Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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COMPOSITIONS AND METHODS FOR THE TREATMENT
AND DIAGNOSIS OF BREAST CANCER
TECHNICAL FIELD
The present invention relates generally to the detection and therapy of
breast cancer. The invention is more specifically related to nucleotide
sequences that are
preferentially expressed in breast tumor tissue and to polypeptides encoded by
such
nucleotide sequences. The nucleotide sequences and polypeptides may be used in
vaccines and pharmaceutical compositions for the prevention and treatment of
breast
cancer. The polypeptides may also be used for the production of compounds,
such as
to antibodies, useful for diagnosing and monitoring the progression of breast
cancer in a
patient.
BACKGROUND OF THE INVENTION
Breast cancer is a significant health problem for women in the United
States and throughout the world. Although advances have been made in detection
and
treatment of the disease, breast cancer remains the second leading cause of
cancer-related
deaths in women, affecting more than 180,000 women in the United States each
year.
For women in North America, the life-time odds of getting breast cancer are
now one in
eight.
No vaccine or other universally successful method for the prevention or
2o treatment of breast cancer is currently available. Management of the
disease currently
relies on a combination of early diagnosis (through routine breast screening
procedures)
and aggressive treatment, which may include one or more of a variety of
treatments such
as surgery, radiotherapy, chemotherapy and hormone therapy. The course of
treatment
for a particular breast cancer is often selected based on a variety of
prognostic
parameters, including an analysis of specific tumor markers. See, e.g., Porter-
Jordan and
Lippman, Breast Cancer 8:73-100 (1994). However, the use of established
markers
often leads to a result that is difficult to interpret, and the high mortality
observed in
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breast cancer patients indicates that improvements are needed in the
treatment, diagnosis
and prevention of the disease.
Accordingly, there is a need in the art for improved methods for therapy
and diagnosis of breast cancer. The present invention fulfills these needs and
further
provides other related advantages.
SUMMARY OF THE INVENTION
Briefly stated, the subject invention provides compositions and methods
for the diagnosis and therapy of breast cancer. In one aspect, isolated
polynucleotides are
provided, comprising (a) a nucleotide sequence preferentially expressed in
breast cancer
to tissue, relative to normal tissue; (b) a variant of such a sequence, as
defined below; or (c)
a nucleotide sequence encoding an epitope of a polypeptide encoded by at least
one of
the above sequences. In one embodiment, the isolated polynucleotide comprises
a
human endogenous retroviral sequence recited in SEQ ID NO:1. In other
embodiments,
the isolated polynucleotide comprises a sequence recited in any one of SEQ ID
NO: 3
26, 28-77, 142, 143, 146-152, 154-166, 168-176, 178-192, 194-198, 200-204,
206, 207,
209-214, 216, 218, 219, 221-240, 243-245, 247, 250, 251, 253, 255, 257-266,
268, 269,
271-273, 275, 276, 278, 280, 281, 284, 288, 291-298, 301-303, 307, 313, 314,
316 and
317.
In related embodiments, the isolated polynucleotide encodes an epitope of
2o a polypeptide, wherein the polypeptide is encoded by a nucleotide sequence
that: (a)
hybridizes to a sequence recited in any one of SEQ ID NO: 1, 3-26, 28-77, 142,
143,
146-152, 154-166, 168-176, 178-192, 194-198, 200-204, 206, 207, 209-214, 216,
218,
219, 221-240, 243-245, 247, 250, 251, 253, 255, 257-266, 268, 269, 271-273,
275, 276,
278, 280, 281, 284, 288, 291-298, 301-303, 307, 313, 314, 316 and 317 under
stringent
conditions; and (b) is at least 80% identical to a sequence recited in any one
of SEQ ID
NO: 1, 3-26, 28-77, 142, 143, 146-152, 154-166, 168-176, 178-192, 194-198, 200-
204,
206, 207, 209-214, 216, 218, 219, 221-240, 243-245, 247, 250, 251, 253, 255,
257-266,
268, 269, 271-273, 275, 276, 278, 280, 281, 284, 288, 291-298, 301-303, 307,
313, 314,
316 and 317.
