 130 family IL-6 (Pleiotrohic) + + + ? 1,3 GAS (IRF1>Lys6>IFP) Il-11(Pleiotrohic) ? + ? ? 1,3 OnM(Pleiotrohic) ? + + ? 1,3 LIF(Pleiotrohic) ? + + ? 1,3 CNTF(Pleiotrohic) -/+ + + ? 1,3 G-CSF(Pleiotrohic) ? + ? ? 1,3 IL-12(Pleiotrohic) + - + + 1,3 BSfaiWly IL-2 (lymphocytes) - + - + 1,3,5 GAS
IL-4 (lymph/myeloid) - + - + 6 GAS (IRF 1 = IFP
Ly6)(IgH) IL-7 (lymphocytes) - + - + 5 GAS
IL-9 (lymphocytes) - + - + 5 GAS
IL-13 (lymphocyte) - + ? ? 6 GAS
IL-15 ? + ? + 5 GAS
,gp140 family IL-3 (myeloid) - - + - 5 GAS (IRF1>IFP Ly6) IL-5 (myeloid) - - + - 5 GAS
GM-CSF (myeloid) - - + - 5 GAS
Growth hormone familX
GH ? - + - 5 PRL ? +/- + - 1,3,5 EPO ? - + - 5 GAS(B-CAS>IRFI=IFP Ly6) Receptor Tyrosine Kinases EGF ? + + - 1,3 GAS (IRF1) PDGF ? + + - 1,3 CSF-1 ? + + - 1,3 GAS (not IRF1) SUBSTITUTE SHEET (RULE 26) To construct a synthetic GAS containing promoter element, which is used in the Biological Assays described in Examples 13-14, a PCR based strategy is employed to generate a GAS-SV40 promoter sequence. The 5' primer contains four tandem copies of the GAS binding site found in the IRFI promoter and previously demonstrated to bind STATs upon induction with a range of cytokines (Rothman et al., Immunity 1:457-468 (1994).), although other GAS or ISRE elements can be used instead.
The 5' primer also contains 18bp of sequence complementary to the SV40 early promoter sequence and is flanked with an Xhol site. The sequence of the 5' primer is:
5':GCGCCTCGAGATTTCCCCGAAATCTAGATTTCCCCGAAATGATTTCCCCG
AAATGATTTCCCCGAAATATCTGCCATCTCAATTAG:3' (SEQ ID NO:3) The downstream primer is complementary to the SV40 promoter and is flanked with a Hind III site: 5':GCGGCAAGCTTTTTGCAAAGCCTAGGC:3' (SEQ ID
NO:4) PCR amplification is performed using the SV40 promoter template present in the B-gal:promoter plasmid obtained from Clontech. The resulting PCR fragment is digested with XhoI/Hind III and subcloned into BLSK2-. (Stratagene.) Sequencing with forward and reverse primers confirms that the insert contains the following sequence:
5' :CTCGAGATTTCCCCGAAATCTAGATTTCCCCGAAATGATTTCCCCGAAATG
ATTTCCCCGAAATATCTGCCATCTCAATTAGTCAGCAACCATAGTCCCGCCC
CTAACTCCGCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGC
CCCATGGCTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGC
CTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTT
TGCAAAAAGCTT:3' (SEQ ID NO:5) With this GAS promoter element linked to the SV40 promoter, a GAS:SEAP2 reporter construct is next engineered. Here, the reporter molecule is a secreted alkaline phosphatase, or "SEAP." Clearly, however, any reporter molecule can be instead of SEAP, in this or in any of the other Examples. Well known reporter molecules that can be used instead of SEAP include chloramphenicol acetyltransferase (CAT), luciferase, alkaline phosphatase, B-galactosidase, green fluorescent protein (GFP), or any protein detectable by an antibody.
The above sequence confirmed synthetic GAS-SV40 promoter element is subcloned into the pSEAP-Promoter vector obtained from Clontech using HindIII
and XhoI, effectively replacing the SV40 promoter with the amplified GAS:SV40 promoter element, to create the GAS-SEAP vector. However, this vector does not contain a neomycin resistance gene, and therefore, is not preferred for mammalian expression systems.

Thus, in order to generate mammalian stable cell lines expressing the GAS-SEAP reporter, the GAS-SEAP cassette is removed from the GAS-SEAP vector using SaII and NotI, and inserted into a backbone vector containing the neomycin resistance gene, such as pGFP-I (Clontech), using these restriction sites in the multiple cloning site, to create the GAS-SEAP/Neo vector. Once this vector is transfected into mammalian cells, this vector can then be used as a reporter molecule for GAS
binding as described in Examples 13-14.
Other constructs can be made using the above description and replacing GAS
with a different promoter sequence. For example, construction of reporter molecules containing NFK-B and EGR promoter sequences are described in Examples 15 and 16.
However, many other promoters can be substituted using the protocols described in these Examples. For instance, SRE, IL-2, NFAT, or Osteocalcin promoters can be substituted, alone or in combination (e.g., GAS/NF-KB/EGR, GAS/NF-KB, I1-2/NFAT, or NF-KB/GAS). Similarly, other cell lines can be used to test reporter construct activity, such as HELA (epithelial), HUVEC (endothelial), Reh (B-cell), Saos-2 (osteoblast), HUVAC (aortic), or Cardiomyocyte.

Example 13: High-Throughput Screening Assay for T-cell Activim.
The following protocol is used to assess T-cell activity by identifying factors, such as growth factors and cytokines, that may proliferate or differentiate T-cells. T-cell activity is assessed using the GAS/SEAP/Neo construct produced in Example 12.
Thus, factors that increase SEAP activity indicate the ability to activate the Jaks-STATS
signal transduction pathway. The T-cell used in this assay is Jurkat T-cells (ATCC
Accession No. TIB-152), although Molt-3 cells (ATCC Accession No. CRL-1552) and Molt-4 cells (ATCC Accession No. CRL-1582) cells can also be used.
Jurkat T-cells are lymphoblastic CD4+ Th 1 helper cells. In order to generate stable cell lines, approximately 2 million Jurkat cells are transfected with the GAS-SEAP/neo vector using DMRIE-C (Life Technologies)(transfection procedure described below). The transfected cells are seeded to a density of approximately 20,000 cells per well and transfectants resistant to 1 mg/n-d genticin selected. Resistant colonies are expanded and then tested for their response to increasing concentrations of interferon gamma. The dose response of a selected clone is demonstrated.
Specifically, the following protocol will yield sufficient cells for 75 wells containing 200 ul of cells. Thus, it is either scaled up, or performed in multiple to generate sufficient cells for multiple 96 well plates. Jurkat cells are maintained in RPMI
+ 10% serum with 1%Pen-Strep. Combine 2.5 mis of OPTI-MEM (Life Technologies) with 10 ug of plasmid DNA in a T25 flask. Add 2.5 ml OPTI-MEM containing 50 ul of DMRIE-C and incubate at room temperature for 15-45 mins.
During the incubation period, count cell concentration, spin down the required number of cells (10' per transfection), and resuspend in OPTI-MEM to a final concentration of 10' cells/mi. Then add 1 ml of I x 10' cells in OPTI-MEM to T25 flask and incubate at 37 C for 6 hrs. After the incubation, add 10 ml of RPMI + 15%
serum.
The Jurkat:GAS-SEAP stable reporter lines are maintained in RPMI + 10%
serum, 1 mg/ml Genticin, and 1% Pen-Strep. These cells are treated with supernatants containing a polypeptide as produced by the protocol described in Example 11.
On the day of treatment with the supernatant, the cells should be washed and resuspended in fresh RPMI + 10% serum to a density of 500,000 cells per ml.
The exact number of cells required will depend on the number of supernatants being screened. For one 96 well plate, approximately 10 million cells (for 10 plates, 100 million cells) are required.
Transfer the cells to a triangular reservoir boat, in order to dispense the cells into a 96 well dish, using a 12 channel pipette. Using a 12 channel pipette, transfer 200 ul of cells into each well (therefore adding 100, 000 cells per well).
After all the plates have been seeded, 50 ul of the supernatants are transferred directly from the 96 well plate containing the supernatants into each well using a 12 channel pipette. In addition, a dose of exogenous interferon gamma (0.1, 1.0, 10 ng) is added to wells H9, H10, and HI 1 to serve as additional positive controls for the assay.
The 96 well dishes containing Jurkat cells treated with supernatants are placed in an incubator for 48 hrs (note: this time is variable between 48-72 hrs). 35 ul samples from each well are then transferred to an opaque 96 well plate using a 12 channel pipette. The opaque plates should be covered (using sellophene covers) and stored at -20 C until SEAP assays are performed according to Example 17. The plates containing the remaining treated cells are placed at 40C and serve as a source of material for repeating the assay on a specific well if desired.
As a positive control, 100 Unit/ml interferon gamma can be used which is known to activate Jurkat T cells. Over 30 fold induction is typically observed in the positive control wells.

Example 14: High-Throughput Screening Assay Identifying Myeloid Activi The following protocol is used to assess myeloid activity by identifying factors, such as growth factors and cytokines, that may proliferate or differentiate myeloid cells.
Myeloid cell activity is assessed using the GAS/SEAP/Neo construct produced in Example 12. Thus, factors that increase SEAP activity indicate the ability to activate the Jaks-STATS signal transduction pathway. The myeloid cell used in this assay is U937, a pre-monocyte cell line, although TF-1, HL60, or KG1 can be used.
To transiently transfect U937 cells with the GAS/SEAP/Neo construct produced in Example 12, a DEAE-Dextran method (Kharbanda et. al., 1994, Cell Growth &
Differentiation, 5:259-265) is used. First, harvest 2x10e7 U937 cells and wash with PBS. The U937 cells are usually grown in RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum (FBS) supplemented with 100 units/ml penicillin and 100 mg/mi streptomycin.
Next, suspend the cells in 1 ml of 20 mM Tris-HCI (pH 7.4) buffer containing 0.5 mg/ml DEAE-Dextran, 8 ug GAS-SEAP2 plasmid DNA, 140 mM NaCI, 5 mM
KC1, 375 uM Na2HPO4.7H20, 1 mM MgC12, and 675 uM CaC12. Incubate at 37 C
for 45 min.
Wash the cells with RPMI 1640 medium containing 10% FBS and then resuspend in 10 ml complete medium and incubate at 370C for 36 hr.
The GAS-SEAPIU937 stable cells are obtained by growing the cells in 400 ug/ml G418. The G418-free medium is used for routine growth but every one to two months, the cells should be re-grown in 400 ug/ml G418 for couple of passages.
These cells are tested by harvesting 1 x 10g cells (this is enough for ten 96-well plates assay) and wash with PBS. Suspend the cells in 200 ml above described growth medium, with a final density of 5x105 cells/ml. Plate 200 ul cells per well in the 96-well plate (or 1x10s cells/well).
Add 50 ul of the supernatant prepared by the protocol described in Example 11.
Incubate at 37 C for 48 to 72 hr. As a positive control, 100 Unit/ml interferon gamma can be used which is known to activate U937 cells. Over 30 fold induction is typically observed in the positive control wells. SEAP assay the supernatant according to the protocol described in Example 17.

Example 15: High-Throughput Screening Assay Identifying Neuronal Activity.
When cells undergo differentiation and proliferation, a group of genes are activated through many different signal transduction pathways. One of these genes, EGR1 (early growth response gene 1), is induced in various tissues and cell types upon activation. The promoter of EGR 1 is responsible for such induction. Using the promoter linked to reporter molecules, activation of cells can be assessed.
Particularly, the following protocol is used to assess neuronal activity in PC

cell lines. PC 12 cells (rat phenochromocytoma cells) are known to proliferate and/or differentiate by activation with a number of mitogens, such as TPA
(tetradecanoyl phorbol acetate), NGF (nerve growth factor), and EGF (epidermal growth factor). The EGR1 gene expression is activated during this treatment. Thus, by stably transfecting PC12 cells with a construct containing an EGR promoter linked to SEAP
reporter, activation of PC 12 cells can be assessed.
The EGR/SEAP reporter construct can be assembled by the following protocol.
The EGR-1 promoter sequence (-633 to +l)(Sakamoto K et al., Oncogene 6:867-871 (1991)) can be PCR amplified from human genomic DNA using the following primers:
5' GCGCTCGAGGGATGACAGCGATAGAACCCCGG -3' (SEQ ID NO:6) 5' GCGAAGCTTCGCGACTCCCCGGATCCGCCTC-3' (SEQ ID NO:7) Using the GAS:SEAP/Neo vector produced in Example 12, EGR1 amplified product can then be inserted into this vector. Linearize the GAS:SEAP/Neo vector using restriction enzymes Xhol/HindIII, removing the GAS/SV40 stuffer.
Restrict the EGR1 amplified product with these same enzymes. Ligate the vector and the EGR1 promoter.
To prepare 96 well-plates for cell culture, two mis of a coating solution (1:30 dilution of collagen type I (Upstate Biotech Inc. Cat#08-115) in 30% ethanol (filter sterilized)) is added per one 10 cm plate or 50 ml per well of the 96-well plate, and allowed to air dry for 2 hr.
PC 12 cells are routinely grown in RPMI- 1640 medium (Bio Whittaker) containing 10% horse serum (JRH BIOSCIENCES, Cat. # 12449-78P), 5% heat-inactivated fetal bovine serum (FBS) supplemented with 100 units/mi penicillin and 100 ug/mi streptomycin on a precoated 10 cm tissue culture dish. One to four split is done every three to four days. Cells are removed from the plates by scraping and resuspended with pipetting up and down for more than 15 times.
Transfect the EGR/SEAP/Neo construct into PC 12 using the Lipofectamine protocol described in Example 11. EGR-SEAP/PC 12 stable cells are obtained by growing the cells in 300 ug/ml G418. The G418-free medium is used for routine growth but every one to two months, the cells should be re-grown in 300 ug/ml for couple of passages.
To assay for neuronal activity, a 10 cm plate with cells around 70 to 80%
confluent is screened by removing the old medium. Wash the cells once with PBS

(Phosphate buffered saline). Then starve the cells in low serum medium (RPMI-containing 1% horse serum and 0.5% FBS with antibiotics) overnight.
The next morning, remove the medium and wash the cells with PBS. Scrape off the cells from the plate, suspend the cells well in 2 ml low serum medium.
Count the cell number and add more low serum medium to reach final cell density as 5x 105 cells/ml.
Add 200 ul of the cell suspension to each well of 96-well plate (equivalent to 1x105 cells/well). Add 50 ul supernatant produced by Example 11, 37 C for 48 to 72 hr. As a positive control, a growth factor known to activate PC 12 cells through EGR
can be used, such as 50 ng/ul of Neuronal Growth Factor (NGF). Over fifty-fold induction of SEAP is typically seen in the positive control wells. SEAP assay the supernatant according to Example 17.

Example 16: High-Throughput Screening Assay for T-cell Activity NF-KB (Nuclear Factor KB) is a transcription factor activated by a wide variety of agents including the inflammatory cytokines IL- l and TNF, CD30 and CD40, lymphotoxin-alpha and lymphotoxin-beta, by exposure to LPS or thrombin, and by expression of certain viral gene products. As a transcription factor, NF-xB
regulates the expression of genes involved in immune cell activation, control of apoptosis (NF-KB appears to shield cells from apoptosis), B and T-cell development, anti-viral and antimicrobial responses, and multiple stress responses.

In non-stimulated conditions, NF- KB is retained in the cytoplasm with I-KB
(Inhibitor xB). However, upon stimulation, I- KB is phosphorylated and degraded, causing NF- xB to shuttle to the nucleus, thereby activating transcription of target genes. Target genes activated by NF- KB include IL-2, IL-6, GM-CSF, ICAM-1 and class 1 MHC.
Due to its central role and ability to respond to a range of stimuli, reporter constructs utilizing the NF-xB promoter element are used to screen the supernatants produced in Example 11. Activators or inhibitors of NF-kB would be useful in treating diseases. For example, inhibitors of NF-xB could be used to treat those diseases related to the acute or chronic activation of NF-kB, such as rheumatoid arthritis.

To construct a vector containing the NF-icB promoter element, a PCR based strategy is employed. The upstream primer contains four tandem copies of the NF-tcB
binding site (GGGGACTTTCCC) (SEQ ID NO:8), 18 bp of sequence complementary to the 5' end of the SV40 early promoter sequence, and is flanked with an Xhol site:
5':GCGGCCTCGAGGGGACTTTCCCGGGGACTTTCCGGGGACTTTCCGGGAC
TT7CCATCCTGCCATCTCAATTAG:3' (SEQ ID NO:9) The downstream primer is complementary to the 3' end of the SV40 promoter and is flanked with a Hind III site:
5':GCGGCAAGCTTTITGCAAAGCCTAGGC:3' (SEQ ID NO:4) PCR amplification is performed using the SV40 promoter template present in the pB-gal:promoter plasmid obtained from Clontech. The resulting PCR fragment is digested with Xhol and Hind III and subcloned into BLSK2-. (Stratagene) Sequencing with the T7 and T3 primers confirms the insert contains the following sequence:
5' : CTCGAGGGGACTTTCCCGGGGACTTTCCGGGGACTTTCCGGGACTTTCC
ATCTGCCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGCCCA
TCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACT
AATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTC
CAGAAGTAGTGAGGAGGCI'T'I"ITTGGAGGCCTAGGCTTTTGCAAAAAGCTT:
3' (SEQ ID NO:10) Next, replace the SV40 minimal promoter element present in the pSEAP2-promoter plasmid (Clontech) with this NF-xB/SV40 fragment using Xhol and HindIII.
However, this vector does not contain a neomycin resistance gene, and therefore, is not preferred for manunalian expression systems.

In order to generate stable mammalian cell lines, the NF-KB/SV40/SEAP
cassette is removed from the above NF-KB/SEAP vector using restriction enzymes Sall and Notl, and inserted into a vector containing neomycin resistance.
Particularly, the NF-xB/SV40/SEAP cassette was inserted into pGFP-.l (Clontech), replacing the GFP
gene, after restricting pGFP-1 with SaII and Notl.

Once NF-KB/SV40/SEAP/Neo vector is created, stable Jurkat T-cells are created and maintained according to the protocol described in Example 13.
Similarly, the method for assaying supernatants with these stable Jurkat T-cells is also described in Example 13. As a positive control, exogenous TNF alpha (0.1,1, 10 ng) is added to wells H9, H 10, and H 11, with a 5-10 fold activation typically observed.

Example 17: Assay for SEAP Activity As a reporter molecule for the assays described in Examples 13-16, SEAP
activity is assayed using the Tropix Phospho-light Kit (Cat. BP-400) according to the following general procedure. The Tropix Phospho-light Kit supplies the Dilution, Assay, and Reaction Buffers used below.
Prime a dispenser with the 2.5x Dilution Buffer and dispense 15 i of 2.5x dilution buffer into Optiplates containing 35 l of a supernatant. Seal the plates with a plastic sealer and incubate at 65 C for 30 min. Separate the Optiplates to avoid uneven heating.
Cool the samples to room temperature for 15 minutes. Empty the dispenser and prime with the Assay Buffer. Add 50 l Assay Buffer and incubate at room temperature 5 min. Empty the dispenser and prime with the Reaction Buffer (see the table below). Add 50 l Reaction Buffer and incubate at room temperature for minutes. Since the intensity of the chemiluminescent signal is time dependent, and it takes about 10 minutes to read 5 plates on luminometer, one should treat 5 plates at each time and start the second set 10 minutes later.
Read the relative light unit in the luminometer. Set H12 as blank, and print the results. An increase in chemiluminescence indicates reporter activity.

Reaction Buffer Formulation:
# of plates Rxn buffer diluent (ml) CSPD (ml) 11 65 3.25 12 70 3.5 13 75 3.75 15 85 4.25 16 90 4.5 17 95 4.75 19 105 5.25 20 110 5.5 21 115 5.75 23 125 6.25 24 130 6.5 135 6.75 27 145 7.25 28 150 7.5 29 155 7.75 31 165 8.25 32 170 8.5 33 175 8.75 35 185 9.25 36 190 9.5 37 195 9.75 39 205 10.25 40 210 10.5 41 215 10.75 43 225 11.25 44 230 11.5 45 235 11.75 47 245 12.25 48 250 12.5 49 255 12.75 Examule 18: High-Throughput Screening Assay Identifying Changes in Small Molecule Concentration and Membrane Permeability Binding of a ligand to a receptor is known to alter intracellular levels of small molecules, such as calcium, potassium, sodium, and pH, as well as alter membrane potential. These alterations can be measured in an assay to identify supernatants which bind to receptors of a particular cell. Although the following protocol describes an assay for calcium, this protocol can easily be modified to detect changes in potassium, sodium, pH, membrane potential, or any other small molecule which is detectable by a fluorescent probe.
The following assay uses Fluorometric Imaging Plate Reader ("FLIPR") to measure changes in fluorescent molecules (Molecular Probes) that bind small molecules. Clearly, any fluorescent molecule detecting a small molecule can be used instead of the calcium fluorescent molecule, fluo-3, used here.
For adherent cells, seed the cells at 10,000 -20,000 cells/well in a Co-star black 96-well plate with clear bottom. The plate is incubated in a CO2 incubator for 20 hours.
The adherent cells are washed two times in Biotek washer with 200 ul of HBSS
(Hank's Balanced Salt Solution) leaving 100 ul of buffer after the final wash.
A stock solution of 1 mg/ml fluo-3 is made in 10% pluronic acid DMSO. To load the cells with fluo-3, 50 ul of 12 ug/ml fluo-3 is added to each well.
The plate is incubated at 37 C in a CO2 incubator for 60 min. The plate is washed four times in the Biotek washer with HBSS leaving 100 ul of buffer.
For non-adherent cells, the cells are spun down from culture media. Cells are re-suspended to 2-5x106 cells/n-d with HBSS in a 50-m1 conical tube. 4 ul of 1 mg/ml fluo-3 solution in 10% pluronic acid DMSO is added to each ml of cell suspension.
The tube is then placed in a 37 C water bath for 30-60 min. The cells are washed twice with HBSS, resuspended to 1x106 cell.s/ml, and dispensed into a microplate, ul/well. The plate is centrifuged at 1000 rpm for 5 min. The plate is then washed once in Denley CellWash with 200 ul, followed by an aspiration step to 100 ul final volume.
For a non-cell based assay, each well contains a fluorescent molecule, such as fluo-3. The supematant is added to the well, and a change in fluorescence is detected.
To measure the fluorescence of intracellular calcium, the FLIPR is set for the following parameters: (1) System gain is 300-800 mW; (2) Exposure time is 0.4 second; (3) Camera F/stop is F/2; (4) Excitation is 488 nm; (5) Etnission is 530 nm; and (6) Sample addition is 50 ul. Increased emission at 530 nm indicates an extracellular signaling event which has resulted in an increase in the intracellular Ca++
concentration.

Example 19: High-Throughput Screening Assay Identifying Tvrosine Kinase Activitv The Protein Tyrosine Kinases (PTK) represent a diverse group of transmembrane and cytoplasmic kinases. Within the Receptor Protein Tyrosine Kinase RPTK) group are receptors for a range of mitogenic and metabolic growth factors including the PDGF, FGF, EGF, NGF, HGF and Insulin receptor subfamilies. In addition there are a large family of RPTKs for which the corresponding ligand is unknown. Ligands for RPTKs include mainly secreted small proteins, but also membrane-bound and extracellular matrix proteins.
Activation of RPTK by ligands involves ligand-mediated receptor dimerization, resulting in transphosphorylation of the receptor subunits and activation of the cytoplasmic tyrosine kinases. The cytoplasmic tyrosine kinases include receptor associated tyrosine kinases of the src-family (e.g., src, yes, lck, lyn, fyn) and non-receptor linked and cytosolic protein tyrosine kinases, such as the Jak family, members of which mediate signal transduction triggered by the cytokine superfamily of receptors (e.g., the Interleukins, Interferons, GM-CSF, and Leptin).
Because of the wide range of known factors capable of stimulating tyrosine kinase activity, the identification of novel human secreted proteins capable of activating tyrosine kinase signal transduction pathways are of interest. Therefore, the following protocol is designed to identify those novel human secreted proteins capable of activating the tyrosine kinase signal transduction pathways.
Seed target cells (e.g., primary keratinocytes) at a density of approximately 25,000 cells per well in a 96 well Loprodyne Silent Screen Plates purchased from Nalge Nunc (Naperville, IL). The plates are sterilized with two 30 minute rinses with 100% ethanol, rinsed with water and dried overnight. Some plates are coated for 2 hr with 100 ml of cell culture grade type I collagen (50 mg/ml), gelatin (2%) or polylysine (50 mg/ml), all of which can be purchased from Sigma Chemicals (St. Louis, MO) or 10% MatrigelT purchased from Becton Dickinson (Bedford,MA), or calf serum, rinsed with PBS and stored at 40C. Cell growth on these plates is assayed by seeding 5,000 cells/well in growth medium and indirect quantitation of cell number through use of alamarBlue as described by the manufacturer Alamar Biosciences, Inc.
(Sacramento, CA) after 48 hr. Falcon plate covers #3071 from Becton Dickinson (Bedford,MA) are used to cover the Loprodyne Silent Screen Plates. Falcon Microtest III cell culture plates can also be used in some proliferation experiments.
To prepare extracts, A431 cells are seeded onto the nylon membranes of Loprodyne plates (20,000/200ml/well) and cultured overnight in complete medium.
Cells are quiesced by incubation in serum-free basal medium for 24 hr. After 5-minutes treatment with EGF (60ng/ml) or 50 ul of the supernatant produced in Example 11, the medium was removed and 100 ml of extraction buffer ((20 mM HEPES pH
7.5, 0.15 M NaC1,1% Triton'N-100, 0.1% SDS, 2 mM Na3VO4, 2 mM Na4P2O7 and a cocktail of protease inhibitors (# 1836170) obtained from Boeheringer Mannheim (Indianapolis, IN) is added to each well and the plate is shaken. on a rotating shaker for 5 minutes at 4 C. The plate is then placed in a vacuum transfer manifold and the extract filtered through the 0.45 mm membrane bottoms of each well using house vacuum.
Extracts are collected in a 96-well catch/assay plate in the bottom of the vacuum manifold and immediately placed on ice. To obtain extracts clarified by centrifugation, the content of each well, after detergent solubilization for 5 minutes, is removed and centrifuged for 15 minutes at 4 C at 16,000 x g.
Test the filtered extracts for levels of tyrosine kinase activity. Although many methods of detecting tyrosine kinase activity are known, one method is described here.
Generally, the tyrosine kinase activity of a supernatant is evaluated by deterrnining its ability to phosphorylate a tyrosine residue on a specific substrate (a biotinylated peptide). Biotinylated peptides that can be used for this purpose include PSK 1(corresponding to amino acids 6-20 of the cell division kinase cdc2-p34) and PSK2 (corresponding to amino acids 1-17 of gastrin). Both peptides are substrates for a range of tyrosine kinases and are available from Boehringer Mannheim.
The tyrosine kinase reaction is set up by adding the following components in order. First, add lOul of 5uM Biotinylated Peptide, then l0u1 ATP/Mg2+ (5mM
ATP/5OmM MgC12), then l0ul of 5x Assay Buffer (40mM imidazole hydrochloride, pH7.3, 40 mM beta-glycerophosphate, 1mM EGTA, 100mM MgC12, 5 mM MnC12, 0.5 mg/ml BSA), then 5ul of Sodium Vanadate(1mM), and then 5u1 of water. Mix the components gently and preincubate the reaction mix at 30 C for 2 min. Initial the reaction by adding lOul of the control enzyme or the filtered supernatant.
The tyrosine kinase assay reaction is then terminated by adding 10 ul of 120mm EDTA and place the reactions on ice.
Tyrosine kinase activity is determined by transferring 50 ul aliquot of reaction mixture to a microtiter plate (MTP) module and incubating at 37 C for 20 min.
This allows the streptavadin coated 96 well plate to associate with the biotinylated peptide.
Wash the MTP module with 300u1/well of PBS four times. Next add 75 ul of anti-phospotyrosine antibody conjugated to horse radish peroxidase(anti-P-Tyr-POD(0.5u/ml)) to each well and incubate at 37 C for one hour. Wash the well as above.
Next add IOOuI of peroxidase substrate solution (Boehringer Mannheim) and incubate at room temperature for at least 5 mins (up to 30 min). Measure the absorbance of the sample at 405 nm by using ELISA reader. The level of bound peroxidase activity is quantitated using an ELISA reader and reflects the level of tyrosine kinase activity.