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In another embodiment, the present invention provides an isolated
polynucleotide encoding an epitope of a polypeptide, the polypeptide being
encoded by:
(a) a nucleotide sequence transcribed from the sequence of SEQ ID NO: 141; or
(b) a
variant of said nucleotide sequence that contains one or more nucleotide
substitutions,
deletions, insertions and/or modifications at no more than 20% of the
nucleotide
positions, such that the antigenic and/or immunogenic properties of the
polypeptide
encoded by the nucleotide sequence are retained. Isolated DNA and RNA
molecules
comprising a nucleotide sequence complementary to a polynucleotide as
described above
are also provided.
to In related aspects, the present invention provides recombinant expression
vectors comprising a polynucleotide as described above and host cells
transformed or
transfected with such expression vectors.
In further aspects, polypeptides comprising an amino acid sequence
encoded by a polynucleotide as described above, and monoclonal antibodies that
bind to
such polypeptides are provided. In certain embodiments, the inventive
polypeptides
comprise an amino acid sequence selected from the group consisting of SEQ ID
NO:
299, 300, 304-306, 308 and 315, and variants thereof as defined below.
In yet another aspect, methods are provided for determining the presence
of breast cancer in a patient. In one embodiment, the method comprises
detecting, within
2o a biological sample, a polypeptide as described above. In another
embodiment, the
method comprises detecting, within a biological sample, an RNA molecule
encoding a
polypeptide as described above. In yet another embodiment, the method
comprises (a)
intradermally injecting a patient with a polypeptide as described above; and
(b) detecting
an immune response on the patient's skin and therefrom detecting the presence
of breast
cancer in the patient. In further embodiments, the present invention provides
methods
for determining the presence of breast cancer in a patient as described above
wherein the
polypeptide is encoded by a nucleotide sequence selected from the group
consisting of
SEQ ID NO: 78-86, 144, 145, 153, 167, 177, 193, 199, 205, 208, 215, 217, 220,
241,
242, 246, 248, 249, 252, 256, 267, 270, 274, 277, 279, 282, 283, 285-287, 289,
290 and
3o sequences that hybridize thereto under stringent conditions.
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In a related aspect, diagnostic kits useful in the determination of breast
cancer are provided. The diagnostic kits generally comprise either one or more
monoclonal antibodies as described above, or one or more monoclonal antibodies
that
bind to a polypeptide encoded by a nucleotide sequence selected from the group
consisting of sequences provided in SEQ ID NO: 78-86, 144, 145, 153, 167, 177,
193,
199, 205, 208, 215, 217, 220, 241, 242 and 246, 248, 249, 252, 256, 267, 270,
274, 277,
279, 282, 283, 285-287, 289, 290 and a detection reagent.
Diagnostic kits are also provided that comprise a first polymerise chain
reaction primer and a second polymerise chain reaction primer, at least one of
the
1 o primers being specific for a polynucleotide described herein. In one
embodiment, at
least one of the primers comprises at least about 10 contiguous nucleotides of
a
polynucleotide as described above, or a polynucleotide encoding a polypeptide
encoded
by a sequence selected from the group consisting of SEQ ID NO: 78-86, 144,
145, 153,
167, 177, 193, 199, 205, 208, 215, 217, 220, 241, 242 246, 248, 249, 252, 256,
267, 270,
274, 277, 279, 282, 283, 285-287, 289 and 290.
Within another related aspect, the diagnostic kit comprises at least one
oligonucleotide probe, the probe being specific for a polynucleotide described
herein. In
one embodiment, the probe comprises at least about 15 contiguous nucleotides
of a
polynucleotide as described above, or a polynucleotide selected from the group
2o consisting of SEQ ID NO: 78-86, 144, 145, 153, 167, 177, 193, 199, 205,
208, 215, 217,
220, 241, 242 246, 248, 249, 252, 256, 267, 270, 274, 277, 279, 282, 283, 285-
287, 289
and 290.
In another related aspect, the present invention provides methods for
monitoring the progression of breast cancer in a patient. In one embodiment,
the method
comprises: (a) detecting an amount, in a biological sample, of a polypeptide
as described
above at a first point in time; (b) repeating step (a) at a subsequent point
in time; and (c)
comparing the amounts of polypeptide detected in steps (a) and (b), and
therefrom
monitoring the progression of breast cancer in the patient. In another
embodiment, the
method comprises (a) detecting an amount, within a biological sample, of an
RNA
3o molecule encoding a polypeptide as described above at a first point in
time; (b) repeating
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step (a) at a subsequent point in time; and (c) comparing the amounts of RNA
molecules
detected in steps (a) and (b), and therefrom monitoring the progression of
breast cancer
in the patient. In yet other embodiments, the present invention provides
methods for
monitoring the progression of breast cancer in a patient as described above
wherein the
5 polypeptide is encoded by a nucleotide sequence selected from the group
consisting of
SEQ ID NO: 78-86, 144, 145, 153, 167, 177, 193, 199, 205, 208, 215, 217, 220,
241,
242, 246, 248, 249, 252, 256, 267, 270, 274, 277, 279, 282, 283, 285-287, 289,
290 and
sequences that hybridize thereto under stringent conditions.
In still other aspects, pharmaceutical compositions, which comprise a
polypeptide as described above in combination with a physiologically
acceptable carrier,
and vaccines, which comprise a polypeptide as described above in combination
with an
immunostimulant or adjuvant, are provided. In yet other aspects, the present
invention
provides pharmaceutical compositions and vaccines comprising a polypeptide
encoded
by a nucleotide sequence selected from the group consisting of SEQ ID NO: 78-
86, 144,
145, 153, 167, 177, 193, 199, 205, 208, 215, 217, 220, 241, 242 and 246, 248,
249, 252,
256, 267, 270, 274, 277, 279, 282, 283, 285-287, 289, 290 and sequences that
hybridize
thereto under stringent conditions.
In related aspects, the present invention provides methods for inhibiting
the development of breast cancer in a patient, comprising administering to a
patient a
2o pharmaceutical composition or vaccine as described above.
These and other aspects of the present invention will become apparent
upon reference to the following detailed description and attached drawings.
All
references disclosed herein are hereby incorporated by reference in their
entirety as if
each was incorporated individually.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the differential display PCR products, separated by gel
electrophoresis, obtained from cDNA prepared from normal breast tissue (lanes
1 and 2)
and from cDNA prepared from breast tumor tissue from the same patient (lanes 3
and 4).
The arrow indicates the band corresponding to Bl8Agl.
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Figure 2 is a northern blot comparing the level of BlBAgI mRNA in
breast tumor tissue (lane 1 ) with the level in normal breast tissue.
Figure 3 shows the level of B18Ag1 mRNA in breast tumor tissue
compared to that in various normal and non-breast tumor tissues as determined
by RNase
protection assays.
Figure 4 is a genomic clone map showing the location of additional
retroviral sequences obtained from ends of XbaI restriction digests (provided
in SEQ ID
N0:3 - SEQ ID NO:10) relative to B 18Ag 1.
Figures SA and SB show the sequencing strategy, genomic organization
1 o and predicted open reading frame for the retroviral element containing B
18Ag 1.
Figure 6 shows the nucleotide sequence of the representative breast
tumor-specific cDNA B 18Ag 1.
Figure 7 shows the nucleotide sequence of the representative breast
tumor-specific cDNA B17Ag1.
Figure 8 shows the nucleotide sequence of the representative breast
tumor-specific cDNA B 17Ag2.
Figure 9 shows the nucleotide sequence of the representative breast
tumor-specific cDNA B13Ag2a.
Figure 10 shows the nucleotide sequence of the representative breast
2o tumor-specific cDNA B 13Ag 1 b.
Figure 11 shows the nucleotide sequence of the representative breast
tumor-specific cDNA B 13Ag 1 a.
Figure 12 shows the nucleotide sequence of the representative breast
tumor-specific cDNA B 11 Ag 1.
Figure 13 shows the nucleotide sequence of the representative breast
tumor-specific cDNA B3CA3c.
Figure 14 shows the nucleotide sequence of the representative breast
tumor-specific cDNA B9CG1.
Figure 15 shows the nucleotide sequence of the representative breast
3o tumor-specific cDNA B9CG3.
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Figure 16 shows the nucleotide sequence of the representative breast
tumor-specific cDNA B2CA2.
Figure 17 shows the nucleotide sequence of the representative breast
tumor-specific cDNA B3CA1.