Example 20: High-Throughput Screening Assay Identifying Phosuhorylation Activity As a potential alternative and/or compliment to the assay of protein tyrosine kinase activity described in Example 19, an assay which detects activation (phosphorylation) of major intracellular signal transduction intermediates can also be used. For example, as described below one particular assay can detect tyrosine phosphorylation of the Erk-1 and Erk-2 kinases. However, phosphorylation of other molecules, such as Raf, JNK, p38 MAP, Map kinase kinase (MEK), MEK kinase, Src, Muscle specific kinase (MuSK), IRAK, Tec, and Janus, as well as any other phosphoserine, phosphotyrosine, or phosphothreonine molecule, can be detected by substituting these molecules for Erk-1 or Erk-2 in the following assay.

Specifically, assay plates are made by coating the wells of a 96-well ELISA
plate with 0.lml of protein G(lug/ml) for 2 hr at room temp, (RT). The plates are then rinsed with PBS and blocked with 3% BSA/PBS for 1 hr at RT. The protein G
plates are then treated with 2 commercial monoclonal antibodies (100ng/well) against Erk-1 and Erk-2 (1 hr at RT) (Santa Cruz Biotechnology). (To detect other molecules, this step can easily be modified by substituting a monoclonal antibody detecting any of the above described molecules.) After 3-5 rinses with PBS, the plates are stored at 40C
until use.
A431 cells are seeded at 20,000/well in a 96-well Loprodyne filterplate and cultured overnight in growth medium. The cells are then starved for 48 hr in basal medium (DMEM) and then treated with EGF (6ng/well) or 50 ul of the supernatants obtained in Example 11 for 5-20 minutes. The cells are then solubilized and extracts filtered directly into the assay plate.
After incubation with the extract for 1 hr at RT, the wells are again rinsed.
As a positive control, a commercial preparation of MAP kinase ( l Ong/well) is used in place of A431 extract. Plates are then treated with a commercial polyclonal (rabbit) antibody (1 ug/nzl) which specifically recognizes the phosphorylated epitope of the Erk-1 and Erk-2 kinases (1 hr at RT). This antibody is biotinylated by standard procedures. The bound polyclonal antibody is then quantitated by successive incubations with Europium-streptavidin and Europium fluorescence enhancing reagent in the Wallac DELFIA instrument (time-resolved fluorescence). An increased fluorescent signal over background indicates a phosphorylation.

Example 21: Method of Determining Alterations in a Gene Corresponding to a Polynucleotide RNA isolated from entire families or individual patients presenting with a phenotype of interest (such as a disease) is be isolated. cDNA is then generated from these RNA samples using protocols known in the art. (See, Sambrook.) The cDNA
is then used as a template for PCR, employing primers surrounding regions of interest in SEQ ID NO:X. Suggested PCR conditions consist of 35 cycles at 95 C for 30 seconds; 60-120 seconds at 52-58 C; and 60-120 seconds at 70 C, using buffer solutions described in Sidransky, D., et al., Science 252:706 (1991).
PCR products are then sequenced using primers labeled at their 5' end with T4 polynucleotide kinase, employing SequiTherm Polymerase. (Epicentre Technologies).
The intron-exon borders of selected exons is also determined and genomic PCR

products analyzed to confirm the results. PCR products harboring suspected mutations is then cloned and sequenced to validate the results of the direct sequencing.
PCR products is cloned into T-tailed vectors as described in Holton, T.A. and Graham, M.W., Nucleic Acids Research, 19:1156 (1991) and sequenced with T7 polymerase (United States Biochemical). Affected individuals are identified by mutations not present in unaffected individuals.
Genomic rearrangements are also observed as a method of determining alterations in a gene corresponding to a polynucleotide. Genomic clones isolated according to Example 2 are nick-translated with digoxigenindeoxy-uridine 5'-triphosphate (Boehringer Manheim), and FISH performed as described in Johnson, Cg. et al., Methods Cell Biol. 35:73-99 (1991). Hybridization with the labeled probe is carried out using a vast excess of human cot-1 DNA for specific hybridization to the corresponding genomic locus.
Chromosomes are counterstained with 4,6-diamino-2-phenylidole and propidium iodide, producing a combination of C- and R-bands. Aligned images for precise mapping are obtained using a triple-band filter set (Chroma Technology, Brattleboro, VT) in combination with a cooled charge-coupled device camera (Photometrics, Tucson, AZ) and variable excitation wavelength filters.
(Johnson, Cv.
et al., Genet. Anal. Tech. Appl., 8:75 (1991).) Image collection, analysis and chromosomal fractional length measurements are performed using the ISee Graphical Program System. (Inovision Corporation, Durham, NC.) Chromosome alterations of the genomic region hybridized by the probe are identified as insertions, deletions, and translocations. These alterations are used as a diagnostic marker for an associated disease.
Example 22: Method of Detecting Abnormal Levels of a Polypentide in a Biological Sample A polypeptide of the present invention can be detected in a biological sample, and if an increased or decreased level of the polypeptide is detected, this polypeptide is a marker for a particular phenotype. Methods of detection are numerous, and thus, it is understood that one skilled in the art can modify the following assay to fit their particular needs.
For example, antibody-sandwich ELISAs are used to detect polypeptides in a sample, preferably a biological sample. Wells of a microtiter plate are coated with specific antibodies, at a final concentration of 0.2 to 10 ug/ml. The antibodies are either monoclonal or polyclonal and are produced by the method described in Example 10.

WO 99/11293 PCT/[JS98/18360 The wells are blocked so that non-specific binding of the polypeptide to the well is reduced.
The coated wells are then incubated for > 2 hours at RT with a sample containing the polypeptide. Preferably, serial dilutions of the sample should be used to validate results. The plates are then washed three times with deionized or distilled water to remove unbounded polypeptide.
Next, 50 ul of specific antibody-alkaline phosphatase conjugate, at a concentration of 25-400 ng, is added and incubated for 2 hours at room temperature.
The plates are again washed three times with deionized or distilled water to remove unbounded conjugate.
Add 75 ul of 4-methylumbelliferyl phosphate (MUP) or p-nitrophenyl phosphate (NPP) substrate solution to each well and incubate 1 hour at room temperature. Measure the reaction by a microtiter plate reader. Prepare a standard curve, using serial dilutions of a control sample, and plot polypeptide concentration on the X-axis (log scale) and fluorescence or absorbance of the Y-axis (linear scale).
Interpolate the concentration of the polypeptide in the sample using the standard curve.
Example 23: Formulating a Polypeptide The secreted polypeptide composition will be formulated and dosed in a fashion consistent with good medical practice, taking into account the clinical condition of the individual patient (especially the side effects of treatment with the secreted polypeptide alone), the site of delivery, the method of administration, the scheduling of administration, and other factors known to practitioners. The "effective amount" for purposes herein is thus determined by such considerations.
As a general proposition, the total pharmaceutically effective amount of secreted polypeptide administered parenterally per dose will be in the range of about 1 g/kg/day to 10 mg/kg/day of patient body weight, although, as noted above, this will be subject to therapeutic discretion. More preferably, this dose is at least 0.01 mg/kg/day, and most preferably for humans between about 0.01 and 1 mg/kg/day for the hormone.
If given continuously, the secreted polypeptide is typically administered at a dose rate of about 1 g/kg/hour to about 50 g/kg/hour, either by 1-4 injections per day or by continuous subcutaneous infusions, for example, using a mini-pump. An intravenous bag solution may also be employed. The length of treatment needed to observe changes and the interval following treatment for responses to occur appears to vary depending on the desired effect.
Pharmaceutical compositions containing the secreted protein of the invention are administered orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, gels, drops or transdermal patch), bucally, or as an oral or nasal spray. "Pharmaceutically acceptable carrier" refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The term "parenteral" as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
The secreted polypeptide is also suitably administered by sustained-release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or mirocapsules.
Sustained-release matrices include polylactides (U.S. Pat. No. 3,773,919, EP
58,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U. et al., Biopolymers 22:547-556 (1983)), poly (2- hydroxyethyl methacrylate) (R. Langer et al., J. Biomed. Mater. Res. 15:167-277 (1981), and R. Langer, Chem. Tech.
12:98-105 (1982)), ethylene vinyl acetate (R. Langer et al.) or poly-D- (-)-3-hydroxybutyric acid (EP 133,988). Sustained-release compositions also include liposomally entrapped polypeptides. Liposomes containing the secreted polypeptide are prepared by methods known per se: DE 3,218,121; Epstein et al., Proc. Natl. Acad. Sci. USA 82:3688-(1985); Hwang et al., Proc. Natl. Acad. Sci. USA 77:4030-4034 (1980); EP
52,322;
EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese Pat. Appl. 83-118008;
U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324. Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the optimal secreted polypeptide therapy.
For parenteral administration, in one embodiment, the secreted polypeptide is formulated generally by mixing it at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. For example, the formulation preferably does not include oxidizing agents and other compounds that are known to be deleterious to polypeptides.
Generally, the formulations are prepared by contacting the polypeptide uniformly and intimately with liquid carriers or finely divided solid carriers or both.
Then, if necessary, the product is shaped into the desired formulation.
Preferably the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes.

The carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts;
antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, manose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and/or nonionic surfactants such as polysorbates, poloxamers, or PEG.
The secreted polypeptide is typically formulated in such vehicles at a concentration of about 0.1 mg/ml to 100 mg/ml, preferably I-10 mg/ml, at a pH
of about 3 to 8. It will be understood that the use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of polypeptide salts.
Any polypeptide to be used for therapeutic administration can be sterile.
Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). Therapeutic polypeptide compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
Polypeptides ordinarily will be stored in unit or multi-dose containers, for example, sealed ampoules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, 10-m1 vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous polypeptide solution, and the resulting mixture is lyophilized. The infusion solution is prepared by reconstituting the lyophilized polypeptide using bacteriostatic Water-for-Injection.
The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. In addition, the polypeptides of the present invention may be employed in conjunction with other therapeutic compounds.
Example 24: Method of Treating Decreased Levels of the Polyge tn ide It will be appreciated that conditions caused by a decrease in the standard or normal expression level of a secreted protein in an individual can be treated by administering the polypeptide of the present invention, preferably in the secreted form.
Thus, the invention also provides a method of treatment of an individual in need of an increased level of the polypeptide comprising administering to such an individual a pharmaceutical composition comprising an amount of the polypeptide to increase the activity level of the polypeptide in such an individual.
For example, a patient with decreased levels of a polypeptide receives a daily dose 0.1-100 ug/kg of the polypeptide for six consecutive days. Preferably, the polypeptide is in the secreted form. The exact details of the dosing scheme, based on administration and formulation, are provided in Example 23.

Example 25: Method of Treating Increased Levels of the Polypeptide Antisense technology is used to inhibit production of a polypeptide of the present invention. This technology is one example of a method of decreasing levels of a polypeptide, preferably a secreted form, due to a variety of etiologies, such as cancer.
For example, a patient diagnosed with abnormally increased levels of a polypeptide is administered intravenously antisense polynucleotides at 0.5, 1.0, 1.5, 2.0 and 3.0 mg/kg day for 21 days. This treatment is repeated after a 7-day rest period if the treatment was well tolerated. The formulation of the antisense polynucleotide is provided in Example 23.

Example 26: Method of Treatment Usini! Gene Therap,y One method of gene therapy transplants fibroblasts, which are capable of expressing a polypeptide, onto a patient. Generally, fibroblasts are obtained from a subject by skin biopsy. The resulting tissue is placed in tissue-culture medium and separated into small pieces. Small chunks of the tissue are placed on a wet surface of a tissue culture flask, approximately ten pieces are placed in each flask. The flask is turned upside down, closed tight and left at room temperature over night.
After 24 hours at room temperature, the flask is inverted and the chunks of tissue remain fixed to the bottom of the flask and fresh media (e.g., Ham's F12 media, with 10% FBS, penicillin and streptomycin) is added. The flasks are then incubated at 37 C
for approximately one week.
At this time, fresh media is added and subsequently changed every several days.
.35 After an additional two weeks in culture, a monolayer of fibroblasts emerge. The monolayer is trypsinized and scaled into larger flasks.

pMV-7 (Kirschmeier, P.T. et al., DNA, 7:219-25 (1988)), flanked by the long terminal repeats of the Moloney murine sarcoma virus, is digested with EcoRI
and HindIII and subsequently treated with calf intestinal phosphatase. The linear vector is fractionated on agarose gel and purified, using glass beads.
The cDNA encoding a polypeptide of the present invention can be amplified using PCR primers which correspond to the 5' and 3' end sequences respectively as set forth in Example 1. Preferably, the 5' primer contains an EcoRI site and the 3' primer includes a HindIII site. Equal quantities of the Moloney murine sarcoma virus linear backbone and the amplified EcoRI and HindIIl fragment are added together, in the presence of T4 DNA ligase. The resulting mixture is maintained under conditions appropriate for ligation of the two fragments. The ligation mixture is then used to transform bacteria HB 101, which are then plated onto agar containing kanamycin for the purpose of confirming that the vector has the gene of interest properly inserted.
The amphotropic pA317 or GP+aml2 packaging cells are grown in tissue culture to confluent density in Dulbecco's Modified Eagles Medium (DMEM) with 10%
calf serum (CS), penicillin and streptomycin. The MSV vector containing the gene is then added to the media and the packaging cells transduced with the vector.
The packaging cells now produce infectious viral particles containing the gene (the packaging cells are now referred to as producer cells).
Fresh media is added to the transduced producer cells, and subsequently, the media is harvested from a 10 cm plate of confluent producer cells. The spent media, containing the infectious viral particles, is filtered through a millipore filter to remove detached producer cells and this media is then used to infect fibroblast cells. Media is removed from a sub-confluent plate of fibroblasts and quickly replaced with the media from the producer cells. This media is removed and replaced with fresh media.
If the titer of virus is high, then virtually all fibroblasts will be infected and no selection is required. If the titer is very low, then it is necessary to use a retroviral vector that has a selectable marker, such as neo or his. Once the fibroblasts have been efficiently infected, the fibroblasts are analyzed to determine whether protein is produced.
The engineered fibroblasts are then transplanted onto the host, either alone or after having been grown to confluence on cytodex 3 microcarrier beads.
It will be clear that the invention may be practiced otherwise than as particularly described in the foregoing description and examples. Numerous modifications and variations of the present invention are possible in light of the above teachings and, - therefore, are within the scope of the appended claims.

INDICATIONS RELATING TO A DEPOSITED MICROORGANISM
(PCT Rule 13bis) A. The indications made below relate to the microorganism referred to in the description on page 62 , line N/A

B. IDENTIFICATION OF DEPOSIT Further deposits are identified on an additional sheet Name of depositary institution American Type Culture Collection Address of depositary institution (including postal code and country) 10801 University Boulevard Manassas, Virginia 20 1 1 0-2209 United States of America Date of deposit August 21, 1997 Accession Number 209215 C. ADDITIONAL INDICATIONS peave blank (fnot appltcable) This information is continued on an additional sheet D. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE (ithe indNcations are notfor all designated States) E. SEPARATE FURNISHING OF INDICATIONS (leave blank f not applicable) The indications listed below will be submitted to the International Bureau later (specify rhe general nature of the indications. e.g.. ".Iccession Number oJDeposlt") For receiving Office use only For International Bureau use only This sheet was received with the intenutiional application ^ This sheet was received by the internationa! Bureau on:
...-.,-.
Authd ' ^
y ~r'~ ~~.,~, Authorized officer ~,~'=T~ A Ltl ~T~~ ~~'k~~ _~/ = , ~/iJ:3".i~%.r-dV -^ .

INDICATIONS RELATING TO A DEPOSITED MICROORGANISM
(PCT Rule 13bis) A. The indications made below relate to the microorganism referred to in the description on page 62 , line N/A

B. IDENTIFICATION OF DEPOSIT Further deposits are identified on an additional sheet Name of depositary institution American Type Culture Collection Address of depositary institution (including postal code and country) 10801 University Boulevard Manassas, Virginia 20110-2209 United States of America Date of deposit June 26, 1998 Accession Number 203027 C. ADDITIONAL INDICATIONS (leave blank ijnot applicable) This information is continued on an additional sheet D. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE (ijtke indications are notfor all designated States) E. SEPARATE FURNISHING OF INDICATIONS (leave blank ijnot applicable) The indications listed below will be submitted to the Interttational Bureau later (specify the general nature of the indications. e.g., ".}ccession Number of Deposit") For receiving Office use only For Intemational Bureau use only is sheet was received with the intemational application ^ This sheet was reaived by the lntemational Bureau on:

Authorized officer Authorized officer ~G'~'~3~;'3 ~4'~' DIVISYQI4 ~;*!'T'F..~. tA~.
` v;;-INDICATIONS RELATING TO A DEPOSITED MICROORGANISM
(PCT Rule 13bis) A. The indications made below relate to the microorganism refen=ed to in the description on page 64 , line N/A

B. IDENTIFICATION OF DEPOSIT Further deposits are identified on an additional sheet Name of depositary institution American Type Culture Collection Address of depositary institution (including postal code and country) 10801 University Boulevard Manassas, Virginia 20110-2209 United States of America Date of deposit August 28, 1997 Accession Number 209224 C. ADDITIONAL INDICATIONS (leave blank ijnot applicable) This information is continued on an additional sheet D. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE (ijthe indJeations are Roa jor a!l designated States) E. SEPARATE FURNISHING OF INDICATIONS (leave blank f not applicable) The indications listed below will be submitted to the Intemational Bureau later (speciJy the general naturt of the tndicarions, e.g.. "Accession Number of Deposit") For receiving Office use only For International Bureau use only roff-eAuthori=zcd was received with the international application ^ This s sheet was reeeived by the [ntemational Bureau on:
r,.,, Authorized officer 1~IVIwIC..1`
Vy V~ =..~vVU

INDICATIONS RELATING TO A DEPOSITED MICROORGANISM
(PCT Rule 13bis) A. The indications made below reiate to the microorganism referred to in the description on page 63 , line N/A

B. IDENTIFICATION OF DEPOSIT Further deposits are identified on an additional sheet Name of depositary institution American Type Culture Collection Address of depositary institution (inclttdingpostal code and country) 10801 University Boulevard Manassas, Virginia 20110-2209 United States of America Date of deposit April 20, 1998 Accession Number 209782 C. ADDITIONAL INDICATIONS (leave blank jnot applicable) This infonnation is continued on an additional sheet D. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE rjt/eelndications are notfor e!1 dedgnated Stwes) E. SEPARATE FURNISHING OF INDICATIONS (leave blank f not applicable) The indications listed below will be submitted to the International Bureau later (specify the general nature oltse indications, e.g., "Accession Number oJDeposit") For receiving Office use only For Intemational Bureau use only is sheet was received with the intemationai applioation ^ This sheet was received by the lnternationai Bureau on:
AuthoriaeVWMED HCtM Authorized officer Nrl-FNATIO1VAT. DIVIStON

INDICATIONS RELATING TO A DEPOSITED MICROORGANISM
(PCT Rule 13bis) A. The indications made below relate to the microorganism referred to in the description on page 65 , line N/A

B. IDENTIFICATION OF DEPOSIT Further deposits are identified on an additional sheet Name of depositary institution American Type Culture Collection Address of depositary institution (including postal code and country) 10801 University Boulevard Manassas, Virginia 20110-2209 United States of America Date of deposit October 2, 1997 Accession Number 209324 C. ADDITIONAL INDICATIONS (leave blank ijnot applicable) This information is continued on an additional sheet D. DESIGNATED STATES FOR"WHICH INDICATIONS ARE MADE
(itbelndieattoxsarenotfora/ldesignatedsYatu) E. SEPARATE FURNISHING OF INDICATIONS (leave blank ifnot applteable) The indications listed below will be submitted to the Intemational Bureau later (specljy the general nature of the indications, e.g., Accesaion Number of Depoait-) For receiving Office use only For International Bureau use only [,T'h'i sheet was received with the international application ~ This sheet was received by the Intemational Bureau on:
Authorizedoi~p,r.~ ~v~, Authorized ofTicer "'a'T77:,.' i i F.1 :, i`Ji~b INDICATIONS RELATING TO A DEPOSITED MICROORGANISM
(PCT Rule 13bis) A. The indications made below relate to the microorganism refen-ed to in the description on page 66 , line N/A

B. IDENTIFICATION OF DEPOSIT Further deposits are identified on an additional sheet Name of depositary institution American Type Culture Collection Address of depositary institution (including postal code and country) 10801 University Boulevard Manassas, Virginia 20110-2209 United States of America Date of deposit April 7, 1998 Accession Number 209745 C. ADDITIONAL INDICATIONS (leave blank ijnor appttcabte) This infonnation is continued on an additional sheet --.~
D. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE (tjtke inddcadons are notfor att designated SYates) E. SEPARATE FURNISHING OF INDICATIONS peave blank (jnot applicable) The indications listed below will be submitted to the International Bureau later (specj& dK general nature ojthe indtcations, e.g., "Accesston Number ojDepostt') For receiving Office use only For Interttational Bureau use only disheet was received with the intemational apTHWIon s sheet was received by the Intemational Bureau on:
Authorized oflicu fl`icer SiGP~.}
~,D HUSTAD ` --IN't~P~'1,,'~ON'AL DIVISIiONt <110> Rosen et al.
Human Genome Sciences, Inc.
<120> 50 Human Secreted Proteins <130> PZ016.PCT