Figure 18 shows the nucleotide sequence of the representative breast
tumor-specific cDNA B3CA2.
Figure 19 shows the nucleotide sequence of the representative breast
tumor-specific cDNA B3CA3.
Figure 20 shows the nucleotide sequence of the representative breast
1o tumor-specific cDNA B4CA1.
Figure 21A depicts RT-PCR analysis of breast tumor genes in breast
tumor tissues (lanes 1-8) and normal breast tissues (lanes 9-13) and H20 (lane
14).
Figure 21B depicts RT-PCR analysis of breast tumor genes in prostate
tumors (lane 1, 2), colon tumors (lane 3), lung tumor (lane 4), normal
prostate (lane 5),
normal colon (lane 6), normal kidney (lane 7), normal liver (lane 8), normal
lung (lane
9), normal ovary (lanes 10, 18), normal pancreases (lanes 11, 12), normal
skeletal muscle
(lane 13), normal skin (lane 14), normal stomach (lane 15), normal testes
(lane 16),
normal small intestine (lane 17), HBL-100 (lane 19), MCF-12A (lane 20), breast
tumors
(lanes 21-23), H20 (lane 24), and colon tumor (lane 25).
2o Figure 22 shows the recognition of a B 11 Ag 1 peptide (referred to as B 11-
8) by an anti-B11-8 CTL line.
Figure 23 shows the recognition of a cell line transduced with the antigen
B 11 Ag 1 by the B 11-8 specific clone A 1.
Figure 24 shows recognition of a lung adenocarcinoma line (LT-140-22)
and a breast adenocarcinoma line (CAMA-1) by the B11-8 specific clone A1.
DETAILED DESCRIPTION OF THE INVENTION
As noted above, the present invention is generally directed to
compositions and methods for the diagnosis. monitoring and therapy of breast
cancer.
The compositions described herein include polypeptides, polynucleotides and
antibodies.
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Polypeptides of the present invention generally comprise at least a portion of
a protein
that is expressed at a greater level in human breast tumor tissue than in
normal breast
tissue (i.e., the level of RNA encoding the polypeptide is at least 2-fold
higher in tumor
tissue). Such polypeptides are referred to herein as breast tumor-specific
polypeptides,
and cDNA molecules encoding such polypeptides are referred to as breast tumor-
specific
cDNAs. Polynucleotides of the subject invention generally comprise a DNA or
RNA
sequence that encodes all or a portion of a polypeptide as described above, or
that is
complementary to such a sequence. Antibodies are generally immune system
proteins,
or fragments thereof, that are capable of binding to a portion of a
polypeptide as
to described above. Antibodies can be produced by cell culture techniques,
including the
generation of monoclonal antibodies as described herein, or via transfection
of antibody
genes into suitable bacterial or mammalian cell hosts, in order to allow for
the production
of recombinant antibodies.
Polypeptides within the scope of this invention include, but are not
limited to, polypeptides (and epitopes thereof) encoded by a human endogenous
retroviral sequence, such as the sequence designated B 18Ag 1 (Figure 5 and
SEQ ID
NO:1 ). Also within the scope of the present invention are polypeptides
encoded by other
sequences within the retroviral genome containing B 18Ag 1 (SEQ ID NO: 141 ).
Such
sequences include, but are not limited to, the sequences recited in SEQ ID
N0:3 - SEQ
2o ID NO:10. B18Ag1 has homology to the gag p30 gene of the endogenous human
retroviral element 571, as described in Werner et al., Virology 174:225-238
(1990) and
also shows homology to about thirty other retroviral gag genes. As discussed m
more
detail below, the present invention also includes a number of additional
breast tumor-
specific polypeptides, such as those encoded by the nucleotide sequences
recited in SEQ
ID NO: 11-26, 28-77, 142, 143, 146-152, 154-166, 168-176, 178-192, 194-198,
200-204,
206, 207, 209-214, 216, 218, 219, 221-240, 243-245, 247, 250, 251, 253, 255,
257-266,
268, 269, 271-273, 275, 276, 278, 280, 281, 284, 288, 291-298, 301-303, 307,
313, 314,
316 and 317.