<140> Unassigned <141>

<150> 60/057,663 <151> 1997-09-05 <150> 60/057,626 <151> 1997-09-05 <150> 60/057,669 <151> 1997-09-05 <150> 60/058,973 <151> 1997-09-12 <150> 60/058,974 <151> 1997-09-12 <150> 60/058,667 <151> 1997-09-12 <150> 60/058,666 <151> 1997-09-12 <160> 132 <170> PatentIn Ver. 2.0 <210> 1 <211> 733 <212> DNA
<213> Homo sapiens <400> 1 gggatccgga gcccaaatct tctgacaaaa ctcacacatg cccaccgtgc ccagcacctg 60 aattcgaggg tgcaccgtca gtcttcctct tccccccaaa acccaaggac accctcatga 120 tctcccggac tcctgaggtc acatgcgtgg tggtggacgt aagccacgaa gaccctgagg 180 tcaagttcaa ctggtacgtg gacggcgtgg aggtgcataa tgccaagaca aagccgcggg 240 aggagcagta caacagcacg taccgtgtgg tcagcgtcct caccgtcctg caccaggact 300 ggctgaatgg caaggagtac aagtgcaagg tctccaacaa agccctccca acccccatcg 360 agaaaaccat ctccaaagcc aaagggcagc cccgagaacc acaggtgtac accctgcccc 420 catcccggga tgagctgacc aagaaccagg tcagcctgac ctgcctggtc aaaggcttct 480 atccaagcga catcgccgtg gagtgggaga gcaatgggca gccggagaac aactacaaga 540 ccacgcctcc cgtgctggac tccgacggct ccttcttcct ctacagcaag ctcaccgtgg 600 acaagagcag gtggcagcag gggaacgtct tctcatgctc cgtgatgcat gaggctctgc 660 acaaccacta cacgcagaag agcctctccc tgtctccggg taaatgagtg cgacggccgc 720 gactctagag gat 733 <210> 2 <211> 5 <212> PRT
<213> Homo sapiens <220>
<221> Site <222> (3) <223> Xaa equals any of the twenty naturally ocurring L-amino acids <400> 2 Trp Ser Xaa Trp Ser <210> 3 <211> 86 <212> DNA
<213> Homo sapiens <400> 3 gcgcctcgag atttccccga aatctagatt tccccgaaat gatttccccg aaatgatttc 60 cccgaaatat ctgccatctc aattag 86 <210> 4 <211> 27 <212> DNA
<213> Homo sapiens <400> 4 gcggcaagct ttttgcaaag cctaggc 27 <210> 5 <211> 271 <212> DNA
<213> Homo sapiens <400> 5 ctcgagattt ccccgaaatc tagatttccc cgaaatgatt tccccgaaat gatttccccg 60 aaatatctgc catctcaatt agtcagcaac catagtcccg cccctaactc cgcccatccc 120 gcccctaact ccgcccagtt ccgcccattc tccgccccat ggctgactaa ttttttttat 180 ttatgcagag gccgaggccg cctcggcctc tgagctattc cagaagtagt gaggaggctt 240 ttttggaggc ctaggctttt gcaaaaagct t 271 <210> 6 <211> 32 <212> DNA
<213> Homo sapiens <400> 6 gcgctcgagg gatgacagcg atagaacccc gg 32 <210> 7 <211> 31 <212> DNA
<213> Homo sapiens <400> 7 gcgaagcttc gcgactcccc ggatccgcct c 31 <210> 8 <211> 12 <212> DNA
<213> Homo sapiens <400> 8 ggggactttc cc 12 <210> 9 <211> 73 <212> DNA
<213> Homo sapiens <400> 9 gcggcctcga ggggactttc ccggggactt tccggggact ttccgggact ttccatcctg 60 ccatctcaat tag 73 <210> 10 <211> 256 <212> DNA
<213> Homo sapiens <400> 10 ctcgagggga ctttcccggg gactttccgg ggactttccg ggactttcca tctgccatct 60 caattagtca gcaaccatag tcccgcccct aactccgccc atcccgcccc taactccgcc 120 cagttccgcc cattctccgc cccatggctg actaattttt tttatttatg cagaggccga 180 ggccgcctcg gcctctgagc tattccagaa gtagtgagga ggcttttttg gaggcctagg 240 cttttgcaaa aagctt 256 <210> 11 <211> 1110 <212> DNA
<213> Homo sapiens <400> 11 gaattcggca cgagcttggt tcggggggga gcaaaatcca gaatctgcta aacaccaatg 60 ctgtcactca gagtttgtgt atctgctgtc tgtggagctc tggaccaggc ttgagggacg 120 cctggggttt ccacccacat ctggggcaaa ccagaccccc aagtcactga catgtcggtt 180 tttctactaa tcacgttggc tttggcaatt ctgtatataa taagaagtat tgtgttctca 240 cttgcacttk ggcagaacgg ttcactccaa ggctgaatga ctgccacgga ccatccccca 300 gcaggggtcc tggggtttag tggtttgatt ctgagcacct ctamgcamag agccccttag 360 tgggttccct aactggacgg ctaaccctgs tgtggaatct gactkkwtct ggaccgaaga 420 ggacaggctg ctctggagaa atccttgggc cttgtgcctg atgctggctc gggccaccct 480 ggccaccctc ccttcatgcc ccatgggacc aggcagcagc atgggagggg gcagcttcca 540 gaacaccctt ctgctagggg ctkctggcct ccctgctggc acggccacat ccatggtctg 600 agtgtgtggt tggaatgttt tatcaacacc agtcctcaca gcttccccag atgagcgaag 660 gggaagggga tggtgtgtgg ggggattgcc tcccttgagg ccccccagct cccaggatac 720 ttgctggcgg agctctgcct gcggtggagg ccctatgact tgacctccat cttctccctg 780 ggcccctcgc tggccctcac tggcaggggc tcctgcacgc ctgcaaggcc agagcctccc 840 gccaggtgca ggagaagtaa atgcaggcca gagataaatc gtatttccct ctaactcgga 900 tgtggagtga gaggaaggaa gcaggagtgg agctgagtgt tagtgagagg tggctgagaa 960 ggcggggtcc cgcttcttgc ttccttgggc atttgctgta ggtgctgggt ttcagcctgg 1020 aagggtgcag cctctgcact aagtctggtt tggtgaacgt tcatggcccc caatataaac 1080 agtgttctgg gcgttctttg tgactctcga 1110 <210> 12 <211> 936 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (294) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (298) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (925) <223> n equals a,t,g, or c <400> 12 gaattcggca cgaggaattt aagataccga agtcttaaag tgacctggac gtgaaggaaa 60 aagtaagatg agaaataaag aaagcctttg taaggtggtt ttaaaagcct tatatgcaaa 120 ccttttaatc tgtgtttctg caagtgccat ccttgtacag tgttaagagg gtaacatggg 180 ttacctttgc accagcttca gtgttaagct caccctgttc tttgaagcac ccatgtcagt 240 attagaagaa taggcagcag ttccttagtt tacatatgtt tgkgcaatta tttnctgnac 300 ttttttgttc attaatttgt cagtattaca ccaaactgtt tttgcaacaa aaaaattttt 360 tttgcattca tttaatttta ggtcaaataa cattttattt atgtggctca ttttatattt 420 cctaatttta tttatttcat actgtagtgt acagtattat agttcttcaa tatatagata 480 tattttagta aaaaaggaac atgacgttga tcatttgggc aaattttacg taaagagaag 540 agcatttatt gtgttttgga acattaattg tgagatggga tttttcaatt ttattatttt 600 atttttgttt ttttccaatt actggaaatt ccaaatttgg gaacttttga tacgatcttg 660 tgaaaacact gtattttcga ctgaaaattc cactttcttc atcttgtttt ttagctaaaa 720 agagggactg ttaaatacaa tgtatgatac catgacaaaa atctttcctg aattgtcttt 780 gtaaaagtat tattgaattt tcaatttgta atttcttttg aaaatgacca tgctcgaata 840 aaaatgtagc caaactaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 900 aaaaaaaaaa aaaaaaaaaa aaaanaaaaa aaaaaa 936 <210> 13 <211> 921 <212> DNA
<213> Homo sapiens <400> 13 ggcacgaggg ccgtttgcgt cggaagcctg aagcatgggc gctgagtggg agctgggggc 60 cgargctggc ggttcgctgc tgctgtgcgc cgcgctgctg gcggcgggct gcgccctggg 120 cctgcgcctg ggccgcgggc agggggcggc ggaccgcggg gcgctcatct ggctctgcta 180 cgacgcgctg gtgcacttcg cgctggaagg cccttttgtc tacttgtctt tagtaggaaa 240 cgttgcaaat tccgatggct tgattgcttc tttatggaaa gaatatggca aagctgatgc 300 aagatgggtt tattttgatc caaccattgt gtctgtggaa attctgaccg tcgccctgga 360 tgggtctctg gcattgttcc tcatttatgc catagtcaaa gaaaaatatt accggcattt 420 cctgcagatc accctgtgcg tgtgcgagct gtatggctgc tggatgacct tcctcccaga 480 gtggctcacc agaagcccca acctcaacac cagcaactgg ctgtactgtt ggctttacct 540 gttttttttt aacggtgtgt gggttctgat cccaggactg ctactgtggc agtcatggct 600 agaactcaag aaaatgcatc agaaagaaac cagttcagtg aagaagtttc agtgaacttt 660 caaaaccagg cacgagccat tatctaactt catgaaccag aatgaatcaa atctttttgt 720 ttggccaaaa tgtaatacat tccagtctac actttgtttt tgtattgttg ctcctgaaca 780 acctgtttca aattggtttt aaggcgacca gttttcgttg tattgttgtt caattaaatg 840 gtgatatagg gaaaagagaa caaatttgaa tttgtaataa taaaatgttt aattataaaa 900 aaaaaaaaaa aaaaaaaaaa a 921 <210> 14 <211> 2541 <212> DNA
<213> Homo sapiens <400> 14 ggcggaaggg gaggacgtgg gatggtggcg gactggctgc agcagagcta ccaagcagtc 60 aaagagaagt cctctgaagc cttggagttt atgaagcggg acctgacgga gtttacccag 120 gtggtgcagc atgacacggc ctgtaccatc gcagccacgg ccagcgtggt caaggagaag 180 ctggctattg cagcctgttc ccggggcgct tgcttcctct gcccgttctc tatacagacg 240 gaaggctcct caggagcaac agagaagatg aagaaagggt tatctgactt cctaggggtg 300 atctcagaca cctttgcccc ttcgccagac aaaaccatcg actgcgatgt catcaccctg 360 atgggcacac cgtctggcac agctgagccc tatgatggca ccaaggctcg cctctatagc 420 ctgcagtcgg acccagcaac ctactgtaat gaaccagayg ggcccccgga attgtttgac 480 gcctggcttt cccagttctg cttggaggag aagaaggggg agatctcaga gctccttgta 540 ggcagcccct ccatccgggc cctctacacc aagatggttc cagcagctgt ttcccattca 600 gaattctggc atcggtattt ctataaagtc catcagttag agcaggagca ggcccggagg 660 acgccctgaa gcagcgggcg gaacagagca tctytgaaga gcccggctgg gaggaggagg 720 aagaggagct catgggcatt tcacccatat ctccaaaaga ggcaaaggtt cctgtggcca 780 aaatttctac attccctgaa ggagaacctg gcccccagag cccctgtgaa gagaatctgg 840 tgacttcagt tgagccccca gcagaggtga ctccatcaga gagcagtgag agcatctccc 900 tcgtgacaca gatcgccaac ccggccactg cacctgaggc acgagtgcta cccaaggacc 960 tgtcccaaaa gctgctagag gcatccttgg aggaacaggg cctggctgtg gatgtgggtg 1020 aractggacc ctcaccccct attcactcca agcccctaac gcctgctggc cacagattct 1080 ggtggctccc tgctggccct cttgggcctc tgctcacacc tgggaagggg ctctctaaat 1140 cccggccaga aactctgact tgtgccaaca ataggatgac ccaagggaga ggaaacctat 1200 cctcctcacc agaagagcct gtgtttttct gctgaacacc cactgttcct gaggactcct 1260 gctgggaagt cccaagggat agttctagcc cttctgcctg tgtagacaga agctaaacca 1320 ccagtctctc tcggaggaag ctgagacaac atactctgtc catacataag caggcaggga 1380 gggccatgcc acctaccctt ggctaaacag ggacagtgaa cacattttgg ttcctatccc 1440 agtgggtaag aggcacttat ctctgggaaa tttgcctctc ttgggactct ccccctccca 1500 ggcattttcc attcctggaa aggctccttt ggggttcaga atccagagac caaaccctga 1560 cccacctcct tcctttcctc cagcccacgc tggtctgtcc ccatgccttc ccagggcttc 1620 ttcatgtcag atgcacccaa gtccttagcc cagctgtgcc acctgcagga gttcgctctt 1680 gcgtttcttc ccctccccaa gaagggaggg ggctacttca ggcccttctg tgtgttgcct 1740 ggcaggatac cttgtccaac cagctaccca cctcaactcc cctgtagttt aggacacaaa 1800 acagctacca gcggtacaga gcggtgatca aagccgagta cttacaactc tggtaagcct 1860 agcttctccg cctcagccct tctgcttctg gaagggctat cctgggggtg aacttgaaac 1920 tctcatcagg cttctgcaaa agctcttctt cctgaagaca gacccagcct ttgtgctctc 1980 accctccact ctggtaaagc tgcacctctg ggggaatgag gggctgcagg aatctctgga 2040 gagcctggtg cttcacgatg ctgctctggt gattcttgta cctaatctgg tgtgctcacc 2100 aatgagtgaa agggatcgtg ggtcagggac accgagagag tgaggtcact tccacttcaa 2160 accttcagtg agggggtggg atggagagaa tgctgaatct tttttttgac gggatggggt 2220 ttttctcttt gtaattattt ctttagttta attaaccttt tggttgtttg tgcaatatta 2280 tatattttaa attataatgc atctccccag agtattttgt agctgggaaa agaaaaaagg 2340 aaaaaaagaa aaaaagattc taacagctgt tagttttata attaaaaaag aaagaaaaaa 2400 gaactttgtc ctgaaccttt tacagacttg ccgttaacag cattaaagtg attcacccga 2460 agctgaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaact cgaggggggg cccgtaccca 2520 atcgcctgtg atgtatcgta t 2541 <210> 15 <211> 1046 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (20) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (21) <223> n equals a,t,g, or c <400> 15 agtgaatcct gagtggggtn ntctttagcc taaacctgga gtcaccacag agcttttata 60 aacagtgaga aacctactac ttcctacaga aactgtgctg tctgcaaagc tcagcgtctg 120 ctccagcctg aatccccagg ccctgtccct gtacacacct agttttgagg tcaggacatc 180 acaaaacatc tgccaacatc gaaaagtcat caggagccac ccagacgtgg ggtgtattgg 240 tgggaagaag gagcatctta gtctgcttcc ttctgaggcc cacagttcca gaaggactag 300 cgtcctcaga gcatgtggta gtggctgttc ttgtcttttc ctggtggtgg ggcctggtga 360 cccctaacac caacggagct gttcccaggt tcatttcgtc cctttttctg tggtgagatg 420 aggctcctcc tgccctcctt gctgggtggt ctttctgttt tgaccacatc ccttggaagc 480 gtggctgggc tgcgtaactc cagagcagcc tggtggtagc tggggctgcc ttctgagttt 540 gggctggtgg atgctgagta tttgcattca gagccttagg cattgacctt ggctttctgg 600 gaccctacgc ccctctgttt gcctttgtca gtagagacct tctcacatta gggattcatt 660 ttttccaaga ctgtttgcta aggtgtgtgt caaacttcct cccagagcag tgacatggat 720 gggaattgtg agtgtgttga gagacctacc ctaaaagatg gggctgcagt catcctcagg 780 ggacctcctg ttctcagctc cacctcagcc acacttggct gtgggtcagc ttcttctgaa 840 tcagcatccg caggacagcg ccacccagcc ctgccacact tgcttcctcc gcgcttcttc 900 agaggctgga gcccaccccc atgctcgtcg tctgttctgc ttttttgatg cacttacttg 960 tccctttcag cgtattgctt atgtcctatg ttggttaaaa aaaaaaaaaa aaaactcgag 1020 ggggggcccg tacccaatcg ccctat 1046 <210> 16 <211> 982 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (4) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (30) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (31) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (149) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (940) <223> n equals a,t,g, or c <400> 16 tcgncccacg cgtccgcgga cgcgtgggtn nctaaccttt ggtttgcgga cggtcgggtg 60 tattctccgc cgcccccacg ccctcgaggt ccccgccacc gaaccagcgg cggaccggcc 120 cgcgcctccc gcggcattcc cgcaccggnt cgctcctcgc tggggcggga cctggcctgg 180 cggctctggt cactatgagt gaaacatctt tcaacctaat atcagaaaaa tgtgacattc 240 tatccattct tcgggaccat cctgaaaaca ggatttaccg gaggaaaatc gaggaactca 300 gcaaaaggtt caccgccatc cgcaagacca aaggggatgg gaactgcttc tacagggcct 360 tgggctattc ctacctggag tccctgctgg ggaagagcag ggagatcttc aagttcaaag 420 aacgcgtact gcagacccca aatgaccttc tggctgctgg'ctttgaggag cacaagttca 480 gaaacttctt caatgctttt acagtgtggt ggaactggta gagaaggatg gctcagtgtc 540 cagcctgctg aargtgtttc aacgaccaga gtgcctcggg accacatcgt gcagttcctg 600 cgcctgctca mgtcggsctt catcaggaac cgagcagact tcttccggca cttcattgat 660 gargagatgg acatcaaaga cttctgcact cacgaagtag agcccatggc camggagtgt 720 gaccacatcc agatcacggc gttgtcgcag gccctgagca ttgccctgca agtggagtac 780 gtggacgaga tggataccgc cctgaaccac cacgtgttcc ctgaggccgc caccccttcc 840 gtttacctgc tctataaaac atcccactac aacatccttt atgcagccga taaacattga 900 ttaattttag gccatgcagt ggaacctgtc acctaatggn actgcattct gaatggaaaa 960 aaaaaaaaaa aaaaaaactc ga 982 <210> 17 <211> 3091 <212> DNA
<213> Homo sapiens <400> 17 aaaccggaaa gtttgtagga aaattgctgc acatggcctt tgcagaaaag agagccttca 60 aaacctctta cattccagta gaaaactctc tctgcaagtc cttaactttg ttcactcatt 120 ccaggaaggt gcttcaatat tggatattca cacagagccc agtttttcaa gtttgctttc 180 acagtcatcg tatgctgaca tgggtgttcc acttcctgca aaaaacttaa tatttaaaga 240 tggtgtctta tcagaakgga gtggacggtc accttcctca cttcttattg ctaatctcca 300 tttgcaataa tttggttaca ccatttgttg ctcacacttt ctgccttttt tctttcttaa 360 cgttagcttt atagtgtcag ccactaaaaa gcatcctgct gctgcagtgc aattcttgct 420 taactaatat taaaagttgg ggaacatatt catgttttct gaagttttgc tcattattgc 480 acatcttatt gcgacaaagt gctttttagc agccagcact gtatttttta ccttgagaca 540 atctgcattt cttttataaa actaagtata tactttatag gctttatgat gactgttatg 600 tttataagca gtcactatga aaattgcaat ggtaatttta tatgttagtt tatcaaacat 660 aaatcttgtt taattttata ttttgttacc tatactttgg gggatcaagg gaagagatgg 720 aactcttcct ctgaaaaggc ttcttggtac ttaaagtagt aaaactataa aacaataaac 780 atccagtatt gagagatgat atgatagggc attatgaatt cctatgggtg tctgtaaatt 840 atgtatgtca gttggacatt gtagaaggta tgtaaatcag catagttgtg tataacttaa 900 ccttgattta taaggtctta agattatgac tattcattga catctcatga gaagctttag 960 aagactttct atttttaaac accatttata tgtggacttc tgttgtcact gactttgggc 1020 tttatatttt catagagtct ttatggaaaa aatagaattt attttccact cttgtagcta 1080 tagctgctgc acactttcac cctgatttat ttttttgttt cttagctttg atgttttcaa 1140 accaaggatt gtgattttag gttagaatta catattagaa gcattaagac tatgtctttg 1200 gatcagaatg ctttagtgat aaacctactt tgaagacata ctcttaagca atctggatct 1260 taaatttatg tgaatacttt tttagaaaat gataaagaaa aatggaatta cttcaaagtg 1320 tttcttgagt cattgattct tttagcatct caaatgttaa ttagaataat tggaatcact 1380 ttttagactt ttcaagttac cttccttggg aagtttgtgc agtgttatag tttagtttag 1440 ctcctcttac agggtaatgg tttgctagtt taaaactgta accaaacgaa ctggtcagac 1500 aacatatatc taaaacactt aaaatgttag gaagtttggg aatgttataa cctaaacgtt 1560 tttgctggta actttttgtt atttatagat atttgtgtat ttaacataca tacttcagga 1620 aatatatgcc tttcctaaaa cttaaccatg cattcaatac catggcctat ctatagaatt 1680 gaatattttg gaccatgtta tctgtggcac agtcagtgct gtgtttgagg taaatgcagt 1740 aacggttagt tttctacttt gtcttataga aggtagaaac catgtgtatg ttatgtttgt 1800 ctataaaaga aaaaatacta atattaaata atttcttacg actctgagtc actcacttat 1860 ttttccaata attgatattg tacattccta gtgccattag gtatgtatgt atgtaacttt 1920 tacagttttt cagctgaaag ttgtaagtat tttttttttt tgatcggggc tctttaatct 1980 cattttaatt tcctttgttt gaactgtagt tatttattcc tatattaacc atctaaacca 2040 actgtaatga catgtacact aatacagaat tgaacatttg tagttgttgg cagtgaaccc 2100 agttgttggt gaatttaaag cttaaaatat gggaatgatt tgctgctata tttcctttga 2160 gagagaaagg aggaagaaat agaacctaat agtgatcatg aattttaggg aaagtaccga 2220 agaaccatgg ggtcccctct ggtttcttgt gttgaatgag gcaagggtaa tcatctgatt 2280 ccgagctgaa gacctctggt cctcttaagg agggagagtg catttttaga gcttttagca 2340 aaatgtgaaa agctgatgtt tgcgccttgc tttgtgaatt tggctttgtt ttacttatac 2400 attaactcat gtaatctctt aaatcttaca agcattgatc catttcaaca aaaaggtaaa 2460 tttaaaatgc agactttgtt atttgccaaa gaagattcat gaaaaattta cgtccaatta 2520 ttttgcaaat agttaatttc atttggcttt ttaccatgtt ccttcctttc tttttcccgc 2580 ttccttaatg taatttaaac cctggcaaac attctttaga aaccaagagg aaagaaagaa 2640 caaatatcaa aaaagacata gaatttaata ttgatacaat ttcacctcta aaatggattt 2700 gaagaaatgc aactttatat caaaaaatgt catctgattt cctttgtttc ttttttaaat 2760 tatgtaatca gatgatttta tgtttttttt tcaggggagc ggaatattgg tttcttttac 2820 ttgttgtttt cagttttctc tgccattcat gtttcttttt tgtgttcagt gtttcaaata 2880 caatttgtat ttaaggattt taaaatacca aactgtaact gagtacagtg gatcgttttc 2940 tgttaggatg ttaatattat acaatgaaat ctataaagtg ttgtcaattt gattattgac 3000 acatataaca tgtttacaaa taaactgtgg tattgatcaa gttactatga aaaaaaaaaa 3060 aaacccgggg ggggccccgg aacccaatcc c 3091 <210> 18 <211> 796 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (398) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (780) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (787) <223> n equals a,t,g, or c <400> 18 gaattcggca cgagctcgtg ccgaattcgg cacgagtcag attgaaggtg gttggttttt 60 attattattt agtgtgattg atagtatcta gaatggcagg tggtgcataa aagttaaaga 120 gaggggaaag attacttagt ttggttatac agttataaac accatgcagt gtattcggtg 180 gactgtgcta tttctgttta tcctttgggt tttggttttt gttttttttt ttgccttcac 240 agtgagactg caaatgattg ttctcataac gtatattatt aataaatgtg gtcctataat 300 ttatactgaa attaccttag gatatttttg cataatactc tcttactgct tacattctat 360 aaatttttca cgtgataatt gtctttgcgt aactgggnaa aaatgccgaa taacttcctt 420 tattatctgg aaaaattaaa tttgttcatt tatattttct acttactaaa ttgagttttt 480 aaaaagactt agtgtgacat ttgacagtgt ctttcaaacg aacttctcta acaagtttat 540 agttattttc ctgtttcaac actattagaa gtcttataaa ttatgctaat tagcatggca 600 gtcatgttac acactcttaa cattgccaaa gaactgttga tttcgtttga gaaaaccctg 660 ggactgtgtg tgtgtaggtt ttgttttgat tttaacaacc aaaaatagaa ataaaattag 720 aactgcgttt taagttctaa aaaaaaaatt taaaaaaaaa aaatttaaaa atttgggacn 780 aaggcgnggg ggtccc 796 <210> 19 <211> 822 <212> DNA
<213> Homo sapiens <400> 19 gatttaccac ctagaaatgg tgtttttaaa tttcttaata tatctccttc ttgtcttttt 60 ctatatatct ttatttcata gtcgagacaa ttttatactc tgaattttta tcatataagt 120 atctacccac attatcagga atgctttgta agcatcattt taatggcttc aaaatagtct 180 atgatttaga taacgatgat ttggccattt ttgtggtcac ctaccactta ttggagacat 240 attatattct gagaatatta tgccatttat aggcattaat tccaatatgc aaaagaactt 300 tgaaatgaag gcgttattat tcccaatttt acagatgctg aaactgaagc tcagagaggt 360 taagttgccc gaggccatac aggacaatag gggcaaagat ggttttgaat caatggatgt 420 ctgacgacaa aggccatgat ctcaccactg cactgcactg tctcctgaag ccctttgtgt 480 gaaatgatta aatacatcat gattatgtca cacttcactt acccttctcc aggtagttga 540 acatctggat gattttacat cgtcaaatac aaggttgtta acaattaaag gataaaacag 600 ggtgcggccg gaaaggcggc cgccccctcg cccatcatgc aatgcacatt cgtggggaac 660 ctggcgctaa gccattcgta gatgacctgc ttctggctcg gggtttcata tgtagcagag 720 cagctccctc gctgcaatct attgaaagtc agccctcgac acaagggttt gtaaaaaaat 780 aaataaataa aacaaaaaac aaaaaaaaaa aaaaaaactc ga 822 <210> 20 <211> 657 <212> DNA
<213> Homo sapiens <400> 20 cgcggcacga gacgaaatga ttcagttctg gacatggcaa gacatgtgcc actctatcgg 60 gcactgctgg aattgcttcg ggccattgct tcttgtgctg ccatggtgcc cctattgttg 120 cccctttcta cagagaacgg tgaagaggaa gaagaacagt cagaatgtca aacttctgtt 180 ggtacattgt tagccaaaat gaagacctgt gttgatacct ataccaaccg tttaaggtac 240 tatatacaat gttcatttct cttgagtttg cctctaacaa tgtttttaaa ataactccat 300 gggtgttttt gtttttcagt gatatgtgct ttttaaaagc mtatacaccc tcggctgggt 360 tgcggtggct cacacctgtg ggtccccagc actgtgggag gccgaggtgg gatggatccc 420 cgaggtcggg agatcgagac catcctggct aacatggtga aaccccgttc tactaaaaat 480 accaaaaaat tagccaggca tggtggcggg cacctgtggt cccagctgct cgggaggctg 540 aggcaggaga atggcgtgaa cccgggaggc ggaggttgca gtgagccgag atcgcgccac 600 tgcactccag cctgggtgac agagagctcc gtctcaaaaa aaaaaaaaaa aaaaaaa 657 <210> 21 <211> 632 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (557) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (571) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (608) <223> n equals a,t,g, or c <400> 21 ggcacgagcc gcagctcccc tcttccttcc tctgcagacg ctggcgctgt ctgccggagg 60 tgttgcccaa aaggccctag tggggcgtgg tcagctccac ctcctgatcc tgtgtgtcct 120 ccgacatgct gctgattcta gtgacccctg tccccaccag gctcagagcc agaccgcgcc 180 tggaccttct tgttctgact ccacgtgcct gcccggcctc cagggtgcgg gggcgccttt 240 cttgcaggcg gaccctgccc aggatggggc cagcctcgtg ctcagctttg gccacaaatg 300 cagcccctgg cccaccccac cctgccggcc ctgccttctc cagtatttcc cacatggcca 360 cgactcctca gtcactagag cctcctgctg ggaacagtgt cccccagagc ctcatgtcta 420 tcctagaccc tgcaagcagc tgggtcccca agagtgcatc tccccctaga gttgcctgcc 480 catgcccacc tgctttgtaa ccttcccagg agattcatgc ttgctctgca cagcagggyt 540 cgaggsccag gscatgnama sggaaytgcc ntcaggtttg ggtcaractg catcctgggg 600 gcatctgntg gaaatgtgag cacacaaacc aa 632 <210> 22 <211> 865 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (365) <223> n equals a,t,g, or c <400> 22 gaattcggca cgagtgccct cgtatctaca tgctcaccta taccctcacc cgacttttcc 60 ctcctcctca ccccatcaaa ggcaataatg cacctgtttt tattcatctg ggcctttggt 120 cttccccttc atatttcccg agacctcgct ttcttctttc tcttgtattt tttatttttc 180 tatctcttat gtgtccttct ctaaaagtta taaacatgca caaaatcttt ccatctcaaa 240 atataatacc ctttacctgg tgtcccctgc aggccatctt ctttatttat ttacttttgc 300 gccaggtctt cctctgaagc ccaggctggg tgcgtacgcg atcatggctc actgcagcct 360 cggantcccg ggctcaagcg atcctcctgc ttggaggatc agatttttta tccttgcaga 420 agtgataata tggcttcttc ctcatctcct aaacaccagt catctgacat acactgcaga 480 tctaaaatgg gccttacgtg ttctgccctt ccttgcctac ctgttgagct tgcaccgctt 540 ctgtgagtct ccccccaccc acaagagatc cttcttcctt cgcgctccac taacccgaca 600 taaatgttta tcatataaag ttttccgttg cactcttgtg tttatgtctc ctggcttctt 660 caccaagctg tgtgacagct gggccctgtc gcctccttcc tcgtatatgc agcgactatc 720 gcagagccgc ttaatctttg ttgaaggcag ctgcggttca gccctgaggg ccacgggacg 780 gacgccactc attcagycct accgggggcg ctgtggcagc cggcattggt tgccgtgccc 840 tccgcttgtc tcgctcagcc ctcga 865 <210> 23 <211> 1222 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (772) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (796) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (823) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (855) <223> n equals a,t,g, or c <400> 23 gaattcggca cgagcacatg wktatatata tattactgtt ttgcctccat tgaacatgcc 60 ttctacttcc taatttgtgc cagaattgac tagtagacgc tatgaatgca tcatgctctt 120 tggcccattt cgaacactca ggtatgtctg tactcttagt tcatctattc atcattgttt 180 ctacagttcc ctcatgcttt aaaaaatata tggcttttat aatttatcca gctttttctt 240 gtcattttaa taagagtatg tgtcttatac aactactaca ttcatcccag aagtagaagc 300 aaactattat aatcccatta tttttattcc tactattctc ttttcagaat ttcttttaga 360 tattccttgg atagttttat tcaatcctcc atggctttca gcttatctta tgttctatct 420 tttggttcat attctgcatt ctggataatt cttcatcttc actttctagt ttgttgatat 480 tccttttggt gactataagc tgctctttaa aatggtcaat aatgcctaag atgtttatta 540 tcttgccctt tgcagaaaaa aattttcagc ttttgctctg gaatgatttt gcatctcttc 600 caccaaactt ccagtgtatc aatggccaga aaataatcta tatgttaatt tgttaatttg 660 atggttcatg gttcaaggct gtataattta aaagtttgaa gtcaaacaac acatgatggg 720 ataatcctga tgttacagat tctcaaggga aaatatgttt ttgttttttc tnccaattgt 780 tctartattt acaganaaac ttcttaatta tactgggttg gtnaataart atttttcttw 840 actctttcaa tctangtcca rctatgcatc accccttcgc tgatgagcat taagaaaatc 900 caaatttggc ccgggcgcgg tggctcacgc ttgtaatccc agcactttgg gaggccgagg 960 cgggtggatc acgaggtcag gagatcgaga ccatcctggc taacacggtg aaaccccgtc 1020 tctactaaaa atacaaaaaa aaattagctg ggcgtgatgg cgggcgcctg tagtcccagc 1080 tactcgggag gctgcggcag gagaatggcg tgaacccggg aggcggagct tgcagtgagc 1140 caagattgcg ccactgcact cccgcctggg ccacagagcg agactccgtc tcaaaaaaaa 1200 aaaaaaaaaa aaaaaaactc ga 1222 <210> 24 <211> 1421 <212> DNA
<213> Homo sapiens <400> 24 ggcagaggga gcggagagcg tgctaaccaa tgacttgagg gagtaggggg ccgggtttgg 60 gccctcagtt gctaagggct acccgagtgg gaagcggttc aagagatggg gtgaagggtg 120 gttcaccggt tcttcaagtc ctcagccttc tggcccgmgg aagttaagca accaagaggc 180 gggcctaaga ccggaagcag gaaggagggc gcaggaagca gggcgccgca gcctgtcgta 240 cggtccttct gtgggtctgt cggtgccgag ggcaggatgg agaagctgcg gctcctgggc 300 ctccgctacc aggagtacgt gactcgtcac ccggccgcca cggcccagct ggagacagca 360 gtgcggggct tcagttacct gctggcaggt cgattcgccg attcgcacga gctgtcagag 420 ctggtgtact ctgcctctaa cctgcttgtg ctgctcaatg acgggatcct acggaaggag 480 cttcggaaaa agttgcctgt gtcgctgtcc cagcagaagc tgctgacatg gctgagcgtg 540 ctggagtgcg tggaggtgtt catggagatg ggagctgcca aggtgtgggg tgaagtgggc 600 cgctggcttg tcatcgccct catccagctg gccaaggctg tactgcggat gctcctgctg 660 ctctggttca aggctggcct ccagacttca ccccctatcg ttccactgga cagagagacc 720 aggcacagcc cccggatggt gaccacagcc ywggyaacca tgagcagtcc tacgtgggga 780 agcggtcaaa ccgggtggtg cgaaccctcc agaacacgcc gtccctgcac tccaggcact 840 ggggagctcc ccagcagcgg gagggacggc agcagcagca tcacgaggag ctgagtgcga 900 cccccacccc cctggggctt gcaggagacc atcgcagagt ttttgtacat tgcccggccg 960 ctgctgcact tgctcagcct gggcctktgg ggtcarargt cgtggaaacc ctggctcttg 1020 gctggtgttg tggacgtgac cagcctgagc ctcctgagtg acagaaaggg cctgacccgg 1080 arggagcggc gggagctgcg gcgccggamc atcctgctgc tctactacct gctgcgctct 1140 cctttctacg accgcttctc cgaggccagg atcctcttcc tgctccagtt gctggccgac 1200 cacgtccctg gcgttggcct ggtcacaagg ccgctcatgg attacttgcc cacctggcag 1260 aaaatctact tctacagttg gggctgacag actcccggaa ggagggtgtg gggaggggtg 1320 ggcagggagc ccctcttccc taataaaact gactccggca gcaaaaaaaa aaaaaaaaaa 1380 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaagggcggc c 1421 <210> 25 <211> 638 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (597) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (628) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (630) <223> n equals a,t,g, or c <400> 25 cggcacgagt ttatttccaa ggtaagtagg ggtagactag aatggacata gcagctcctg 60 tcttatttgc tttaaggctg caatttctgt tcattctctt acccatgcac tttgaaattt 120 cattgctctg caaagtttcc actgaaacat caggtcgaga agacaaaatg tagagaatag 180 caaaccaaaa atatactctt cagagagccc agtgatggaa attatattct acgtaaggcc 240 attaaccagc tacaaagcag tagcagctaa ctaacctggg gataaaagac catctgctgg 300 ctgcatactg attccaagca taatgggtct cccattccca cctccacctg gctccacaat 360 tccctgcatg tcttttaacc tcctcttctt cagactcaat gcttccttat gcaactccag 420 aaacccagta tcttatttaa acacacctgc catttgaagt agacaggtca aggagaggta 480 ggtccttctt ctggtataac ctcaggttca tcatgggaat atagataagc tgtttcactt 540 tcttggccta tttactctcc tgtaaaaaga gggagttgca ggagattctt caaagcnaaa 600 ctgaatattt tgatggattg aaaaaaanan aaaaaaaa 638 <210> 26 <211> 749 <212> DNA
<213> Homo sapiens <400> 26 aaggccaagc caatggtaga agaaaacagc tttattgaag gggcagtgtt atagctccag 60 ccctgttaca actctgatta ctcctgcaca gcaggctctg gcagagacta gcagctcagg 120 gcagttttgc agtcatttat akswaytygg cacgagggca gattaagggg tgatttgtgc 180 aaaaatttct agggaatggg taataacttt tgggtcatcg agtcaatgcc atggaagaga 240 ggggggataa ccccctggtg ttgcgatggc aacggtaaac tgacatggca actgatgagc 300 gtgtcttacg gaaagctcat tccaccccag ccctgtttca gctagtcctc aatttggtcc 360 agtgtccgag ccctgcctct ggagtcaagt cccacctcct acctcataag gagagacata 420 aatcaatgga atagaatcga gagttccaga aataaactca tacctcgatg atcaattgat 480 tttcaacaac agtgccaaga ccattcagtk gggggaaaga atcatatttt caacaaatgg 540 tgccagataa cgacatccaa aggagtgcaa ctgggcccct gtctcacacc atctacagaa 600 attaagtcaa agtgcctcaa acactaagag ctaagactat aacattctta gaagaataca 660 gggttacctc tttatgatct tgatttggta attgattttt agataacact aaaagcacaa 720 gcaacaatag gaaaaaaaaa aaaaaaaaa 749 <210> 27 <211> 788 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (290) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (768) <223> n equals a,t,g, or c <400> 27 aggggcmckg mctcccaccc accccatcac cagctttcca cttggaggcc ccctgtgccc 60 tgcagcctca gggtargccg tgggtcacca ggctggagar ggcccctgcc ttggccaggg 120 gtgcgaggtg acccggctgc attgctgggt gggagctgct gtctgttgtt caggggcctg 180 gcccccgccc tcccccccga ccccgacctc gcaaagsgca ctcccgggca gggtgtggtc 240 tggaargcgg ggctggcggg gacatgggtg ttctgcatct cctagcgcan ttcctgctgg 300 tggktggaag ggtgcctggt ttaggcgggg tcccaggagg gggtgagggg tgacaccttg 360 gggagggggc ctkcaaaggr cactgcctgt ggccacgtgg tgtctgtggg aattggtcct 420 ggggactttg atgggtgttt gcggccccag ttgccgccct gctccctctt ccagggctcc 480 tggcttgggc cccccgaccc ccctgctcag ctcgggaaaa tccccgtgcg gctccagccc 540 cgggtcacgc tcaggagcga tgagaggggc gccctggcca cgcttcagga aagcctgtgt 600 ctgcgcgcgg ggcaaggggc tccacgacaa aaggacaaga tttgacttaa attaagtttt 660 tcccttgagg atattttcat tttctttaaa agaatataat tttcttctaa gatcttggwa 720 aaaaaaaaaa aaaaaaaaaa aaaaaaaata cgtagggggg gtcccgtnac ccaattgtcc 780 tgacgtgg 788 <210> 28 <211> 941 <212> DNA
<213> Homo sapiens <400> 28 ggcacgagat tttggcaagt gctgttatgt gaacaccacc atcacaatca agatagtcta 60 tagttctagt accccctgcc ctgaaacttg cttgttctgt ttagtcagct cctctcccca 120 ccaccagccc ttgtcaactg actcattttc tgtctgtata gtttatatca tttccagaat 180 gtcatataaa tggaattcta gagtatgttt cctttggagt cgcacctttc acttaatgct 240 tctgagactc atctgtcttg ttgcatatat cagtacagaa gtcatttctt ttattgctga 300 gtagtaatct gtcatatgga tgttccacag tttgtttatc catttatcac tggtggggat 360 acttgggktt tcagttttca gtgattatga agaaagctgc tgtcaacatt tgcaaacagt 420 ttgtgtgtcc acattgtckt agtaaataac taggagtgga attgccgggt tgtatggtaa 480 cagtatactt atctatgaaa aactgacaga cttttctaaa ataactgtac cattttacat 540 tcccaccacc agtgtatgaa agtcccagtt ccttaacttc actgacaatt ggtatgtcag 600 ggtttggttt catttttatt ttgttgttag gatttcaaag ggttatagcg ggatttcatt 660 ttggttttaa tttacacttc cctaatggcc attgagcatc tccactgctc gtttgctatc 720 catttgccta ttttcttttg tgaactatgt tcaaatcttt tgtccatttt tttaaaacct 780 ggattgtttc ttattgattt ttgagagttc tttatatgtt ctggatagat atctttgtca 840 gttatgtgtt ttgcaaatat tgtataccat tatgtggctt gtgtttttat tccattaaca 900 gtatttttca cacaagaaaa aaaaaaaaaa aaaaaaaaaa a 941 <210> 29 <211> 835 <212> DNA
<213> Homo sapiens <400> 29 ggcacgagca caaaccctag aattcccagg gtacacctgt tagttgctaa agatatttca 60 agaacagtta tctctctggt aaagtttatt tgctcctgtg caaggtttca tttctttcaa 120 cagagtgaaa caacttgggg tacaatgtta ttgttagtat attttcttct tatgtctgta 180 atatttggca ctaaattCtt tcctttaata atacacatgt ttaacccatg catacttaac 240 cttataaaac ttgttttttc tctcatgcct ggaagccatc aaactccaaa tgttcaggca 300 accagagcct cagatgatgg ctccgctttg ctaggaaccc ccagtagacc tctcggaagc 360 atccgacagc agtttacccc aaaagaatgc cccctgtcag caggaagcag ctaagaccag 420 tcattgtccc atattctcat ggcagttaga tacacctctt cagagagggg aaataatatg 480 ggagtgctag gaagggaaga acatggctgg ctagggctcc ataccctggc tagtcctggc 540 tagggctcca cactcacgga cctaactgag aacaggtatt tctcgcccaa atgttgcatt 600 tcccaagacc accctggctg gacattgaga ggaacacact gacaggcacc agcatgctgg 660 taggccactg actgacagaa caatgcagag tttggctggg gcagctggag gacagtctgg 720 gccactgagc agcctgactt caggggaaaa ccatctccct tctgactctc ccatctgctg 780 gtagctattt ccactcaata aaaccttgca ctcattaaaa aaaaaaaaaa aaaaa 835 <210> 30 <211> 553 <212> DNA
<213> Homo sapiens <400> 30 gtgtgccgga tttggttagc tgagcccacc gagaggcgcc tgcaggatga aagctctctg 60 tctcctcctc ctccctgtcc tggggctgtt ggtgtctagc aagaccctgt gctccatgga 120 agaagccatc aatgagagga tccaggaggt cgccggctcc ctaatattta gggcaataag 180 cagcattggc ctggagtgcc agagcgtcac ctccaggggg gacctggcta cttgcccccg 240 aggcttcgcc gtcaccggct gcacttgtgg ctccgcctgt ggctcgtggg atgtgcgcgc 300 cgagaccaca tgtcactgcc agtgcgcggg catggactgg accggagcgc gctgctgtcg 360 tgtgcagccc tgaggtcgcg cgcagtggca acagcgcggg cggaggcggc tccaggtccg 420 gagggttgcg ggggagctgg aaataaacct ggagatgatg atgatgatga tgatggaaaa 480 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 540 aaaaaaaaaa aaa 5S3 <210> 31 <211> 1346 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (637) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (850) <223> n equals a,t,g, or c <400> 31 ggtcgaccca cgcgtccgct gagagtagcc atgggctctg gaggagacag cctcctgggg 60 ggcaggggtt ccctgcctct gctgctcctg ctcatcatgg gaggcatggc tcaggactcc 120 ccgccccaga tcttagtcca cccccaggac cagctgttcc agggccctgg ccctgccagg 180 atgagctgcc gagcctcagg ccagccacct cccaccatcc gctggttgct gaatgggcag 240 cccctgagca tggtgccccc agacccacac cacctcctgc ctgatgggac ccttctgctg 300 ctacagcccc ctgcccgggg acatgcccac gatggccagg ccctgtccac agacctgggt 360 gtctacacat gtgaggccag caaccggctt ggcacggcag tcagcagagg cgctcggctg 420 tctgtggctg tcctccggga ggatttccag atccagcctc gggacatggt ggctgtggtg 480 ggtgagcagt ttactctgga atgtgggccg ccctggggcc acccagagcc cacagtctca 540 tggtggaaag atgggaaacc cctggccctc cagcccggaa ggcacacagt gtccgggggg 600 tccctgctga tggcaagagc agagaagagt gacgaangga cctacatgtg tgtggccacc 660 aacagcgcag gacacaggga gagccgcgca gcccgggttt ccatccagga gccccaggac 720 tacacggagc ctgtggagct tctggctgtg cgaattcagc tggaaaatgt gacactsctg 780 aacccggatc ctgcagargg ccccaagcct agaccggcgg tgtggctcar ctggaargtc 840 agtggccctn tgcgcctgcc caatcttaca cggccttgtt caggacccag actgccccgg 900 gaggccaggg agctccgtgg gcagaggagg aacacaggat aaaaatggaa gttctcaata 960 aaaagaagat gtattgggaa agaaaactac aaacttttac caaggaatgg cctgtttcct 1020 catttaaccg gccctttccc aattcgccct aagactttgg gggtggctct cttgtaatta 1080 atctgtgttg gcaaagaatg tctggaacat ggacttggcg gtcagtaacc tgtaacagag 1140 ctacaactag gaaaattaga gtggtagtag tcacttattt aagaattcat tcaggtaaac 1200 agctgcaccc tctgtacccc ttaagtggca aagaagctgt tatagtcttc tgaaaattat 1260 cactatgagt gctataattc tgaatataat gtctcttaat tagaattcat acaagaacca 1320 aaaaaaaaaa aaaaaaaagg gcggcc 1346 <210> 32 <211> 626 <212> DNA
<213> Homo sapiens <400> 32 ggcacgagaa acattttcct ttgggttttt tttttctttc ttttttctcc cctttactct 60 ttgggtggtg ttgcttttcc tttccttttc cctttgagat ttttttgttg ttgtttcctt 120 tttgtatttt actgatatca ccaggatagt ttactctcct tctagctttc tgcttaccgc 180 acactggata acacacacat acacacccac aaaaatgctc atgaacccaa tccggagaag 240 gttccagcag gtcccccacc ctcccctcct cctcctactt ctcctcttga cagcgaggac 300 aggaggggga caaggggaca cctgggcaga cccgccggct ctccccccac cccaccccgc 360 ccctcacatc atactccaat cataaccttg tatattacgc agtcattttg gttttcgcgg 420 acgcgcctac ctaagtacca tttacagaaa gtgactctgg ctggtcatta ttttgtttat 480 ttgttcccta tgcaaaaaaa aaatgaaaat gaaaaaaggg ggattccata aaagattcaa 540 taaaagacaa aaaaaaagaa aaaagaaaaa aatgtataaa aattaaacaa gctatgcttc 600 gactcttaaa aaaaaaaaaa aaaaaa 626 <210> 33 <211> 1018 <212> DNA
<213> Homo sapiens <400> 33 ccacgcgtcc gcggacgcgt ggctttgaac cattcaaata ccacattagg caagactgtg 60 ataggccttt tgtcttcaaa tacaacaggc ctccactgac ccatccctca aagcagaagg 120 accctttgag gagagtacag atgggattcc acagtggggt gggtggaatg gaaacctgta 180 ctagaccacc cagaggttcc ttctaaccca ctggtttggt ggggaactca cagtaattcc 240 aaatgtacaa tcagattcta gggtctgttt tcggaagaag caagaattat cagtggcacc 300 ctccccactg cccccagtgt aaaacaatag acattctgtg aaatgcaaag ctattctttg 360 gtttttctag tagtttatct cattttaccc tattcttcct ttaaggaaaa ctcaatcttt 420 atcacagtca attagagcga tcccaaggca tgggaccagg cctgcttgcc tatgtgtgat 480 ggcaattgga gatctggatt tagcactggg gtctcagcac cctgcaggtg tctgagacta 540 agtgatctgc cctccaggtg gcgatcacct tctgctccta ggtaccccca ctggcaaggc 600 caaggtctcc tccacgtttt ttctgcaatt aataatgtca tttaaaaaat gagcaaagcc 660 ttatccgaat cggatatagc aactaaagtc aatacatttt gcaggaggct aagtgtaaga 720 gtgtgtgtgt gtgtgtgtgc gtgcatgtgt gtgtgtgtgt atgtgtgtga ataagtcgac 780 ataaagtctt taattttgag caccttacca aacataacaa taatccatta tccttttggc 840 aacaccacaa agatcgcatc tgttaaacag gtacaagttg acatgaggtt agtttaattg 900 tacaccatga tattggtggt atttatgctg ttaagtccaa acctttatct gtctgttatt 960 cttaatgttg aataaacttt gaattttttc ctttcaaaaa aaaaaaaaaa aaaaaaaa 1018 <210> 34 <211> 767 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (292) <223> n equals a,t,g, or c <400> 34 cggcacgagg ggacagatgg ggtttagggg gttgtragcc ggggcttcar agctctgctg 60 tctgggggta ggggggagct ggaagctgga ggtgtggcag ccatggctct aggagccctg 120 agcctgaatg ctgcccttgc accctgggcc tcctcccctg gcccagacct ccccattctr 180 aaagagaagc agcccctctc tagttacccg tyttctgggg gagccaggtt ccgattaccc 240 accacctccc tgggcacacg tgaaagttct tcatttacca cctgtyttgt gncaggagcg 300 ggattgtgaa ggtcatggat gactaccagg tcatggatga atcctctaca acctcagctt 360 cgagatgaac ttcaatgaca agtgagtggg agcttggccc ccatgccagg tgcggggtgg 420 agcatgaggg gagctgctga gctgcagagg ctcccaaatg ccccagctgc cacagtctgt 480 gcaatctccc cagaaacacc ccactgagat ttcagaggcc agggctccac acatgggccg 540 ggaccagcca gggccaggtg gccgaaggaa ttcatttggg cctcttggcc tcagctgctc 600 cccaaccctg tctctgtcct gtcaatggcc tggcacatgt tttgcttgtt gttttttgaa 660 acagagtttt gctttgtcac tccagtctgg gcaatagtga gtcggtcaaa ttccatttcc 720 ccctccgccc catacctctt caaatgttta aaaaaaaaaa aaaaaaa 767 <210> 35 <211> 840 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (364) <223> n equals a,t,g, or c <400> 35 agattttttt ttttttaatg tccggagaag gaactctcag attactctcc tccctgcaaa 60 acgactattt accacctccc ctttgcttca acttggtctg agcgtcttta acctcaccat 120 tttgaatgtg cgcaaaatga ttaccagtca tctgagggag gccaaattaa aggtgcatct 180 gcaagaggag ctctggcctg acatcgctaa ctgagagcag ccctggcgga aaggtgctga 240 tcccgggagt agagcgactg ctgcggctcg agcggggtgt ctgcgtgccg agcctcactg 300 acaatcgggg aaaatgcaga cgcccagcaa aacgacggca acagaaggct cctcggggga 360 gggntgctgc aggcctgtgg cgtaagatgg ttccgctcta cgcgggktga cgggaaaccg 420 cagaagtggg tgtgaggtgt tggttggggg gcaaactctt gtacagtggc gagtgtaggg 480 gaaagccagc gggctccttg gccaagtcac caaggacagc agaagaggca gcagtaaaga 540 gcggcagcga agaccccgat accaaccaat gtcatctgtc ggggggcggc gggcgcgacc 600 gtcccggata ggagcgcggc ccgggtccgg gctggacagg gcccaggagg cgaagaaggc 660 ctcccacagc catcaacccc acccaccatg gccggcgcag caggccaggg acaagccccg 720 ctccttccga agctagagac agagaaactg aggagctgaa cgcagcaatt tcctcgcccc 780 gacccccaca ctcccgacag cggaacaagc cagactgaaa aaaaaaaaaa aaaaactcga 840 <210> 36 <211> 1148 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (820) <223> n equals a,t,g, or c <400> 36 atcagaccat cagaaggatt tgtataaaga gtgactctcc tatgaaggta aaggccaccc 60 ctcttcagtt ccagtgactg agatacattt ttccaatcct gggggcaaat acagacacag 120 caagttcctt cttccctttg gaaatttggc agctgccttc accagtgagc acaaagccac 180 atttcaaagg aaactgacaa attatcccca gctgccagaa gaagaaatcc tcactggacg 240 gcttcctgtt tcctgtggtt cattatctga ttggctgcag ggatgaaagt ttttaagttc 300 ataggactga tgatcctcct cacctctgcg ttttcagccg gttcaggaca aagtccaatg 360 actgtgctgt gctccataga ctggttcatg gtcacagtgc accccttcat gctaaacaac 420 gatgtgtgtg tacactttca tgaactacac ttgggcctgg gttgcccccc aaaccatgtt 480 cagccacacg cctaccagtt cacctaccgt gttactgaat gtggcatcag ggccaaagct 540 gtctctcagg acatggttat ctacagcact gagatacact actcttctaa gggcacgcca 600 tctaagtttg tgatcccagt gtcatgtgct gccccccaaa agtccccatg gctcaccaag 660 ccctgctcca tgagagtagc cagcaagagc agggccacag ccagaaggat gagaaatgct 720 acgaggtgtt cagcttgtca cagtccagtc aaaggcccaa ctgcgattgt ccaccttgtg 780 tcttcagtga agaagagcat acccaggtcc cttgtcaccn aagcaggggc tcaggaggct 840 caacctctgc agccatctca ctttcttgat atttctgagg attggtctct tcacacagat 900 gatatgattg ggtccatgtg atcctcaggt ttggggtctc ctgaagatgc tatttctaga 960 attagtatat agtgtacaaa tgtctgacaa ataagtgctc ttgtgaccct catgtgagca 1020 cttttgagaa agagaaacct atagcaactt catgaattaa gcctttttct atatttttat 1080 attcatgtgt aaacaaaaaa taaaataaaa ttctgatcgc ataaaaaaaa aaaaaaaaaa 1140 gggcggcc 1148 <210> 37 <211> 1367 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (15) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (28) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (480) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (796) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (896) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (1243) <223> n equals a,t,g, or c <400> 37 atgtatagat catanaggca aacggtanct gacagtaccg gtccgaattc ccggtcgacc 60 cacgcgtccg tgtttctact ctttgactat tatgaataat gctgctaaga acattaatgt 120 acaagtttct gtgtggacat atgctttcat ttctcttatt ttcattttat tccacctagg 180 agtggaattg ctgggttgta tggtagtgtt atgtttaact gtttgagaaa ccaccaaatt 240 atttttgttt tctttttaag atgaggtctc gctatgttgc ccaggctggt cttgaactcc 300 tggcctcaag tgatcctccc acctcagcat cccaaagcgc tgggattaca ggcatgaggc 360 atgccaccat tacacacccg gccagccacc aaattatttt ccaaagcagc tacaccacct 420 tacattccca ccagcagtgt atgagcatcc catctctcta cacctcraca gtaattttgn 480 gtctgtctaa tttactatag ccattctagt gggtaagaac tcacacacac ttctgcttct 540 tcttggcaat gcatccatgt ggagccatgc tggggctttc caggactggc tgactttcac 600 ctccacttgt agaaagaagg acatatctgg caatactgta gccccagagc ttggtccagg 660 gcctagaact aaggatgcac ccctgaatgg ctcctggatg gataatgggc tgggtgaggg 720 aggtacatgg tgagggggat actggtttca gtgcaattgg agctcagtga tatctgaraa 780 rtctgggggc tggganggga gatgtgcata tctaaggaca ccacccaccg tatgataggg 840 twtagaagar gcagggtaac ctgtgtaraa atcagctccc arcctcctgc tcgganctta 900 ccctcaagga atgcagaacc cctgtgtatc cctttctcct cctgatatag tttagatatt 960 tatccccacc aaatcttcat gttgaattgt aatcccagtg ttggagatgg ggcctggtgg 1020 gaggagtttt ggtcatgggg gtggacccct catggcttgg tgctgtcctc actgtagtaa 1080 gttctcacaa gatctaattg tttaggtgtg tgccacctac cccctcccac tctctctctc 1140 ttttgctcct gcttttgcta tatgaggtac ctgatcctgc ttcaccgtcc accatgactg 1200 taagcttctt gaggcctccc cagaagccaa gcagatgcca gcnccatgct tgtacagcct 1260 gcagaaccat gaaccaatta aacctctttt ctttataaaa aaaaaaaaaa aaaaaaaaaa 1320 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaag ggcggcc 1367 <210> 38 <211> 921 <212> DNA
<213> Homo sapiens <400> 38 ggcacgagga cgatgatgtc atcaaacact tatatagtgc ttgtatgcca ggcactcctc 60 atcacagcta tgaatcgtgg tccaccaaat aagtgcaaca gagtttatct atttttaaat 120 ctttgccatc actactaatg ttgcagcgag tgttttcttg tacatacatc cttgcggaag 180 tgtttgggta tatacctacg gtagagttcc ttggttatgt ggtaccagca tcttcaccta 240 ccaactctgt ccaaatggtt accccaagtg tttgtatgac cctgtcagta tgtgcgaggg 300 gttttttact ccacatttcc tcccaaactt tttttttttt ttttgacaga gtctgggctc 360 tgtcgcccag gctagttgca gtggagctgg aatcgcgcca tggcattcca gcttggggca 420 acagagtgag gcttcatccc cctccaagag aaaagccaaa ctaataagat tcaaaatgta 480 aaataataaa ttggtgtttt tttatacttt gcccctatag tagtttcctt gcctcttcca 540 gcttctggtg gctgccccag cattccgagc gtgtggctgc gaaactccag tctcccccac 600 cttcacatca tcttctccat gtctccttac cttcctttgc ctctgtcttg aaaagacact 660 gtgatggcat ttaggaccca cccagctaat tcagtgtgtt ctcatctgca gatccttgat 720 caagtcacat ttgcagagac ctctttttca aataaggtaa catttccaaa ttcctgggat 780 taagacttga tatctttggg tggtcattat ttaacctact acaattgggc ctatccctag 840 gccatgccag cctgggtgat aaagcgagac tctgtctcaa aaaaaaaaaa aaaaaaaaaa 900 aaaaaaaaaa aaaaaaaaaa a 921 <210> 39 <211> 632 <212> DNA
<213> Homo sapiens <400> 39 tgacgtccac tgccttgtca ccagcgacct gcctgtcatg cccaccccct gaggaagcat 60 ggggacccta acaccctggt gccctgcacc agacaggccg tggtcaggcc caggccaccg 120 gccgggttct gccacagctt cccacgtgct tgctgacatg cgtgtgcctg tgtgtggtgt 180 ctgttgctgt gtcgtgaaac tgtgaccatc actcagtcca aacaagtgag tggccctcga 240 ggccacagtt atgcaacttt cagtgtgtgt cataacgacg tcactgcttt ttaactcgat 300 aactctttat tttagtaaaa tgcccaggag tcctggaagc tacgcggact tgcagaggtt 360 ttattttttg gccttagaat ctgcagaaat taggaggcac cgagcccagc gcagcagcct 420 cgggacccgg attgcgtttg ccttagcggg atatgtttat acagatgaat ataaaatgtt 480 tttttctttg ggctttttgc ttcttttttc ccccccttct caccttccct tctccccgac 540 cccacccccc aaaaaagcta cttcttcatt ccgtggtacg attatttttt ttaactaaag 600 gaagataaaa ttctaaaaaa aaaaaaaaaa aa 632 <210> 40 <211> 608 <212> DNA
<213> Homo sapiens <400> 40 ggtgaagtca tcatgagctt tttccaactc ctgatgaaaa ggaaggaact cattcccttg 60 gtggtgttca tgactgtggc ggcgggtgga gcctcatctt tcgctgtgta ttctctttgg 120 aaaaccgatg tgatccttga tcgaaaaaaa aatccagaac cttgggaaac tgtggaccct 180 actgtacctc aaaagcttat aacaatcaac caacaatgga aacccattga agagttgcaa 240 aatgtccaaa gggtgaccaa atgacgagcc ctcgcctctt tcttctgaag agtactctat 300 aaaatctagt ggaaacattt ctggcacaaa mtagattctg gacaccagtg tgcggaaatg 360 cttctgctac atttttaggg tttgtctaca ttttttgggc tctggataag gaattaaagg 420 agtgcagcaa taactgcact gttctaaaag tttgtggctt attttcttgt aaatttgaat 480 attgcatatt gaaatttttg tttatgatct atgaatgttt ttcttaaaat ttacaaagct 540 ttgtaaatta gattttcttt aataaaatgc catttgtgca agatttctca aaaaaaaaaa 600 aaaaaaaa 608 <210> 41 <211> 877 <212> DNA
<213> Homo sapiens <400> 41 ggcacgagaa cttcataaag atgattttta aaatgcccag ctctgagtgc aggtcctcag 60 ctttactcct gaatgtgagc ctcgctgagt ccgaagccgg tcgcaggcct gggaaaccag 120 ggtgggctga ggaggcaacg ggaggcagaa gggccagcag gaaggatggg acccaaggct 180 aggctggggg gtcagcagca gacatgggtt gaaggggagt gggtcatggg aagggcctgt 240 gcaggatgga gcccagcagg ggatgggaga ggacacaaag ccaggcagaa ggcggtgatg 300 gcagcagaga ggagcaccca ggggccgccg cttggccacg agtgtaggcc acccaggggc 360 cgccgcttgg ccacgagtgt aggcccacgg tgcccttcag cacagtgccc cagggctcgc 420 cagccaccca ggaccgagac tcgtagtgct ggggggctgc agctccttcc catcctttcc 480 tgggctgcct ctagccccca tctctccaaa ttagcagggg agctggagcc cctaagaccc 540 cagcctcaca tcatcctcac gcctctgttg ggagccatgc cctgctgcac ccgaatcttc 600 tgtttctccc tgaccatggg ctcctgaagt tcgaggcctg tggttgttcc tctcttcaac 660 ttggttgctg cggtgagttt ctgggaggtt tgtcttacta gattctgtgc ttccctccac 720 catgggaacc tggaatctct gttttgcttt ttagcatgca ggtaatttcc agcctttaca 780 tctgcctatc agacaaatcc tatcttcata cctcaggcag tatcaccccc aacgtgtggt 840 ctaaatttgg acttctgtat gcatgaactc acctcga 877 <210> 42 <211> 978 <212> DNA
<213> Homo sapiens <400> 42 acgagccaaa acactccctc cgctcccact tcacttagag tcaaggccaa agtctccact 60 caccatggcc caccgcagtt ggattctcag ctcctccctg ctcccaattc ccatcttttt 120 cctcctccct ccctcctctg cagccaccct agccacacca gggtcctaga atctgttccc 180 tggagatgtc cacgtggctt gctccctctt ctcctccagg tctctgctca gatgccacct 240 cctctgtgtt gaaagattcc tttagtccac ttaatttttc atctcagtgc ctaccatgtc 300 ctggcattct ttattattat tattattatt atttattagc ttgattttct gtggctccca 360 gaacaatgca agttcacgag ggaacaggga tttttgtctg tcctgtttac agctgcaccc 420 ccagtgccta caagggtgcc tggcccagag taggtgctca ggacaatttg ttcaatgaat 480 aaagaattca accaggtgcg gtggctcaca cctgtaatcc cggcactttg ggatgccaag 540 gtgggtagat cacatgaggt caggatttcg agaccagcct agccaacatg gtgaaccctg 600 tctctactaa aaatacagaa attagctggg catggtggcg tgcacctgta atcccagcta 660 cttgggaggc tgaggcagga gaactgcttg aacctggaag gcgggaggtt gcagtgagcc 720 aagatcgtgc cactgcactc caacctgaat gacagagcaa gactccatct caaaaactat 780 ataataataa taataattca accagatgtg gtggcttatg cctgtaatcc caacactttg 840 ggaggctgag gcaggaggat tgcttgagtc cacgagttca agaccagcct gggcaataaa 900 acaagacctc atctttacaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 960 aaaaaaaaaa aaaaaaaa 978 <210> 43 <211> 999 <212> DNA
<213> Homo sapiens <400> 43 gaattcggca cgagcaggag ggcaagtcaa attttatggg cctccaagac tctgcagaag 60 agactcccag gctgaataca agccttaggc cactggaata tgctggtttt cctaccattc 120 accgttttgg tacttatcag ttacattttt tcctcccact ccttcaaccc cttatttact 180 ctatgtgatt ttgagcaagt acttttacat ctaaagatat tttctcatcc ctaaaataag 240 aacaaggtga tagagaatca ctgtaactac aagtccaata gaataaggtt ctatttcaga 300 ttgtctcagc cttaatattt agtctactaa ctgggcaaca tttagattct attccaaatt 360 ccctcaaacc ctttctaaca tcaacagact aattccctta gccccactcc ttcctcatta 420 aaataaaatc actgggctgg gcactatggc tcctgcctgt aaccccagca cttcaggagg 480 ccaaggcagg aggatcactt ggggtaagga gtttgaaatc agcctgggga gcatagtgag 540 accccatctc taaaaaaaaa aaaagaatta accgggtgtg gtggtatgca tctgtagtcc 600 ctggtactgg ggaagctggg gcaggaggat tgcttgagcc taggagtttg aggttgcagt 660 gagctatctt tgttgcagtg agccatgttg ttgcaaataa ccagatctca ttcttttttt 720 tatggctgaa tagcactgca ttgtgtatat gtaccacata taccagcctg tgtgacaggg 780 caagacgtgt ttctaaaaaa aaaaattttt tttaaatact ctgcagtatt ttttcaaaat 840 ctacagtcac tttttcctaa taatcaactt taaaaaatat ttcaaaataa gcttgaattt 900 ggccctttgc tctcacaaca ccaaaacacc attttcccaa ttacagcaca gcaaacacac 960 gacattcatt tctgtcttct gaattttggg ggccccgta 999 <210> 44 <211> 510 <212> DNA
<213> Homo sapiens <400> 44 gaattcggca cagtcttcca cacttgcttg tcaaggtgat aaccctgaca tctgtcaagt 60 gtaatcctat tatgaatata gcaagagtta tttactgcca agtaagaaac agattagtta 120 tggccctggt aatttctgcc cctcccccaa acagcccatg taattgcttc ttttttatct 180 ttcttttcat tttgcctctc atttttcctc tcttcaaagg cctttttgct acttttgtct 240 ttttctaagt ttttctttat cttgttcttt tctttctgtt gtctcaaatt ctcacatttg 300 gccagtcttt ctcttgtcgt ctcccggggt gtaccttgga cccggaaaca cggagggagc 360 ttggctgagt gggttttcgg tgccgaaacc tcccgagggc ctccttccag tgatctcatt 420 gactgattta gagacggcat ctcgctccgt caccccggca gtggtgccgt cgtaactcac 480 tccctgcagc gtggacgctc ctggactcga 510 <210> 45 <211> 986 <212> DNA
<213> Homo sapiens <400> 45 ggcacgagct taagttgaat tataaaaatg atggatataa gtggtagctg tatctagtga 60 agtgtctgtc agtaagtgaa acattttttg gtggtggctt atccacaaac agtttagttg 120 tagaataaaa cttatgagtg acatctggaa agtaaccatg ctaagatggc aagcacactg 180 gaaacaatta ggccacttgg ctttcttttg ctgtattgtt ttataagcct actttacctc 240 ccagtcttgg aaacaagttt tagtttttta ttggtttgga gactagagcc aatagtataa 300 tgttctcaaa ggaaacagac ttgagttgtt ggattagagg aactaaccca acttatatga 360 tttttttttt gtttttgtcg tgtagttatg gcactgtctt atttggaaca tttgcaacta 420 ggggataata caacattttt aactctcatt tgacaaccta ctactaatca cagaccacaa 480 gggtaatgac caaatttatg tgggttttgc acccatagtt gtcctagccc aacttcaaac 540 tcttacgatt acttgggtaa cgctctggag gaccttcctt gagatcccta atatttaaga 600 tatttgatat cttgaagata gtataggata tagagattta ccaaatagga atataaggag 660 tatgttaaaa tgaccagata cctgtttgat agtttactga cctagcagat gtgtggaaaa 720 ggaatcagat cttgattctt ctgggtttat actggttgta aaacagaatg atacagaaaa 780 tgttttcctt gtttaactgg tagttgaaca tagaacttgg gtattataga tcacttttca 840 ctttttggaa tgttttgtat tgaaacttaa taaaacttta acatggcaaa aaaaaaaaaa 900 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 960 aaaaaaaaaa aaaaaaaaaa aaaaaa 986 <210> 46 <211> 660 <212> DNA
<213> Homo sapiens <400> 46 gcacgagacc aagcaaagcc tacttagttt agatctccag aaattggctg gtggaaaaaa 60 atcaaacatg aagattgcag ttttgttttg tttttttctg cttatcattt ttcaaactga 120 ctttggaaaa aatgaagaaa ttcctaggaa gcaaaggagg aagatctacc acagaaggtt 180 gaggaaaagt tcaacctcac acaagcacag atcaaacaga cagcttggaa ttccgcaaac 240 aacagttttt acaccagtag caagacttcc tattgttaac tttgattata gcatggagga 300 aaagtttgaa tcctttcaag ttttcctgga gtagaatcaa gttataatgt gttaccagga 360 aagaagggac actgtttggt aaagggcata accatgtaca acaaagctgt gtggtcgcct 420 gagccctgca ctacctgcct ctgctcagat ggaagagttc tttgtgatga aaccatgtgc 480 catccccaga ggtgccccca aacagttata cctgaagggg aatgctgccc ggtctgtccg 540 ctactggtac agagctttag ctaagcaaaa tatcagtgtg tgattaatct ttaacttcca 600 tttgtttttg ttactaattt tagattaaaa ttatgataca ttaaaaaaaa aaaaaaaaaa 660 <210> 47 <211> 340 <212> DNA
<213> Homo sapiens <400> 47 acgagcagca gccctggcat gttcctgccc cacaggaata gaatggaggg agctccagaa 60 actttccatc ccaaaggcag tctccgtggt tgaagcagac tggatttttg ctctgcccct 120 gaccccttgt ccctctttga gggaggggag ctatgctagg actccaacct cagggactcg 180 ggtggcctgc gctacttctt ttgatactga aaacttttaa ggtgggaggg tggcaaggga 240 tgtgcttaat aaatcaattc caagcctcaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 300 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 340 <210> 48 <211> 567 <212> DNA
<213> Homo sapiens <400> 48 ggcacgagag catttcctac ctagtgaaga aggggacagc cactgagtcc agcagagaga 60 tcccaatgtc cacactccct cgaaggaaca tggaatccat tgggctgggt atggcccgca 120 cagggggcat ggtggtcatc acggtgctgc tctctgtcgc ccatgttcct gctggtgctg 180 ggcttcatca ttgccctggc actgggctcc cgcaagtaag gaggtctgcc cggagcagca 240 gcttctccag gaagcccagg gcaccatcca gctccccagc ccacctgctc ccaggcccca 300 ggcctgtggc tcccttggtg ccctcgctcc tcctctgccc tcctctcccc tagagccctc 360 tcctccctct gtccctctcc ttgcccccag tgcctcacct tccaacactc cattattcct 420 ctcaccccac tcctgtcaga gttgactttc ctcccatttt accactttaa acacccccat 480 aacaattccc ccatccttca gtgaactaag tccctataat aaaggctgag cctgcatctg 540 ccaaaaaaaa aaaaaaaaaa aaaaaaa 567 <210> 49 <211> 1357 <212> DNA
<213> Homo sapiens <400> 49 agtaggatcc agtctgtggg gctcatttga gggagaatga gcacggggct tttggaggct 60 gcagcctagg gccaagggat ggaggctcac ctgagtgcag gttaggcagg tgaagtgtct 120 ccccggaaac caagctagag tgccccacct gctcggccct gccttctcgg atcggatcca 180 gcacatccag gcttctcctc ctcccgagga accagtggtg acagctgagg ccatgtgagt 240 aggatcctga atgaggcttt atctctggct gttcgtccca tcgtccaccg tggcaccagc 300 tccctcagcc agccgggatg ggaccagcga ctgagagagc cagaggcaga gaggtgaggg 360 tgaccatatc ctggactgtg agaggaatgg gactctgggc ctgtagctgc caagcaggtg 420 gcaggtgctc caggctgtga tctgcaccct ctgacccctg acattgacct cctaccctga 480 cccctgcctg accaagccat gtctgaacag gaggctcaag ccccaggggg ccgggggctg 540 cccccggaca tgctggcaga gcaggtggag ctgtggtggt cccagcagcc gcggcgctcg 600 gcgctctgct tcgtcgtggc cgtgggcctc gtggcaggct gtggcgcggg cggcgtkgca 660 ctgctgtyaa ccamcagcaa gccgctcarg tgaatggcgg ctaagcaamg ggcactgtgc 720 tctgtttgct ggctctsctg gttctggtga acagctgatg agctcggctg tcaggacatg 780 aactgcatcc gccaggccca ccatgtggcc ctgctgcgca gtggtggagg ggccgacgcc 840 ctcgtggtgc tgctcagtgg cctcgtgctg ctggtcaccg gcctgaccct ggccgggctg 900 gccgmcgccc ctgcccctgc tcggccgctg gcckccatgc tgtctgtggg cattgctctg 960 gctgccttgg gctcgctttt gctgctgggc ctgctgctgt atcaagtggg tgtgagcgga 1020 cactgcccct ccatctgtat ggccactccc tccacccaca gtggycatgg cggccatggc 1080 agcatcttca gcatctcagg acagttgtct gctggccggc gtcacgagac cacatccagc 1140 attgccagsc tcatctgacg gagccagagc cgtccttctt ctcacagcgg cctcagcgtc 1200 cccaragccg agccagggtg tgagtgcatg tgaacgttga gtacacatga gtgcgtgtat 1260 gcccccaggc tgggtcagct cttctgtgga ttgcatggcg tgtgattaaa agtcccatgt 1320 gttcccacac atccaaaaaa aaaaaaaaaa aactcga 1357 <210> 50 <211> 1038 <212> DNA
<213> Homo sapiens <400> 50 ggcacgaggc gcctcggacg gccgtcgggg ccgagaaacc atgagcccca ggggcacggg 60 ctgctccgcc gggctgctga tgactgtcgg ctggctgctt ctggcgggcc tccagtccgc 120 gcgcgggacc aacgtcaccg ctgccgtcca ggatgccggc ctggcccacg aaggcgaggg 180 cgaggaggag accgaaaaca acgacagcga gaccgcggag aactacgctc cgtctgaaac 240 cgaggatgtt tcaaatagga atstcgtcaa agaagtagaa ttcggaatgt gcaccgttac 300 atgtggtatt ggtgttagag aagttatatt aacaaatgga tgccctggtg gtgaatccaa 360 gtgtgttgta cgggtagaag aatgcccgtg gaccaacaga ttgtggctgg ggtaaaccaa 420 tttcagaaag tcttgaaagt gttagattgg catgtattca cacatctccc ttaaatcgtt 480 tcaaatatat gtggaacttc taagacaaga ccacaatcca ttatacttgt aaatgattca 540 gcaatcctag aagtacgcaa ggaaagtcac cccttggctt tcgagtgtga cacactggat 600 aataatgaaa tartagcaac tattaaattc acagtctata cgagcagtga attgcagatg 660 agaagatcaa gcctaccagc cactgatgcc agccctaatt tttgtgctga ccataggagt 720 cattatctgt gtatttataa ttttcttatt gatcttcata atcataaatt gggcagcagt 780 caaggctttc tggggggcaa aagcctctac acctgaggta caatccgagc agagttctgt 840 gagatacaaa gattcaactt ctcttgacca attaccaaca gaaatgcctg gtgaagatga 900 tgctttaagt gaatggaatg aatgatgttt gaatgatata taacaaacca aaggatatta 960 cagaatatta gattcattat tacaaaaata aaatacacat tgaaatactt taaaaaaaaa 1020 aaaaaaaaaa aaactcga 1038 <210> 51 <211> 1009 <212> DNA
<213> Homo sapiens <400> 51 aggttgcagt gaagctggag atggcgctac tgcagtccag cctgggcgac agggcaagac 60 tccacctcaa aaaaatatat aaaataaagt gggattcatc caagagcttg ggacatgatt 120 aactaktgtc aaggagatat gtymtgccat tattatcctc cttacttggt agggtacaac 180 agaaacagaa caacaaggtg acagcctttt gctcaagtca aaaagaaaat aagtccctca 240 tcttagttta aagttgttca ttcagtagta cagacttgca tttgaagact tattcttgat 300 cttctgtagc tttgacagca aggacatcac tacaatgggt acagaaataa cacattctga 360 tccttgctga gatccttgta tgggcctatc ttaaatctag cctattgtct gtcttaccct 420 ttgattttta taagtrgaaa acaggaaaag gctaaccaag caagaggaag gcatagattc 480 atcttccttt caatcttgac tatagtttaa agagaatacc atgatctttc tgttctattc 540 ttggcttact tgaatattta gccaggtctc tgcatcttat tcagtcagaa aacagacaca 600 gattcagata actcaaagga tgttacttgc ttgagtaatc cttgggcctc gctttaactt 660 tgtagatcca ggaacagaat taagcagaca gttcggtcta cactgccaaa tttcttaggg 720 aaaaagaggg caagtcagaa ggaggaagtt ggcatttggc tcaaatgacc aaattattta 780 aggtctctac acttcacttt gcaccaagta gacccaagaa tgattataat tcagctacgt 840 gtggtggtgc agatcagtag tcctagctat tcaggaggct gaggcgggtg gattggttga 900 gcccgggagt ttgaggctgc aatgggctat gatctcrgmc tgcgctttag cctgggcaac 960 agaacaagac cctgtctcaa attaaaaaaa aaaaaaaaaa aaaactcga 1009 <210> 52 <211> 908 <212> DNA
<213> Homo sapiens <400> 52 ggcagagaaa tatgccaggt agacaccagc ccaagtaccc tcctccagaa gtctgtgact 60 accttgtcac tactttaggc ccattccaca aagcccatct ctggtttgag aattcatttt 120 gatctgtatc tacaccaccc aaagttaggc ctcctataat gtccaaaaca ttcctttcag 180 cctttttatt tcttactgta ctgtctctta ctgtactgtc tatctgcagt aattgaggac 240 ccataaaatt tagataacta catgtctttc tcttagaatt gtcactcagc ataatgagca 300 tttaacatac aaaggcaatg tactgttttg tgttgatcta tgtaaaagaa tacaattctt 360 ttttacataa ttagtgaaat tttatttttt attaggaaac actaaatagt gtaatatttc 420 tttgctttta aaaaaattcc tggtagcaaa tcaagattaa ataatkgctt cattttcttg 480 agcaatactg aagcaggatg aagtaagagg aatgccattc atttaaacat gctttgcttt 540 atgaattttg tctctttttt ggtctctttt tcttatattc aagttacaaa tgtacaagta 600 tccttactaa gagtgctcct tttgtatttt acatatatac agtatgaaaa tacattggaa 660 cactaggaaa gtttttaaat aacagttcta atttatcaga aaattgtgtt ttgggattga 720 gttctttgtc tcagcccaga atcccaggtc ctgggcctgg ttttctaatg ctgtcatctc 780 agttcgatat tttactttag aacctggaat ctcctactta atatatgacc atgactttga 840 aaggcaaaag aggaatcaag aataaataaa acaaacttaa tcttcatctt taaaaaaaaa 900 aaaaaaaa 908 <210> 53 <211> 1255 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (1236) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (1237) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (1255) <223> n equals a,t,g, or c <400> 53 gaattcggca cgagaactct tggcttccag gttctagcac tcattactac catggacagc 60 agcttccttt taattcagtg ggattctgcc aggcaggctt ccaggggagc tgtggggtct 120 agtacaagtt tctcccctgt tgctgcttca gtggctttca ccctgcccaa tacatattta 180 atatgacacc atgtgtctct ttgtcagtct cctcatattg agcctaggaa ttggcaaaca 240 ctccatgaat atttacacat tgactttttt ttaagctctt aagagaggaa tatcccttgg 300 agtcctcttt ggagatttcc agtgtctcat catcaagcaa tatgtccttt cagctaataa 360 gatctttatg tttcataatc attgcttaat atccaaagat taaatttaga ccatggaaag 420 gaaaaaagat ctcaaagcaa ctcatgtccc taaaaggaaa tcacactcat caaacaaata 480 cgctgtgttc acacaaagat attactattt tctaccttca gtactggcag actttaagtg 540 ggatatgaaa agcctcagct gcttttgaat gtgggtactt taccctggta aacatagatt 600 ccactcttca gcttggccaa tgtttataat actcagccct gcagaaaagc gtcctacttg 660 gctctcttat cctccattgg cttagacagg aattggggaa atacgcatgt cagtattagc 720 aaaatcagca gcaaagggac agargcatat gaaagtcacc tcmcaaaggc aatgcatatt 780 aaccctatcc ttggaraaat atgtgcttcc ytccagaaga aggaatattc actccagtgt 840 aaamccactt aaattatctt ttccattatc ttgtttaata atcaaaattc ttagaggctg 900 atagggttac acccatttat aggcaaagaa atggaaaccc agagagataa aatgactttc 960 ccaaattctc ttagcaaaat ggagatagaa tcaaaactga atcccaatct ctggtcccca 1020 ttttgttaca atcacagtat ttttcacaat attatctcaa actttaccca tcgcgatgag 1080 gttcctggtc tcgcagctct ctcacagatg attttaagcc agggaaactg ctatttttta 1140 atgcttattg ttttctttgt ttaatatgta ttcattgtag agatttgggg aaaataaaat 1200 gaccaaaaat cttaaaaaaa aaaaaaaaaa actcgnnggg gggcccgtac ccaan 1255 <210> 54 <211> 1142 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (92) <223> n equals a,t,g, or c <400> 54 aattcggcag agctgcctgg aagttccagc tccgagttcc ctgggaggac tttttcagat 60 gttagggacc cgctccagag ccccctctgg tncaccctgg gttcctccag ccccaccgag 120 tcactcactg tgggaccctg cctctgaata atcaggaacg gtggcttcag agacgtctct 180 tgggccttcc ctctggccac gtctgcaccc acccctsctg ggcaccctcc tagcctgcca 240 tccctcacct gcagccaggc tctcagggaa ggtccatgct gcttggcctg agttcaaggc 300 tttctgcctg tagcctggac tcccgtggac ccccgtgggc aggtggcttc cccgtggcat 360 ctccacaccg cctctgcctg cccctgtgga ctgatgctat cgcgcaccgt cccacgaccc 420 caccccgagc tcctgaagcc ggggtctgag cctgcatcac ctctggcctc tcatccccca 480 ctctcctgag agcagtggtc acagcggccg gccgttctgc tgagaaggca gagaggcagg 540 ctcaggcctc agcgtggaca gcagggataa ggggcacgaa ggacggggac tcggcccctt 600 cagaattcct caggactctc aggtgcagct ttgccaaaaa ggaacttttc atgtcatgca 660 gttgagggga cttagtctca atcccaggct cctcttgact ctgggcagct ttaatcaggt 720 tgggcagcct ctgctacagc gtggagtggg atggctctct tccctcagcc acgccgcttg 780 tgaggacaga ggtgggggag tgggaagtgg gaagtcacca gagaacagga gagggatttg 840 agggcgcgac cccagcgctc tccacggacc agccagaggg actggagcca ggtgtgcatg 900 ggttcaaggc cctggccctg cccagcctct gtyttgggag ctcagcccca gggttcggtc 960 gtcagcagtt tcccaagaac aagatgtgat ggcatctgct gctgaaaccc tgatgaggac 1020 caggccccct gcaccgctgt cagcctgagg aattaaagct ttggtgctgg gaaraaaaaa 1080 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaac 1140 tc 1142 <210> 55 <211> 1923 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (144) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (1910) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (1912) <223> n equals a,t,g, or c <400> 55 aattcggcac agccttatgc cacagtagtg cctgtagcag agaaaggatt ccctcctcca 60 cctcagggcc cactgctgct gctctccagc ctgcagtttc ctctaaggct ctggattggc 120 tggaagagca acagagggct gggnaaagag cttctatata tacctcagga ggaaaggcat 180 cccagacagt tttgaagttt tcaaagactg gctctgctgt taagaagttg tacttaaagc 240 ggaggagcta agccacctgc caaaatgtgc aaaggacttg cagctttgcc ccactcatgc 300 ctggaaaggg ccaaggagat taagatcaag ttgggaattc tcctccagaa gccagactca 360 gttggtgacc ttgtcattcc gtacaatgag aagccagaga aaccagccaa gacccagaaa 420 acctcgctgg acgaggccct gcagtggcgt gattccctgg acaaactcct gcagaacaac 480 tatggacttg ccagtttcaa aagtttcctg aagtctgaat tcagtgagga aaaccttgag 540 ttctggattg cctgtgagga ttacaagaag atcaagtccc ctgccaagat ggctgagaag 600 gcaaagcaaa tttatgaaga attcattcaa acggaggctc ctaaagaggt gaatattgac 660 cacttcacta aggacatcac aatgaagaac ctggtggaac cttccctgag cagctttgac 720 atggcccaga aaagaatcca tgccctgatg gaaaaggatt ctctgcctcg ctttgtgcgc 780 tctgagtttt atcaggagtt aatcaagtag taatttagcc aggctatgaa atcatcctgt 840 gagttatttc ctccataata accctgcatt tcccattaat ctacatatct tcccacagca 900 gctttgctca gtgataccca catgggaaaa atcccagggg atgttgctta ctctttttgc 960 ccacactgct ttggatactt atctactgtc cgaagccttc tttccccact caattcttcc 1020 tgccctgtta ttaattaaga tatcttcagc ttgtagtcag acacaatcag aatcacagaa 1080 aaatcctgcc taaggcaaag aaatataaga caagactatg atatcaatga atgtgggtta 1140 agtaatagat ttccagctaa attggtctaa aaaagaatat taagtgtgga cagacctatt 1200 tcaaaggagc ttaattgatc tcacttgttt tagttctgat ccagggagat cacccctcta 1260 attatttctg aacttggtta ataaaagttt ataagatttt tatgaagcag ccactgtatg 1320 atattttaag caaatatgtt atttaaaata ttgatccttc ccttggacca ccttcatgtt 1380 agttgggtat tataaataag agatacaacc atgaatatat tatgtttata caaaatcaat 1440 ctgaacacaa ttcataaaga tttctctttt ataccttcct cactggcccc ctccacctgc 1500 ccatagtcac caaattctgt tttaaatcaa tgacctaaga tcaacaatga agtattttat 1560 aaatgtattt atgctgctag actgtgggtc aaatgtttcc attttcaaat tatttagaat 1620 tcttatgagt ttaaaatttg taaatttcta aatccaatca tgtaaaatga aactgttgct 1680 ccattggagt agtctcccac ctaaatatca agatggctat atgctaaaaa gagaaaatat 1740 ggtcaagtct aaaatggcta attgtcctat gatgctatta tcatagacta atgacattta 1800 tcttcaaaac accaaattgt ctttagaaaa attaatgtga ttacaggtag aggccttcta 1860 ggtgagacac ttttaaggta cactgcattt tgcaaaaaaa aaaaaaaaan gnaaattttt 1920 tgg 1923 <210> 56 <211> 1228 <212> DNA
<213> Homo sapiens <400> 56 gaattcggca cgagccattt tggtgtggga gtgggaggag ctgtgaatta tgacagttct 60 aattaatata attttgtctt tagtaaaaac aggccctgga cagcacttaa accacagtga 120 attggcaatt ctactaaacc tactacaatc taaaacaagt gttaatatgg ctgattttgt 180 ccaagtgttg aacattaagg taaactctga gactcaacag cagctaaata aaataaacct 240 tcctgctgga attttggcaa caggtgaaaa acagacagat ccatcaacac cacaacagga 300 gtcttcgaaa ccgttgggag gaattcagcc ttcttctcag accatccagc ctaaagtgga 360 gactgatgct gcccaggcgg ctgtgcagag tgcatttgca gttctgttga ctcagttaat 420 aaaggctcag cagtcaaagc agaaagatgt gctactagaa gagagggaaa atggatcggg 480 acatgaagcg tcattacaac tcaggccact ccagaaccta gcactccggt gtcgggtaag 540 tgtgcagata ccagaccact aacacagctg cattacatkg tctactcagt gttgctgact 600 atatataatg tgtatagttc agtgacattg ccaaaagatg tcctgaagaa tctcaggtaa 660 ctggcaatag gttggttttt cagtctgttt acttccagga atggattctt taacaaatta 720 tccatgtgag atagaactca ttrtgaatga taaagatatt tctaaggtaa acctatggtt 780 aagaaataat atttaactcc aaatacgaaa ggatgcttga ctaaggcata atttatgtac 840 acagtagctt ttgttcctca agcaatgaag tatacgtgaa ttctgcacct agccgtaatt 900 agctttaaaa agccaattac ggctgggtgc agtggctcac acctgtaatc ccagcacttt 960 gagaagctga agtgggaaga ttgcctgaac ccaggaattc agtacctatc tgtgcaacat 1020 agtgagaccc tgtctctaaa acaatttttt ttaattaact gggcatggta gcacatgcct 1080 gtgattccag ctacttggaa ggctgaggtg ggtggatcac ttgagcccag gaggtcaagg 1140 ctgcagtgag ctgtgatcac tccactgcac tccagtctgg gtgacagagt gagaccgtgt 1200 caccaaaaaa aaaaaaaaaa aactcgta 1228 <210> 57 <211> 1038 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (2) <223> n equals a,t,g, or c <400> 57 gnaattcggc acgagttaat gtataaaata tttctataat gaattttaat gggaattaga 60 gcatcataga aaaaatgctc ttactgttga aaacattatt tgttacattt tggtcaacta 120 atctttcaat aacttttagt aactataatg ttaagttgta ccagtggcag tcttatatag 180 taaatggcag ctgacagcat gaaaataaca tatctaatat tttgtgacta tcttattagg 240 aaaatcagag aatttcaaaa ccttgttagt ttttagggta tagtcacatt ttataaatgt 300 gcggtatatt tatacatgat ttgacgtttg tgwaaatatt ttccctggac ttttatttta 360 gatgagatct acagtgtagg caaacttata taatctgtca actccattag tgtcatagtc 420 agactcatcc ccatgctaaa attatagttg tkaaaatacg cttttgtaaa tagttgtgtt 480 aggtcattat caccaagtct tcaaggkatt acattataaa aaccttggkt tttattcttg 540 tgaatamccg ttttttccat gcaaagttaa aattcttcag cctttaattt ttttattaat 600 atataaggat gtgatgagta tgactacaaa acaggaaaaa ataaacagat ttcgtttgtg 660 gcttttgcta aattgttacc tgacaaaatc ttagccagtt cttcattttc gttttgagat 720 gaagatactt agttttagtc caggggctgg gcgcgatagc tgatgcctgt ggtcccagtg 780 ctttgcgggg ccgaggcagg tggatcactt aaggtcagga gtttgagacc agcctgccca 840 acatggtgaa acgttgtctc tactaaaaat acaaaaatta gacaggcgtg gtggcacaca 900 tctgtaattc cagctactca ggaggctaac acaggaaaat tccttgaacc tgggaggcag 960 aggttgcagt gagccattgc actccagcct gggcaacaca gtgagactct tgtctcaaaa 1020 aaaaaaaaaa aaactcga 1038 <210> 58 <211> 990 <212> DNA
<213> Homo sapiens <400> 58 gaattcggca cgagaatttt gaaagaagtt ctactgtgga taaaaagcta tgaaacagca 60 tcacatacta cagagaaacc ttttgggaaa ggaagagcca atagatatgg caaacatcat 120 tgttgtctta ttttcagaaa ttgccgcagc taccccagcc ttcagcagcc accaccctga 180 tccgtcagca gccagcaaca taaaagcaag gttctctacc agccaaaaga agaaaactct 240 ctgaaggctc aggtgtttta taaaattttt ttagcaataa aatatttttt aaagtatgta 300 tattttttag atgtaatgct actgcatagt taatcagcya tattatagtg aaaatagaac 360 ttttgtatgt actgggagac caaaacattc atgtgaataa cttttttgca atttttaact 420 tatttcagtg atctgggccc aaacctgaaa tatccgagcg gtatatttct ctctggcccc 480 aagttttgtg atattgttgt cctacatttt awttgtacat atgktataaa ctccacactg 540 tacttcygtk atttcattta agctgtcagt tatcttttta gagatttaga taaacagaga 600 catgttttta ttctttccat tgctgcttat tcctctgcgt aggttcatat ttcagkcctt 660 ttacttcaag agctctaaaa aaaatgtctt atagtgcagc tctattggta atcgattcct 720 ttagcttttg gatgtttaaa aagtgctttc tttaccttgc cttaattttt gaatgatatt 780 ttgctgagta atattctgag ttggtgattt tctctgacac tgcttttttt tttttttttt 840 tttttttttg tcatttgaca cagaatcttr cagtgagttg agatcgtgcc actgaactcc 900 agcttggggg acagagcaag actccatctc aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 960 aaaaaaaaaa aaaaaaaaaa aaaaactcga 990 <210> 59 <211> 1767 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (26) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (68) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (80) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (107) <223> n equals a,t,g, or c <220>
<221> SITE
<222> (1762) <223> n equals a,t,g, or c <400> 59 aagaaaaaaa taggcctggt tgccanatta aggtcccctg ggctatttta aaccggattt 60 ggataccnag gtctttccan aggccgtatt ttgccccccg taacccntaa aaaaaaaaaa 120 agatttccaa aatgccgttt tcagaacctg ggttttaata gcagtattga atttgtaagc 180 ttagtagttg cagaaattga acactaggtg gcactcagtt atcttaacag gggaagtact 240 gatacaattg ttgacttttc ttttactatg tgtaagaaat accccaaaca tgaaaagatt 300 gttttgatca~tatgcatgta tgtagaatat ttttgcagag cagaaagatt atgttagaag 360 tgtgattttt attttcagaa gtcatataca tgtaagctac aattttgagt gctttataaa 420 cacttaagat atatatataa attttaattt catagcaact tgtaaaaaat aaaatacttg 480 ttgaaaagcc tttttcaaca tatccctaag ctaagggaag aggaaggaat aacaactcag 540 tgaaaagatg gtctccagtt tctgaatgaa aaagctacag ctgagaaata aaataaaatg 600 tcatgctgca gaatatgtta tacccttatt ttgtgttaag gatatatttt attatgtgaa 660 tggttttgtt tttgtttttt gtttttgttt tttgcttgta ttgggaatta gctttactgg 720 taacttcctt atttagtttt tagtggtcaa ctctaataaa atgaaactag ggctgagcta 780 gttagccctc actagccaaa ctgaaactct atgcaacatt aaaagaagag atccatcatg 840 tagcttgtga cacttttatt ttattagtca ccggggaact tttcagtgat gaaaatacac 900 agggtaataa accttcacat ggcttcaaaa ggaaaacaag caaatcttct ctaatctact 960 cttactataa tttcctaagt gtacaccaaa ctctggattt aaaaatctga agtactatag 1020 aacattaagt tgaagaatgg aaattaagag tacgtattca tggtttatat ttcttattct 1080 atggagttcg tgaacacatc taggtggaat gcatctgaga ctaagggctg gtttttaatc 1140 ctcataagaa accagccttg aagaattaac aattctcttc attggtattc taaacctcct 1200 aagatattta ggcttctgta cataaaagtg tttttgctaa atttacagta tatatagatc 1260 ctttcatatt attttactaa gaatgtttga actttgcata tttgatatag ttcctggtag 1320 gaatagcaca gctcaaacat tagtttttct acttacctcc tctaacacgt ggtttgtctg 1380 gagagtttct aaaaattcag ctataacccc agttcatgta tttactggtg attgttcttg 1440 ctgaggtagt aacagcccaa tcttgggctg ttaaatccta ggaaatctcg aatcatagtg 1500 attaaaatag ttggggtaaa gttgtagctt atatgcaata ctacttggag gaattcttct 1560 actaatttgt atttaatgtg gaaattgtat agtttcattg atttaatcat aaataatgga 1620 aatggtctcc aagaagtttt atttttcatt tttttgctta tacactctga ttcctataat 1680 acagtgctat aagctatgca cagaaaataa aatgtttgaa atccaaaaaa aaaaaaaaaa 1740 aaaaaaaaaa aaaaaaaaaa anggggg 1767 <210> 60 <211> 1625 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (1336) <223> n equals a,t,g, or c <400> 60 gaattcggca cgagaatcta ccagccatga gtgaagtcta cccttggaag actgattgtg 60 ctcagttcgg ctctaaataa aatctttcca ttaactctgg cttccagtgt tttgtactct 120 gggagaacca gtcctccaag ggagagtttt gtcagccagc tgaattgctg cttcagtgac 180 aaaatggaat tcactcaaat tgttctgagc tttaggacaa aagaaatgcc tgtcatcttc 240 ctgatagtga acttagcaaa gcaccgttta aaagaatggc tctcatcact cccgagtacc 300 ttgtcattac tgctcatctg tgctaagtgc cactgtctac ttctgatccc caaaacagtg 360 gsCtctagcc tttgccttct gcctaactcc aagtagagtg ttctttttat aatccttcat 420 gttcatataa cactttagca tttacagagt gttttcacat gcttatttgt gaggtattat 480 cacagtgcta raaataagga aaggctgaga cctaccaaaa tgacagtgtt gtacgtgagc 540 aggctgagcc ttgaaagcag gacctctgtc tcccacatta gcgcttcatt ccatcacacc 600 tctgcaagga caggtagcct gctggggggc catggtggca ctggggtata aaatctctaa 660 actgctaata tcctcttttc cttctaggct gagaacatct ctaaggamct ctacatagaa 720 rtatatccag ggamctattc tgtcactgtg ggctcaaatg acttaaccaa gaaamtcatg 780 tggtagcagt tgattctgga caaagcgtgg amctggtcyt ccctgtgtga tgttgaccat 840 cactgccatc acatcacctt tttttaagta gtaagaataa agccactgta tgattctctt 900 aatagctata cattaatcct gtttttagtg ctgactgggt cagccttccg ggaactggag 960 tctgtctctt tcagtgcttt tttgtttgtt tggttggttg ttttttgaga cagcctgggc 1020 gacagagcca gactgtctca aataaataaa tatgagataa tgcagtcggg agaagggagg 1080 gagagaattt tattaaatgt gacgaactgc cccccccccc cccccagcag gagagcagca 1140 aaatttatgc aaatctttga cggggttttc cttgtcctgc caggattaaa agccatgagt 1200 ttcttgtcac atgcctttct atgccttcca tggctgggtc tcagggagcc ggaagcagct 1260 gctgaggagg gatgaaaatg tcagtgtgtg acgatgcctc atgggttcac cccccaaagc 1320 ctgggcacag ctggtnttgg gtctgccgtg cctcccttcc ttcctcctct tggggccact 1380 ggctgctcca gttccccatc cgtggcaagc cggtagagcc attcatcccc gcagccttyt 1440 tcctgaccct cgtacagttt caaatgcagc agacagccaa agcaatgagt ggggggctgt 1500 ggaacttcat ttcccaaagg cagcgccagt ggctcctgag caatgagaat gtcctgtcct 1560 gtccaccata ttcaaggcca gcagaagagc ccgattaaac cctcgcagca cctggcctcg 1620 tgccc 1625 <210> 61 <211> 899 <212> DNA
<213> Homo sapiens <400> 61 ccaaagctcc agctccaccg cggtggcggc cgctctagaa ctagtggatc ccccgggctg 60 caggaattcg gcacgagtgt aaggtggttt taaaagcctt atatgcaaac cttttaatct 120 gtgtttctgc aagtgccatc cttgtacagt gttaagaggg taacatgggt tacctttgca 180 ccagcttcag tgttaagctc accctgttct ttgaagcacc catgtcagta ttagaagaat 240 aggcagcagt tccttagttt acatatgttt gtgcaattat tttctgtact tttttgktca 300 ttaattttgt cagtattaca ccaaactgtt tttgcaacaa aaaaattttt tttgcattca 360 tttaatttta ggtcaaataa cattttattt atgtggctca ttttatattt cctaatttta 420 tttatttcat actgtagtgt acagtattat agttcttcaa tatatagata tattttagta 480 aaaaaggaac atgacgttga tcatttgggc aaattttacg taaagagaag agcatttatt 540 gtgttttgga acattaattg tgagatggga tttttcaatt ttattatttt atttttgttt 600 ttttccaatt actggaaatt ccaaatttgg gaacttttga tacgatcttg tgaaaacact 660 gtattttcga ctgaaaattc cactttcttc atcttgtttt ttagctaaaa agagggactg 720 ttaaatacaa tgtatgatac catgacaaaa atctttcctg aattgtcttt gtaaaagtat 780 tattgaattt tcaatttgta atttcttttg aaaatgacca tgctcgaata aaaatgtagc 840 caaactaaaa aaaaaaaaaa aaaactcgag ggggggcccg gacccaattc ggaagagta 899 <210> 62 <211> 1588 <212> DNA
<213> Homo sapiens <400> 62 actggaagat gtagagtggg aggactggga gtgagggagc cagagggagc agctccccca 60 cccatggcat ctctcgcctc cctcgctcgt ctcagcccag ccctggaaga ctgagaatgt 120 tcccccaaat ctcctctgcc aaccagagct ctgggcacag attctggtgg ctccctgctg 180 gccctcttgg gcytctgctc acacctggga aggggctctc taaatcccgg ccagaaactc 240 tgacttgtgc caacaatagg atgacccaag ggagaggaaa cctatcctcc tcaccagaag 300 agcctgtgtt tttctgctga acacccactg ttcctgagga ctcctgctgg gaagtcccaa 360 gggatagttc tagcccttct gcctgtgtag acagaagcta aaccaccagt ctctctcgga 420 ggaagctgag acaacatact ctgtccatac ataagcaggc agggagggcc atgccaccta 480 cccttggcta aacagggaca gtgaacacat tttggttcct atcccagtgg gtaagaggca 540 cttatctctg ggaaatttgc ctctcttggg actctccccc tcccaggcat tttccattcc 600 tggaaaggct cctttggggt tcagaatcca gagaccaaac cctgacccac ctccttcctt 660 tcctccagcc cacgctggtc tgtccccatg ccttcccagg gcttcttcat gtcagatgca 720 cccaagtcct tagcccagct gtgccacctg caggagttcg ctcttgcgtt tcttcccctc 780 cccaagaagg gagggggcta cttcaggccc ttctgtgtgt tgcctggcag gataccttgt 840 ccaaccagct acccacctca actcccctgt agtttaggac acaaaacagc taccagcggt 900 acagagcggt gatcaaagcc gagtacttac aactctggta agcctagctt ctccgcctca 960 gcccttctgc ttctggaagg gctatcctgg gggtgaactt gaaactctca tcaggcttct 1020 gcaaaagctc ttcttcctga agacagaccc agcctttgtg ctctcaccct ccactctggt 1080 aaagctgcac ctctggggga atgaggggct gcaggaatct ctggagagcc tggtgcttca 1140 cgatgctgct ctggtgattc ttgtacctaa tctggtgtgc tcaccaatga gtgaaaggga 1200 tcgtgggtca gggacaccga gagagtgagg tcacttccac ttcaaacctt cagtgagggg 1260 gtgggatgga gagaatgctg aatctttttt ttgacgggat ggggtttttc tctttgtaat 1320 tatttcttta gtttaattaa ccttttggtt gtttgtgcaa tattatatat tttaaattat 1380 aatgcatctc cccagagtat tttgtagctg ggaaaagaaa aaaggaaaaa aagaaaaaaa 1440 gattctaaca gctgttagtt ttataattaa aaaagaaaga aaaaagaact ttgtcctgaa 1500 ccttttacag acttgccgtt aacagcatta aagtgattca cccgaagctg aaaaaaaaaa 1560 aaaaaaaaaa aaaaaaaaaa aaactcga 1588 <210> 63 <211> 536 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (508) <223> n equals a,t,g, or c <400> 63 ggtcgaccca cgcgtccgcc cacgcgtccg gcttccttaa tgtaatttaa accctggcaa 60 acattcttta gaaaccaaga ggaaagaaag aacaaatatc aaaaaagaca tagaatttaa 120 tattgataca atttcacctc taaaatggat ttgaagaaat gcaactttat atcaaaaaat 180 gtcatctgat ttcctttgtt tcttttttaa attatgtaat cagatgattt tatgtttttt 240 tttcagggga gcggaatatt ggtttctttt acttgttgtt ttcagttttc tctgccattc 300 atgtttcttt tttgtgttca gtgtttcaaa tacaatttgt atttaaggat tttaaaatac 360 caaactgtaa ctgagtacag tggatcgttt tctgttagga tgttaatatt atacaatgaa 420 atctataaag tgttgtcaat ttgattattg acacatataa catgtttaca aataaactgt 480 ggtattgatc aaaaaaaaaa aaaaaaancc cggggggggc cccggaaccc aatccc 536 <210> 64 <211> 886 <212> DNA
<213> Homo sapiens <400> 64 ggtcgaccca cgcgtccgga aatgcaaagc tattctttgg ttttcacaga atgtctattg 60 ttttacactg ggggcagtgg ggagggtgcc actgataatt cttgcttctt ccgactgccc 120 ccagtgtaaa acaatagaca ttctgtgaaa tgcaaagcta ttctttggtt tttctagtag 180 tttatctcat tttaccctat tcttccttta aggaaaactc aatctttatc acagtcaatt 240 agagcgatcc caaggcatgg gaccaggcct gcttgcctat gtgtgatggc aattggagat 300 ctggatttag cactggggtc tcagcaccct gcaggtgtct gagactaagt gatctgccct 360 ccaggtggcg atcaccttct gctcctaggt acccccactg gcaaggccaa ggtctcctcc 420 acgttttttc tgcaattaat aatgtcattt aaaaaatgag caaagcctta tccgaatcgg 480 atatagcaac taaagtcaat acattttgca ggaggctaag tgtaagagtg tgtgtgtgtg 540 tgtgtgcgtg catgtgtgtg tgtgtgtatg tgtgtgaata agtcgacata aagtctttaa 600 ttttgagcac cttaccaaac ataacaataa tccattatcc ttttggcaac accacaaaga 660 tcgcatctgt taaacaggta caagttgaca tgaggttagt ttaattgtac accatgatat 720 tggtggtatt tatgctgtta agtccaaacc tttatctgtc tgttattctt aatgttgaat 780 aaactttgaa ttttttcctt tcaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 840 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaggg 886 <210> 65 <211> 716 <212> DNA
<213> Homo sapiens <220>
<221> SITE
<222> (1) <223> n equals a,t,g, or c <400> 65 ncctgcaggt accggtccgg aattcccggg tcgacccagc gtccgcgtcc gtgcgcaccg 60 cccggcgtcc agatttggca attcttcgct gaagtcatca tgagcttttt ccaactcctg 120 atgaaaagga aggaactcat tcccttggtg gtgttcatga ctgtggcggc gggtggagcc 180 tcatctttcg ctgtgtattc tctttggaaa accgatgtga tccttgatcg aaaaaaaaat 240 ccagaacctt gggaaactgt ggaccctact gtacctcaaa agcttataac aatcaaccaa 300 caatggaaac ccattgaaga gttgcaaaat gtccaaaggg tgaccaaatg acgagccctc 360 gcctctttct tctgaagagt actctataaa tctagtggaa acatttctgc acaaactaga 420 ttctggacac cagtgtgcgg aaatgcttct gctacatttt tagggtttgt ctacattttt 480 tgggctctgg ataaggaatt aaaggagtgc agcaataact gcactgtcta aaagtttgtg 540 cttattttct tgtaaatttg aatattgcat attgaaattt ttgtttatga tctatgaatg 600 tttttcttaa aatttacaaa gctttgtaaa ttagattttc tttaataaaa tgccatttgt 660 gcaagaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaagcgg ccgctcgaat taagcc 716 <210> 66 <211> 35 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (27) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (35) <223> Xaa equals stop translation <400> 66 Met Ser Val Phe Leu Leu Ile Thr Leu Ala Leu Ala Ile Leu Tyr Ile Ile Arg Ser Ile Val Phe Ser Leu Ala Leu Xaa Gln Asn Gly Ser Leu Gln Gly Xaa <210> 67 <211> 33 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (33) <223> Xaa equals stop translation <400> 67 Met Arg Asn Lys Glu Ser Leu Cys Lys Val Val Leu Lys Ala Leu Tyr Ala Asn Leu Leu Ile Cys Val Ser Ala Ser Ala Ile Leu Val Gln Cys Xaa <210> 68 <211> 206 <212> PRT
<213> Homo sapiens <400> 68 Met Gly Ala Glu Trp Glu Leu Gly Ala Glu Ala Gly Gly Ser Leu Leu Leu Cys Ala Ala Leu Leu Ala Ala Gly Cys Ala Leu Gly Leu Arg Leu Gly Arg Gly Gln Gly Ala Ala Asp Arg Gly Ala Leu Ile Trp Leu Cys Tyr Asp Ala Leu Val His Phe Ala Leu Glu Gly Pro Phe Val Tyr Leu Ser Leu Val Gly Asn Val Ala Asn Ser Asp Gly Leu Ile Ala Ser Leu Trp Lys Glu Tyr Gly Lys Ala Asp Ala Arg Trp Val Tyr Phe Asp Pro Thr Ile Val Ser Val Glu Ile Leu Thr Val Ala Leu Asp Gly Ser Leu Ala Leu Phe Leu Ile Tyr Ala Ile Val Lys Glu Lys Tyr Tyr Arg His Phe Leu Gln Ile Thr Leu Cys Val Cys Glu Leu Tyr Gly Cys Trp Met Thr Phe Leu Pro Glu Trp Leu Thr Arg Ser Pro Asn Leu Asn Thr Ser Asn Trp Leu Tyr Cys Trp Leu Tyr Leu Phe Phe Phe Asn Gly Val Trp Val Leu Ile Pro Gly Leu Leu Leu Trp Gln Ser Trp Leu Glu Leu Lys Lys Met His Gln Lys Glu Thr Ser Ser Val Lys Lys Phe Gln <210> 69 <211> 215 <212> PRT
<213> Homo sapiens <400> 69 Met Val Ala Asp Trp Leu Gln Gln Ser Tyr Gln Ala Val Lys Glu Lys Ser Ser Glu Ala Leu Glu Phe Met Lys Arg Asp Leu Thr Glu Phe Thr Gln Val Val Gln His Asp Thr Ala Cys Thr Ile Ala Ala Thr Ala Ser Val Val Lys Glu Lys Leu Ala Ile Ala Ala Cys Ser Arg Gly Ala Cys Phe Leu Cys Pro Phe Ser Ile Gln Thr Glu Gly Ser Ser Gly Ala Thr Glu Lys Met Lys Lys Gly Leu Ser Asp Phe Leu Gly Val Ile Ser Asp Thr Phe Ala Pro Ser Pro Asp Lys Thr Ile Asp Cys Asp Val Ile Thr Leu Met Gly Thr Pro Ser Gly Thr Ala Glu Pro Tyr Asp Gly Thr Lys Ala Arg Leu Tyr Ser Leu Gln Ser Asp Pro Ala Thr Tyr Cys Asn Glu Pro Asp Gly Pro Pro Glu Leu Phe Asp Ala Trp Leu Ser Gln Phe Cys Leu Glu Glu Lys Lys Gly Glu Ile Ser Glu Leu Leu Val Gly Ser Pro Ser Ile Arg Ala Leu Tyr Thr Lys Met Val Pro Ala Ala Val Ser His Ser Glu Phe Trp His Arg Tyr Phe Tyr Lys Val His Gln Leu Glu Gln Glu Gln Ala Arg Arg Thr Pro <210> 70 <211> 34 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (34) <223> Xaa equals stop translation <400> 70 Met Arg Leu Leu Leu Pro Ser Leu Leu Gly Gly Leu Ser Val Leu Thr Thr Ser Leu Gly Ser Val Ala Gly Leu Arg Asn Ser Arg Ala Ala Trp Trp Xaa <210> 71 <211> 187 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (73) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (92) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (94) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (126) <223> Xaa equals any of the naturally occurring L-amino acids <400> 71 Met Gly Thr Ala Ser Thr Gly Pro Trp Ala Ile Pro Thr Trp Ser Pro Cys Trp Gly Arg Ala Gly Arg Ser Ser Ser Ser Lys Asn Ala Tyr Cys Arg Pro Gln Met Thr Phe Trp Leu Leu Ala Leu Arg Ser Thr Ser Ser Glu Thr Ser Ser Met Leu Leu Gln Cys Gly Gly Thr Gly Arg Glu Gly Trp Leu Ser Val Gln Pro Ala Glu Xaa Val Ser Thr Thr Arg Val Pro Arg Asp His Ile Val Gln Phe Leu Arg Leu Leu Xaa Ser Xaa Phe Ile Arg Asn Arg Ala Asp Phe Phe Arg His Phe Ile Asp Glu Glu Met Asp Ile Lys Asp Phe Cys Thr His Glu Val Glu Pro Met Ala Xaa Glu Cys Asp His Ile Gln Ile Thr Ala Leu Ser Gln Ala Leu Ser Ile Ala Leu Gln Val Glu Tyr Val Asp Glu Met Asp Thr Ala Leu Asn His His Val Phe Pro Glu Ala Ala Thr Pro Ser Val Tyr Leu Leu Tyr Lys Thr Ser His Tyr Asn Ile Leu Tyr Ala Ala Asp Lys His <210> 72 <211> 48 <212> PRT
<213> Homo sapiens <400> 72 Met Phe Ala Pro Cys Phe Val Asn Leu Ala Leu Phe Tyr Leu Tyr Ile Asn Ser Cys Asn Leu Leu Asn Leu Thr Ser Ile Asp Pro Phe Gln Gln Lys Gly Lys Phe Lys Met Gln Thr Leu Leu Phe Ala Lys Glu Asp Ser <210> 73 <211> 92 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (79) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE

<222> (92) <223> Xaa equals stop translation <400> 73 Met Gln Cys Ile Arg Trp Thr Val Leu Phe Leu Phe Ile Leu Trp Val Leu Val Phe Val Phe Phe Phe Ala Phe Thr Val Arg Leu Gln Met Ile Val Leu Ile Thr Tyr Ile Ile Asn Lys Cys Gly Pro Ile Ile Tyr Thr Glu Ile Thr Leu Gly Tyr Phe Cys Ile Ile Leu Ser Tyr Cys Leu His Ser Ile Asn Phe Ser Arg Asp Asn Cys Leu Cys Val Thr Gly Xaa Lys Cys Arg Ile Thr Ser Phe Ile Ile Trp Lys Asn Xaa <210> 74 <211> 29 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (29) <223> Xaa equals stop translation <400> 74 Met Val Phe Leu Asn Phe Leu Ile Tyr Leu Leu Leu Val Phe Phe Tyr Ile Ser Leu Phe His Ser Arg Asp Asn Phe Ile Leu Xaa <210> 7S
<211> 87 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (87) <223> Xaa equals stop translation <400> 75 Met Ala Arg His Val Pro Leu Tyr Arg Ala Leu Leu Glu Leu Leu Arg Ala Ile Ala Ser Cys Ala Ala Met Val Pro Leu Leu Leu Pro Leu Ser Thr Glu Asn Giy Glu Glu Glu Glu Glu Gln Ser Glu Cys Gln Thr Ser Val Gly Thr Leu Leu Ala Lys Met Lys Thr Cys Val Asp Thr Tyr Thr Asn Arg Leu Arg Tyr Tyr Ile Gln Cys Ser Phe Leu Leu Ser Leu Pro Leu Thr Met Phe Leu Lys Xaa <210> 76 <211> 125 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (125) <223> Xaa equals stop translation <400> 76 Met Leu Leu Ile Leu Val Thr Pro Val Pro Thr Arg Leu Arg Ala Arg Pro Arg Leu Asp Leu Leu Val Leu Thr Pro Arg Ala Cys Pro Ala Ser Arg Val Arg Gly Arg Leu Ser Cys Arg Arg Thr Leu Pro Arg Met Gly Pro Ala Ser Cys Ser Ala Leu Ala Thr Asn Ala Ala Pro Gly Pro Pro His Pro Ala Gly Pro Ala Phe Ser Ser Ile Ser His Met Ala Thr Thr Pro Gln Ser Leu Glu Pro Pro Ala Gly Asn Ser Val Pro Gln Ser Leu Met Ser Ile Leu Asp Pro Ala Ser Ser Trp Val Pro Lys Ser Ala Ser Pro Pro Arg Val Ala Cys Pro Cys Pro Pro Ala Leu Xaa <210> 77 <211> 39 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (39) <223> Xaa equals stop translation <400> 77 Met His Leu Phe Leu Phe Ile Trp Ala Phe Gly Leu Pro Leu His .Ile Ser Arg Asp Leu Ala Phe Phe Phe Leu Leu Tyr Phe Leu Phe Phe Tyr Leu Leu Cys Val Leu Leu Xaa <210> 78 <211> 65 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (65) <223> Xaa equals stop translation <400> 78 Met Asn Ala Ser Cys Ser Leu Ala His Phe Glu His Ser Gly Met Ser Val Leu Leu Val His Leu Phe Ile Ile Val Ser Thr Val Pro Ser Cys Phe Lys Lys Tyr Met Ala Phe Ile Ile Tyr Pro Ala Phe Ser Cys His Phe Asn Lys Ser Met Cys Leu Ile Gln Leu Leu His Ser Ser Gln Lys Xaa <210> 79 <211> 109 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (62) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (63) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (109) <223> Xaa equals stop translation <400> 79 Met Gly Ala Ala Lys Val Trp Gly Glu Val Gly Arg Trp Leu Val Ile Ala Leu Ile Gln Leu Ala Lys Ala Val Leu Arg Met Leu Leu Leu Leu Trp Phe Lys Ala Gly Leu Gln Thr Ser Pro Pro Ile Val Pro Leu Asp Arg Glu Thr Arg His Ser Pro Arg Met Val Thr Thr Ala Xaa Xaa Thr Met Ser Ser Pro Thr Trp Gly Ser Gly Gln Thr Gly Trp Cys Glu Pro Ser Arg Thr Arg Arg Pro Cys Thr Pro Gly Thr Gly Glu Leu Pro Ser Ser Gly Arg Asp Gly Ser Ser Ser Ile Thr Arg Ser Xaa <210> 80 <211> 44 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (44) <223> Xaa equals stop translation <400> 80 Met Asp Ile Ala Ala Pro Val Leu Phe Ala Leu Arg Leu Gln Phe Leu Phe Ile Leu Leu Pro Met His Phe Glu Ile Ser Leu Leu Cys Lys Val Ser Thr Glu Thr Ser Gly Arg Glu Asp Lys Met Xaa <210> 81 <211> 50 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (50) <223> Xaa equals stop translation <400> 81 Met Ala Thr Asp Glu Arg Val Leu Arg Lys Ala His Ser Thr Pro Ala Leu Phe Gln Leu Val Leu Asn Leu Val Gln Cys Pro Ser Pro Ala Ser Gly Val Lys Ser His Leu Leu Pro His Lys Glu Arg His Lys Ser Met Glu Xaa <210> 82 <211> 30 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (9) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (14) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE

<222> (30) <223> Xaa equals stop translation <400> 82 Met Gly Val Leu His Leu Leu Ala Xaa Phe Leu Leu Val Xaa Gly Arg Val Pro Gly Leu Gly Gly Val Pro Gly Gly Gly Glu Gly Xaa <210> 83 <211> 42 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (42) <223> Xaa equals stop translation <400> 83 Met Ser Tyr Lys Trp Asn Ser Arg Val Cys Phe Leu Trp Ser Arg Thr Phe His Leu Met Leu Leu Arg Leu Ile Cys Leu Val Ala Tyr Ile Ser Thr Glu Val Ile Ser Phe Ile Ala Glu Xaa . 35 40 <210> 84 <211> 90 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (90) <223> Xaa equals stop translation <400> 84 Met Leu Leu Leu Val Tyr Phe Leu Leu Met Ser Val Ile Phe Gly Thr Lys Phe Phe Pro Leu Ile Ile His Met Phe Asn Pro Cys Ile Leu Asn Leu Ile Lys Leu Val Phe Ser Leu Met Pro Gly Ser His Gln Thr Pro Asn Val Gln Ala Thr Arg Ala Ser Asp Asp Gly Ser Ala Leu Leu Gly Thr Pro Ser Arg Pro Leu Gly Ser Ile Arg Gln Gln Phe Thr Pro Lys Glu Cys Pro Leu Ser Ala Gly Ser Ser Xaa <210> 85 <211> 109 <212> PRT

<213> Homo sapiens <220>
<221> SITE
<222> (109) <223> Xaa equals stop translation <400> 85 Met Lys Ala Leu Cys Leu Leu Leu Leu Pro Val Leu Gly Leu Leu Val Ser Ser Lys Thr Leu Cys'Ser Met Glu Glu Ala Ile Asn Glu Arg Ile Gln Glu Val Ala Gly Ser Leu Ile Phe Arg Ala Ile Ser Ser Ile Gly Leu Glu Cys Gln Ser Val Thr Ser Arg Gly Asp Leu Ala Thr Cys Pro Arg Gly Phe Ala Val Thr Gly Cys Thr Cys Gly Ser Ala Cys Gly Ser Trp Asp Val Arg Ala Glu Thr Thr Cys His Cys Gln Cys Ala Gly Met Asp Trp Thr Gly Ala Arg Cys Cys Arg Val Gln Pro Xaa <210> 86 <211> 304 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (203) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (267) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (274) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (304) <223> Xaa equals stop translation <400> 86 Met Gly Ser Gly Gly Asp Ser Leu Leu Gly Gly Arg Gly Ser Leu Pro Leu Leu Leu Leu Leu Ile Met Gly Gly Met Ala Gln Asp Ser Pro Pro Gln Ile Leu Val His Pro Gln Asp Gln Leu Phe Gln Gly Pro Gly Pro Ala Arg Met Ser Cys Arg Ala Ser Gly Gln Pro Pro Pro Thr Ile Arg Trp Leu Leu Asn Gly Gln Pro Leu Ser Met Val Pro Pro Asp Pro His His Leu Leu Pro Asp Gly Thr Leu Leu Leu Leu Gln Pro Pro Ala Arg Gly His Ala His Asp Gly Gln Ala Leu Ser Thr Asp Leu Gly Val Tyr Thr Cys Glu Ala Ser Asn Arg Leu Gly Thr Ala Val Ser Arg Gly Ala Arg Leu Ser Val Ala Val Leu Arg Glu Asp Phe Gln Ile Gln Pro Arg Asp Met Val Ala Val Val Gly Glu Gln Phe Thr Leu Glu Cys Gly Pro Pro Trp Gly His Pro Glu Pro Thr Val Ser Trp Trp Lys Asp Gly Lys Pro Leu Ala Leu Gln Pro Gly Arg His Thr Val Ser Gly Gly Ser Leu Leu Met Ala Arg Ala Glu Lys Ser Asp Glu Xaa Thr Tyr Met Cys Val Ala Thr Asn Ser Ala Gly His Arg Glu Ser Arg Ala Ala Arg Val Ser Ile Gln Glu Pro Gln Asp Tyr Thr Glu Pro Val Glu Leu Leu Ala Val Arg Ile Gln Leu Glu Asn Val Thr Leu Leu Asn Pro Asp Pro Ala Glu Gly Pro Lys Pro Arg Pro Ala Val Trp Leu Xaa Trp Lys Val Ser Gly Pro Xaa Arg Leu Pro Asn Leu Thr Arg Pro Cys Ser Gly Pro Arg Leu Pro Arg Glu Ala Arg Glu Leu Arg Gly Gln Arg Arg Asn Thr Gly Xaa <210> 87 <211> 57 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (57) <223> Xaa equals stop translation <400> 87 Met Leu Met Asn Pro Ile Arg Arg Arg Phe Gln Gln Val Pro His Pro Pro Leu Leu Leu Leu Leu Leu Leu Leu Thr Ala Arg Thr Gly Gly Gly Gln Gly Asp Thr Trp Ala Asp Pro Pro Ala Leu Pro Pro Pro His Pro Ala Pro His Ile Ile Leu Gln Ser Xaa <210> 88 <211> 31 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (31) <223> Xaa equals stop translation <400> 88 Met Gln Ser Tyr Ser Leu Val Phe Leu Val Val Tyr Leu Ile Leu Pro Tyr Ser Ser Phe Lys Glu Asn Ser Ile Phe Ile Thr Val Asn Xaa <210> 89 <211> 69 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (37) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (62) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (64) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (69) <223> Xaa equals stop translation <400> 89 Met Ala Leu Gly Ala Leu Ser Leu Asn Ala Ala Leu Ala Pro Trp Ala Ser Ser Pro Gly Pro Asp Leu Pro Ile Leu Lys Glu Lys Gin Pro Leu Ser Ser Tyr Pro Xaa Ser Gly Gly Ala Arg Phe Arg Leu Pro Thr Thr Ser Leu Gly Thr Arg Glu Ser Ser Ser Phe Thr Thr Cys Xaa Val Xaa Gly Ala Gly Leu Xaa.
<210> 90 <211> 26 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (26) <223> Xaa equals stop translation <400> 90 Met Ile Thr Ser His Leu Arg Glu Ala Lys Leu Lys Val His Leu Gln Glu Glu Leu Trp Pro Asp Ile Ala Asn Xaa <210> 91 <211> 213 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (180) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (213) <223> Xaa equals stop translation <400> 91 Met Lys Val Phe Lys Phe Ile Gly Leu Met Ile Leu Leu Thr Ser Ala Phe Ser Ala Gly Ser Gly Gln Ser Pro Met Thr Val Leu Cys Ser Ile Asp Trp Phe Met Val Thr Val His Pro Phe Met Leu Asn Asn Asp Val Cys Val His Phe His Glu Leu His Leu Gly Leu Gly Cys Pro Pro Asn His Val Gln Pro His Ala Tyr Gln Phe Thr Tyr Arg Val Thr Glu Cys Gly Ile Arg Ala Lys Ala Val Ser Gln Asp Met Val Ile Tyr Ser Thr Glu Ile His Tyr Ser Ser Lys Gly Thr Pro Ser Lys Phe Val Ile Pro Val Ser Cys Ala Ala Pro Gln Lys Ser Pro Trp Leu Thr Lys Pro Cys Ser Met Arg Val Ala Ser Lys Ser Arg Ala Thr Ala Arg Arg Met Arg Gly Ala Gly Leu Xaa.
<210> 90 <211> 26 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (26) <223> Xaa equals stop translation <400> 90 Met Ile Thr Ser His Leu Arg Glu Ala Lys Leu Lys Val His Leu Gln Glu Glu Leu Trp Pro Asp Ile Ala Asn Xaa <210> 91 <211> 213 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (180) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (213) <223> Xaa equals stop translation <400> 91 Met Lys Val Phe Lys Phe Ile Gly Leu Met Ile Leu Leu Thr Ser Ala Phe Ser Ala Gly Ser Gly Gln Ser Pro Met Thr Val Leu Cys Ser Ile Asp Trp Phe Met Val Thr Val His Pro Phe Met Leu Asn Asn Asp Val Cys Val His Phe His Glu Leu His Leu Gly Leu Gly Cys Pro Pro Asn His Val Gln Pro His Ala Tyr Gln Phe Thr Tyr Arg Val Thr Glu Cys Gly Ile Arg Ala Lys Ala Val Ser Gln Asp Met Val Ile Tyr Ser Thr Glu Ile His Tyr Ser Ser Lys Gly Thr Pro Ser Lys Phe Val Ile Pro Val Ser Cys Ala Ala Pro Gln Lys Ser Pro Trp Leu Thr Lys Pro Cys Ser Met Arg Val Ala Ser Lys Ser Arg Ala Thr Ala Arg Arg Met Arg Asn Ala Thr Arg Cys Ser Ala Cys His Ser Pro Val Lys Gly Pro Thr Ala Ile Val His Leu Val Ser Ser Val Lys Lys Ser Ile Pro Arg Ser Leu Val Thr Xaa Ala Gly Ala Gln Glu Ala Gln Pro Leu G1n Pro Ser His Phe Leu Asp Ile Ser Glu Asp Trp Ser Leu His Thr Asp Asp Met Ile Gly Ser Met Xaa <210> 92 <211> 45 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (45) <223> Xaa equals stop translation <400> 92 Met Asn Asn Ala Ala Lys Asn Ile Asn Val Gln Val Ser Val Trp Thr Tyr Ala Phe Ile Ser Leu Ile Phe Ile Leu Phe His Leu Gly Val Glu Leu Leu Gly Cys Met Val Val Leu Cys Leu Thr Val Xaa <210> 93 <211> 41 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (41) <223> Xaa equals stop translation <400> 93 Met Ser Ser Asn Thr Tyr Ile Val Leu Val Cys Gln Ala Leu Leu Ile Thr Ala Met Asn Arg Gly Pro Pro Asn Lys Cys Asn Arg Val Tyr Leu Phe Leu Asn Leu Cys His His Tyr Xaa <210> 94 <211> 115 <212> PRT
<213> Homo sapiens <400> 94 Met Gin Leu Ser Val Cys Val Ile Thr Thr Ser Leu Leu Phe Asn Ser Ile Thr Leu Tyr Phe Ser Lys Met Pro Arg Ser Pro Gly Ser Tyr Ala Asp Leu Gln Arg Phe Tyr Phe Leu Ala Leu Glu Ser Ala Glu Ile Arg Arg His Arg Ala Gln Arg Ser Ser Leu Gly Thr Arg Ile Ala Phe Ala Leu Ala Gly Tyr Val Tyr Thr Asp Glu Tyr Lys Met Phe Phe Ser Leu Gly Phe Leu Leu Leu Phe Ser Pro Pro Ser His Leu Pro Phe Ser Pro Thr Pro Pro Pro Lys Lys Ala Thr Ser Ser Phe Arg Gly Thr Ile Ile Phe Phe Asn <210> 95 <211> 84 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (84) <223> Xaa equals stop translation <400> 95 Met Ser Phe Phe Gln Leu Leu Met Lys Arg Lys Glu Leu Ile Pro Leu Val Val Phe Met Thr Val Ala Ala Gly Gly Ala Ser Ser Phe Ala Val Tyr Ser Leu Trp Lys Thr Asp Val Ile Leu Asp Arg Lys Lys Asn Pro Glu Pro Trp Glu Thr Val Asp Pro Thr Val Pro Gln Lys Leu Ile Thr Ile Asn Gln Gln Trp Lys Pro Ile Glu Glu Leu Gln Asn Val Gln Arg Val Thr Lys Xaa <210> 96 <211> 50 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (50) <223> Xaa equals stop translation <400> 96 Met Pro Ser Ser Glu Cys Arg Ser Ser Ala Leu Leu Leu Asn Val Ser Leu Ala Glu Ser Glu Ala Gly Arg Arg Pro Gly Lys Pro Gly Trp Ala Glu Glu Ala Thr Gly Gly Arg Arg Ala Ser Arg Lys Asp Gly Thr Gln Gly Xaa <210> 97 <211> 35 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (35) <223> Xaa equals stop translation <400> 97 Met Ala His Arg Ser Trp Ile Leu Ser Ser Ser Leu Leu Pro Ile Pro Ile Phe Phe Leu Leu Pro Pro Ser Ser Ala Ala Thr Leu Ala Thr Pro Gly Ser Xaa <210> 98 <211> 45 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (45) <223> Xaa equals stop translation <400> 98 Met Leu Val Phe Leu Pro Phe Thr Val Leu Val Leu Ile Ser Tyr Ile Phe Ser Ser His Ser Phe Asn Pro Leu Phe Thr Leu Cys Asp Phe Glu Gln Val Leu Leu His Leu Lys Ile Phe Ser His Pro Xaa <210> 99 <211> 43 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (43) <223> Xaa equals stop translation <400> 99 Met Ala Leu Val Ile Ser Ala Pro Pro Pro Asn Ser Pro Cys Asn Cys Phe Phe Phe Ile Phe Leu Phe Ile Leu Pro Leu Ile Phe Pro Leu Phe Lys Gly Leu Phe Ala Thr Phe Val Phe Phe Xaa <210> 100 <211> 44 <212> PRT
<213> Homo sapiens <400> 100 Met Ala Ser Thr Leu Glu Thr Ile Arg Pro Leu Gly Phe Leu Leu Leu Tyr Cys Phe Ile Ser Leu Leu Tyr Leu Pro Val Leu Glu Thr Ser Phe Ser Phe Leu Leu Val Trp Arg Leu Glu Pro Ile Val <210> 101 <211> 89 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (89) <223> Xaa equals stop translation <400> 101 Met Lys Ile Ala Val Leu Phe Cys Phe Phe Leu Leu Ile Ile Phe Gln Thr Asp Phe Gly Lys Asn Glu Glu Ile Pro Arg Lys Gln Arg Arg Lys Ile Tyr His Arg Arg Leu Arg Lys Ser Ser Thr Ser His Lys His Arg Ser Asn Arg Gln Leu Gly Ile Pro Gln Thr Thr Val Phe Thr Pro Val Ala Arg Leu Pro Ile Val Asn Phe Asp Tyr Ser Met Glu Glu Lys Phe Glu Ser Phe Gln Val Phe Leu Glu Xaa <210> 102 <211> 62 <212> PRT
<213> Homo sapiens <400> 102 Met Leu Gly Leu Gln Pro Gin Gly Leu Gly Trp Pro Ala Leu Leu Leu Leu Ile Leu Lys Thr Phe Lys Val Gly Gly Trp Gln Gly Met Cys Leu Ile Asn Gln Phe Gln Ala Ser Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys <210> 103 <211> 75 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (75) <223> Xaa equals stop translation <400> 103 Met Val Val Ile Thr Val Leu Leu Ser Val Ala His Val Pro Ala Gly Ala Gly Leu His His Cys Pro Gly Thr Gly Leu Pro Gln Val Arg Arg Ser Ala Arg Ser Ser Ser Phe Ser Arg Lys Pro Arg Ala Pro Ser Ser Ser Pro Ala His Leu Leu Pro Gly Pro Arg Pro Val Ala Pro Leu Val Pro Ser Leu Leu Leu Cys Pro Pro Leu Pro Xaa <210> 104 <211> 73 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (71) <223> Xaa equals any of the naturally occurring L-amino acids <400> 104 Met Leu Ser Val Gly Ile Ala Leu Ala Ala Leu Gly Ser Leu Leu Leu Leu Gly Leu Leu Leu Tyr Gln Val Gly Val Ser Gly His Cys Pro Ser Ile Cys Met Ala Thr Pro Ser Thr His Ser Gly His Gly Gly His Gly Ser Ile Phe Ser Ile Ser Gly Gln Leu Ser Ala Gly Arg Arg His Glu Thr Thr Ser Ser Ile Ala Xaa Leu Ile <210> 105 <211> 125 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (75) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (125) <223> Xaa equals stop translation <400> 105 Met Ser Pro Arg Gly Thr Gly Cys Ser Ala Gly Leu Leu Met Thr Val Gly Trp Leu Leu Leu Ala Gly Leu Gln Ser Ala Arg Gly Thr Asn Val Thr Ala Ala Val Gln Asp Ala Gly Leu Ala His Glu Gly Glu Gly Glu Glu Glu Thr Glu Asn Asn Asp Ser Glu Thr Ala Glu Asn Tyr Ala Pro Ser Glu Thr Glu Asp Val Ser Asn Arg Asn Xaa Val Lys Glu Val Glu Phe Gly Met Cys Thr Val Thr Cys Gly Ile Gly Val Arg Glu Val Ile Leu Thr Asn Gly Cys Pro Gly Gly Glu Ser Lys Cys Val Val Arg Val Glu Glu Cys Pro Trp Thr Asn Arg Leu Trp Leu Gly Xaa <210> 106 <211> 35 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (35) <223> Xaa equals stop translation <400> 106 Pro Leu Leu Ser Ser Leu Leu Gly Arg Val Gln Gln Lys Gln Asn Asn Lys Val Thr Ala Phe Cys Ser Ser Gln Lys Glu Asn Lys Ser Leu Ile Leu Val Xaa <210> 107 <211> 26 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (26) <223> Xaa equals stop translation <400> 107 Met Ser Lys Thr Phe Leu Ser Ala Phe Leu Phe Leu Thr Val Leu Ser Leu Thr Val Leu Ser Ile Cys Ser Asn Xaa <210> 108 <211> 28 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (28) <223> Xaa equals stop translation <400> 108 Met Cys Leu Phe Val Ser Leu Leu Ile Leu Ser Leu Gly Ile Gly Lys His Ser Met Asn Ile Tyr Thr Leu Thr Phe Phe Xaa <210> 109 <211> 62 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (62) <223> Xaa equals stop translation <400> 109 Met Gln Leu Arg Gly Leu Ser Leu Asn Pro Arg Leu Leu Leu Thr Leu Gly Ser Phe Asn Gln Val Gly Gln Pro Leu Leu Gln Arg Gly Val Gly Trp Leu Ser Ser Leu Ser His Ala Ala Cys Glu Asp Arg Gly Gly Gly Val Gly Ser Gly Lys Ser Pro Glu Asn Arg Arg Gly Ile Xaa <210> 110 <211> 51 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (51) <223> Xaa equals stop translation <400> 110 Met Leu Leu Thr Leu Phe Ala His Thr Ala Leu Asp Thr Tyr Leu Leu Ser Glu Ala Phe Phe Pro His Ser Ile Leu Pro Ala Leu Leu Leu Ile Lys Ile Ser Ser Ala Cys Ser Gln Thr Gln Ser Glu Ser Gln Lys Asn Pro Ala Xaa <210> 111 <211> 171 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (171) <223> Xaa equals stop translation <400> 111 Met Thr Val Leu Ile Asn Ile Ile Leu Ser Leu Val Lys Thr Gly Pro Gly Gln His Leu Asn His Ser Glu Leu Ala Ile Leu Leu Asn Leu Leu Gln Ser Lys Thr Ser Val Asn Met Ala Asp Phe Val Gln Val Leu Asn Ile Lys Val Asn Ser Glu Thr Gln Gln Gln Leu Asn Lys Ile Asn Leu Pro Ala Gly Ile Leu Ala Thr Gly Glu Lys Gln Thr Asp Pro Ser Thr Pro Gin Gln Glu Ser Ser Lys Pro Leu Gly Gly Ile Gln Pro Ser Ser Gln Thr Ile Gln Pro Lys Val Glu Thr Asp Ala Ala Gln Ala Ala Val Gln Ser Ala Phe Ala Val Leu Leu Thr Gln Leu Ile Lys Ala Gln Gln Ser Lys Gln Lys Asp Val Leu Leu Glu Glu Arg Glu Asn Gly Ser Gly His Glu Ala Ser Leu Gln Leu Arg Pro Leu Gln Asn Leu Ala Leu Arg Cys Arg Val Ser Val Gln Ile Pro Asp His Xaa <210> 112 <211> 40 <212> PRT
<213> Homo sapiens <220>

<221> SITE
<222> (40) <223> Xaa equals stop translation <400> 112 Met Leu Leu Leu Leu Lys Thr Leu Phe Val Thr Phe Trp Ser Thr Asn Leu Ser Ile Thr Phe Ser Asn Tyr Asn Val Lys Leu Tyr Gln Trp Gln Ser Tyr Ile Val Asn Gly Ser Xaa <210> 113 <211> 65 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (65) <223> Xaa equals stop translation <400> 113 Met Lys Gln His His Ile Leu Gln Arg Asn Leu Leu Gly Lys Glu Glu Pro Ile Asp Met Ala Asn Ile Ile Val Val Leu Phe Ser Glu Ile Ala Ala Ala Thr Pro Ala Phe Ser Ser His His Pro Asp Pro Ser Ala Ala Ser Asn Ile Lys Ala Arg Phe Ser Thr Ser Gin Lys Lys Lys Thr Leu Xaa <210> 114 <211> 28 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (28) <223> Xaa equals stop translation <400> 114 Met Val Leu Phe Leu Phe Phe Val Phe Val Phe Cys Leu Tyr Trp Glu Leu Ala Leu Leu Val Thr Ser Leu Phe Ser Phe Xaa <210> 115 <211> 71 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (60) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (71) <223> Xaa equals stop translation <400> 115 Met Glu Phe Thr Gin Ile Val Leu Ser Phe Arg Thr Lys Glu Met Pro Val Ile Phe Leu Ile Val Asn Leu Ala Lys His Arg Leu Lys Glu Trp Leu Ser Ser Leu Pro Ser Thr Leu Ser Leu Leu Leu Ile Cys Ala Lys Cys His Cys Leu Leu Leu Ile Pro Lys Thr Val Xaa Ser Ser Leu Cys Leu Leu Pro Asn Ser Lys Xaa <210> 116 <211> 148 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (11) <223> Xaa equals any of the naturally occurring L-amino acids <220>
<221> SITE
<222> (148) <223> Xaa equals stop translation <400> 116 Met Phe Val Gln Leu Phe Ser Val Leu Phe Xaa Ser Leu Ile Leu Ser Val Leu His Gln Thr Val Phe Ala Thr Lys Lys Phe Phe Leu His Ser Phe Asn Phe Arg Ser Asn Asn Ile Leu Phe Met Trp Leu Ile Leu Tyr Phe Leu Ile Leu Phe Ile Ser Tyr Cys Ser Val Gln Tyr Tyr Ser Ser Ser Ile Tyr Arg Tyr Ile Leu Val Lys Lys Glu His Asp Val Asp His Leu Gly Lys Phe Tyr Val Lys Arg Arg Ala Phe Ile Val Phe Trp Asn Ile Asn Cys Glu Met Giy Phe Phe Asn Phe Ile Ile Leu Phe Leu Phe Phe Ser Asn Tyr Trp Lys Phe Gin Ile Trp Glu Leu Leu Ile Arg Ser Cys Glu Asn Thr Val Phe Ser Thr Glu Asn Ser Thr Phe Phe Ile Leu Phe Phe Ser Xaa <210> 117 <211> 22 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (22) <223> Xaa equals stop translation <400> 117 Gly Ala Ala Gly Ile Ser Gly Glu Pro Gly Ala Ser Arg Cys Cys Ser Gly Asp Ser Cys Thr Xaa <210> 118 <211> 56 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (56) <223> Xaa equals stop translation <400> 118 Met Ser Ser Asp Phe Leu Cys Phe Phe Phe Lys Leu Cys Asn Gln Met Ile Leu Cys Phe Phe Phe Arg Gly Ala Glu Tyr Trp Phe Leu Leu Leu Val Val Phe Ser Phe Leu Cys His Ser Cys Phe Phe Phe Val Phe Ser Val Ser Asn Thr Ile Cys Ile Xaa <210> 119 <211> 31 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (31) <223> Xaa equals stop translation <400> 119 Met Gln Ser Tyr Ser Leu Val Phe Leu Val Val Tyr Leu Ile Leu Pro Tyr Ser Ser Phe Lys Glu Asn Ser Ile Phe Ile Thr Val Asn Xaa <210> 120 <211> 77 <212> PRT
<213> Homo sapiens <220>
<221> SITE
<222> (77) <223> Xaa equals stop translation <400> 120 Met Lys Arg Lys Glu Leu Ile Pro Leu Val Val Phe Met Thr Val Ala Ala Gly Gly Ala Ser Ser Phe Ala Val Tyr Ser Leu Trp Lys Thr Asp Val Ile Leu Asp Arg Lys Lys Asn Pro Glu Pro Trp Glu Thr Val Asp Pro Thr Val Pro Gln Lys Leu Ile Thr Ile Asn Gln Gln Trp Lys Pro Ile Glu Glu Leu Gln Asn Val Gln Arg Val Thr Lys Xaa <210> 121 <211> 206 <212> PRT
<213> Homo sapiens <400> 121 Met Gly Ala Glu Trp Glu Leu Gly Ala Glu Ala Gly Gly Ser Leu Leu Leu Cys Ala Ala Leu Leu Ala Ala Gly Cys Ala Leu Gly Leu Arg Leu Gly Arg Gly Gln Gly Ala Ala Asp Arg Gly Ala Leu Ile Trp Leu Cys Tyr Asp Ala Leu Val His Phe Ala Leu Glu Gly Pro Phe Val Tyr Leu Ser Leu Val Gly Asn Val Ala Asn Ser Asp Gly Leu Ile Ala Ser Leu Trp Lys Glu Tyr Gly Lys Ala Asp Ala Arg Trp Val Tyr Phe Asp Pro Thr Ile Val Ser Val Glu Ile Leu Thr Val Ala Leu Asp Gly Ser Leu Ala Leu Phe Leu Ile Tyr Ala Ile Val Lys Glu Lys Tyr Tyr Arg His Phe Leu Gln Ile Thr Leu Cys Val Cys Glu Leu Tyr Gly Cys Trp Met Thr Phe Leu Pro Glu Trp Leu Thr Arg Ser Pro Asn Leu Asn Thr Ser Asn Trp Leu Tyr Cys Trp Leu Tyr Leu Phe Phe Phe Asn Gly Val Trp Val Leu Ile Pro Gly Leu Leu Leu Trp Gln Ser Trp Leu Glu Leu Lys Lys Met His Gln Lys Glu Thr Ser Ser Val Lys Lys Phe Gln <210> 122 <211> 55 <212> PRT
<213> Homo sapiens <400> 122 Met Asn Gln Ile Phe Leu Phe Gly Gln Asn Val Ile His Ser Ser Leu His Phe Val Phe Val Leu Leu Leu Leu Asn Asn Leu Phe Gln Ile Gly Phe Lys Ala Thr Ser Phe Arg Cys Ile Val Val Gln Leu Asn Gly Asp Ile Gly Lys Arg Glu Gln Ile <210> 123 <211> 121 <212> PRT
<213> Homo sapiens <400> 123 Leu Ser Ala Tyr Arg Thr Leu Asp Asn Thr His Ile His Thr His Lys Asn Ala His Glu Pro Asn Pro Glu Lys Val Pro Ala Gly Pro Pro Pro Ser Pro Pro Pro Pro Thr Ser Pro Leu Asp Ser Glu Asp Arg Arg Gly Thr Arg Gly His Leu Gly Arg Pro Ala Gly Ser Pro Pro Thr Pro Pro Arg Pro Ser His His Thr Pro Ile Ile Thr Leu Tyr Ile Thr Gln Ser Phe Trp Phe Ser Arg Thr Arg Leu Pro Lys Tyr His Leu Gln Lys Val Thr Leu Ala Gly His Tyr Phe Vai Tyr Leu Phe Pro Met Gln Lys Lys Asn Glu Asn Glu Lys Arg Gly Ile Pro <210> 124 <211> 29 <212> PRT

<213> Homo sapiens <400> 124 Leu Ser Ala Tyr Arg Thr Leu Asp Asn Thr His Ile His Thr His Lys Asn Ala His Glu Pro Asn Pro Glu Lys Val Pro Ala Gly <210> 125 <211> 13 <212> PRT
<213> Homo sapiens <400> 125 Leu Asp Ser Glu Asp Arg Arg Gly Thr Arg Gly His Leu <210> 126 <211> 28 <212> PRT
<213> Homo sapiens <400> 126 Ile Ile Thr Leu Tyr Ile Thr Gln Ser Phe Trp Phe Ser Arg Thr Arg Leu Pro Lys Tyr His Leu Gln Lys Val Thr Leu Ala <210> 127 <211> 10 <212> PRT
<213> Homo sapiens <400> 127 Val Ile Ile Leu Phe Ile Cys Ser Leu Cys <210> 128 <211> 10 <212> PRT
<213> Homo sapiens <400> 128 Pro Glu Gly Glu Cys Cys Pro Val Cys Pro <210> 129 <211> 68 <212> PRT
<213> Homo sapiens <400> 129 Ile Ser Tyr Leu Val Lys Lys Gly Thr Ala Thr Glu Ser Ser Arg Glu Ile Pro Met Ser Thr Leu Pro Arg Arg Asn Met Glu Ser Ile Gly Leu Gly Met Ala Arg Thr Gly Gly Met Val Val Ile Thr Val Leu Leu Ser Val Ala Met Phe Leu Leu Val Leu Gly Phe Ile Ile Ala Leu Ala Leu Gly Ser Arg Lys <210> 130 <211> 24 <212> PRT
<213> Homo sapiens <400> 130 Met Ala Arg Thr Gly Gly Met Val Val Ile Thr Val Leu Leu Ser Val Ala Met Phe Leu Leu Val Leu Gly <210> 131 <211> 25 <212> PRT
<213> Homo sapiens <400> 131 Asn Met Glu Ser Ile Gly Leu Gly Met Ala Arg Thr Gly Gly Met Val Val Ile Thr Val Leu Leu Ser Val Ala <210> 132 <211> 42 <212> PRT
<213> Homo sapiens <400> 132 His Glu Ser Ile Ser Tyr Leu Val Lys Lys Gly Thr Ala Thr Glu Ser Ser Arg Glu Ile Pro Met Ser Thr Leu Pro Arg Arg Asn Met Glu Ser Ile Gly Leu Gly Met Ala Arg Thr Gly Gly

Claims

THE EMBODIMENTS OF THE INVENTION FOR WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An isolated nucleic acid molecule comprising a polynucleotide selected from:
(a) a polynucleotide comprising the entire nucleotide sequence of SEQ ID NO:
31;
(b) a polynucleotide comprising a nucleotide sequence encoding a full length polypeptide of SEQ ID NO: 86;
(c) a polynucleotide encoding a polypeptide epitope of SEQ ID NO: 86, wherein the polypeptide epitope comprises amino acid residues 55 to 62, 164 to 174 or 197 to 202 of SEQ ID NO:86 and is for use in generation or selection of an antibody that specifically binds the polypeptide of SEQ ID NO:86;
(d) a polynucleotide encoding a polypeptide having an amino acid sequence at least 90% identical to the entire amino acid sequence of a polypeptide encoded by the polynucleotide of (a) or (b), wherein the polypeptide encoded by said polynucleotide has the same endothelial cell proliferation activity as a polypeptide having the amino acid sequence as set forth in SEQ ID NO:86; or (e) a polynucleotide that hybridizes to the complement of (a) or (b) under stringent hybrization conditions comprising an overnight incubation at 42°C in a solution comprising 50% formamide, 5x SSC, 50mM sodium phosphate (pH7.6), 5x Denhardt's solution, 10% dextran sulfate and 20µg/ml denatured, sheared salmon sperm DNA, followed by washing in 0.1x SSC at 65°C, wherein the polynucleotide encodes a polypeptide having the same endothelial cell proliferation activity as a polypeptide having the amino acid sequence as set forth in SEQ ID NO:86.

2. The isolated nucleic acid molecule according to claim 1, wherein the nucleic acid molecule is DNA or RNA.

3. The isolated nucleic acid molecule according to claim 1 or 2, wherein the polynucleotide is fused to a heterologous nucleic acid.

4. A vector comprising the nucleic acid molecule according to any one of claims 1 to 3.

5. The vector according to claim 4, wherein the nucleic acid molecule is operatively linked to expression control sequences allowing expression in prokaryotic or eukaryotic host cells.

6. A process for producing a host cell comprising genetically engineering a cell with the nucleic acid molecule of any one of claims 1 to 3, or the vector of claim 4 or 5.

7. A host cell genetically engineered to contain the nucleic acid molecule according to any one of claims 1 to 3, or with the vector according to claim 4 or 5, or produced by the process according to claim 6.

8. The host cell of claim 7, wherein said host cell expresses a polypeptide encoded by the nucleic acid molecule of any one of claims 1 to 3.

9. A host cell genetically engineered to contain the nucleic acid molecule according to any one of claims 1 to 3 operatively associated with a heterologous regulatory control sequence that controls gene expression.

10. A process for producing a polypeptide encoded by the nucleic acid molecule of any one of claims 1 to 3 comprising:
(a) culturing the host cell according to any one of claims 7 to 9 under conditions such that said polypeptide is expressed; and (b) recovering said polypeptide.

11. An isolated polypeptide comprising an amino acid sequence encoded by the nucleic acid molecule according to any one of claims 1 to 3, or produced by the process according to claim 10.

12. An isolated polypeptide comprising a polypeptide selected from:
(a) a polypeptide comprising amino acid residues 1 to 303 of SEQ ID NO:86;
(b) a polypeptide comprising amino acid residues 2 to 303 of SEQ ID NO:86;
(c) a polypeptide epitope of SEQ ID NO:86, wherein the polypeptide epitope comprises amino acid residues 55 to 62, 164 to 175 or 197 to 202 of SEQ ID
NO:86 and is for use in generation or selection of an antibody that specifically binds the polypeptide of SEQ ID NO:86;
(d) a polypeptide comprising amino acid residues 28 to 303 of SEQ ID NO:86;
or (e) a polypeptide comprising an amino acid sequence at least 90% identical to any one of the entire polypeptides specified in (a), (b) or (d), wherein the polypeptide has the same endothelial cell proliferation activity as a polypeptide having the amino acid sequence as set forth in SEQ ID NO:86.

13. The polypeptide of claim 11 or 12, wherein said polypeptide is post-translationally modified.

14. The polypeptide of claim 11 or 12, wherein said polypeptide is fused to a heterologous polypeptide, or coupled to polyethylene glycol.

15. An antibody that binds specifically to the polypeptide of any one of claims 11 to 13.

16. A process for determining the presence of the polypeptide according to any one of claims 11 to 13 comprising:
(a) contacting a sample obtained from a host with an antibody that specifically binds said polypeptide under conditions allowing for the binding of said antibody to said polypeptide; and (b) detecting the bound antibody;

thereby determining the presence or amount of expression of the polypeptide according to any one of claims 11 to 13 in the sample.

17. A nucleic acid comprising a nucleotide sequence complementary to the nucleotide sequence of the nucleic acid molecule according to claim 1, wherein said nucleic acid is for use as a probe to detect the nucleic acid molecule of claim 1.

18. A nucleic acid comprising a nucleic acid sequence that hybridizes to any one of the polynucleotides set forth in claim 1(a) to (c) under stringent hybrization conditions comprising an overnight incubation at 42°C in a solution comprising 50%
formamide, 5x SSC, 50mM sodium phosphate (pH7.6), 5x Denhardt's solution, 10% dextran sulfate and 20µg/ml denatured, sheared salmon sperm DNA, followed by washing in 0.1x SSC at 65°C, wherein said nucleic acid is for use as a probe to detect the nucleic acid molecule of claim 1.

19. A plasmid as deposited under ATCC Deposit No. 209224.

20. The antibody of claim 15, which is labeled.

21. The antibody of claim 15, wherein said polypeptide bound by said antibody is glycosylated.

22. The antibody of claim 15, wherein said antibody specifically binds to said polypeptide in a Western blot.

23. The antibody of claim 15, wherein said antibody specifically binds to said polypeptide in an ELISA.

24. A method of detecting a polypeptide comprising amino acid residues 1 to 303 of SEQ ID NO:86 in a biological sample comprising: (a) contacting the biological sample with the antibody or fragment thereof of claim 15; (b) allowing a complex to form between said polypeptide comprising amino acid residues 1 to 303 of SEQ ID
NO:86 and said antibody of claim 15; and, (c) detecting said complex.