As used herein, the term "polypeptide" encompasses amino acid chains of
3o any length, including full length proteins containing the sequences recited
herein. A
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polypeptide comprising an epitope of a protein containing a sequence as
described herein
may consist entirely of the epitope, or may contain additional sequences. The
additional
sequences may be derived from the native protein or may be heterologous, and
such
sequences may (but need not) possess immunogenic or antigenic properties.
An "epitope," as used herein is a portion of a polypeptide that is
recognized (i.e., specifically bound) by a B-cell and/or T-cell surface
antigen receptor.
Epitopes may generally be identified using well known techniques, such as
those
summarized in Paul, Fundamental Immunology, 3rd ed., 243-247 (Raven Press,
1993)
and references cited therein. Such techniques include screening polypeptides
derived
to from the native polypeptide for the ability to react with antigen-specific
antisera and/or
T-cell lines or clones. An epitope of a polypeptide is a portion that reacts
with such
antisera and/or T-cells at a level that is similar to the reactivity of the
full length
polypeptide (e.g., in an ELISA and/or T-cell reactivity assay). Such screens
may
generally be performed using methods well known to those of ordinary skill in
the art,
such as those described in Harlow and Lane, Antibodies: A Laboratory Manual,
Cold
Spring Harbor Laboratory, 1988. B-cell and T-cell epitopes may also be
predicted via
computer analysis. Polypeptides comprising an epitope of a polypeptide that is
preferentially expressed in a tumor tissue (with or without additional amino
acid
sequence) are within the scope of the present invention.
The term "polynucleotide(s)," as used herein, means a single or double-
stranded polymer of deoxyribonucleotide or ribonucleotide bases and includes
DNA and
corresponding RNA molecules, including HnRNA and mRNA molecules, both sense
and
anti-sense strands, and comprehends cDNA, genomic DNA and recombinant DNA, as
well as wholly or partially synthesized polynucleotides. An HnRNA molecule
contains
introns and corresponds to a DNA molecule in a generally one-to-one manner. An
mRNA molecule corresponds to an HnRNA and DNA molecule from which the introns
have been excised. A polynucleotide may consist of an entire gene, or any
portion
thereof. Operable anti-sense polynucleotides may comprise a fragment of the
corresponding polynucleotide, and the definition of "polynucleotide" therefore
includes
3o all such operable anti-sense fragments.
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The compositions and methods of the present invention also encompass
variants of the above polypeptides and polynucleotides.
A polypeptide "variant," as used herein, is a polypeptide that differs from
the recited polypeptide only in conservative substitutions and/or
modifications, such that
5 the antigenic properties of the polypeptide are retained. In a preferred
embodiment,
variant polypeptides differ from an identified sequence by substitution,
deletion or
addition of five amino acids or fewer. Such variants may generally be
identified by
modifying one of the above polypeptide sequences, and evaluating the antigenic
properties of the modified polypeptide using, for example, the representative
procedures
to described herein. Polypeptide variants preferably exhibit at least about
70%, more
preferably at least about 90% and most preferably at least about 95% identity
(determined as described below) to the identified polypeptides.
As used herein, a "conservative substitution" is one in which an amino
acid is substituted for another amino acid that has similar properties, such
that one skilled
in the art of peptide chemistry would expect the secondary structure and
hydropathic
nature of the polypeptide to be substantially unchanged. In general, the
following groups
of amino acids represent conservative changes: (1) ala, pro, gly, glu, asp,
gln, asn, ser,
thr; (2) cys, ser, tyr, thr; (3) val, ile, leu, met, ala, phe; (4) lys, arg,
his; and (5) phe, tyr,
trp, his.
2o Variants may also, or alternatively, contain other modifications, including
the deletion or addition of amino acids that have minimal influence on the
antigenic
properties, secondary structure and hydropathic nature of the polypeptide. For
example,
a polypeptide may be conjugated to a signal (or leader) sequence at the N-
terminal end of
the protein which co-translationally or post-translationally directs transfer
of the protein.
The polypeptide may also be conjugated to a linker or other sequence for ease
of
synthesis, purification or identification of the polypeptide (e.g., poly-His),
or to enhance
binding of the polypeptide to a solid support. For example, a polypeptide may
be
conjugated to an immunoglobulin Fc region.
A nucleotide "variant" is a sequence that differs from the recited
nucleotide sequence in having one or more nucleotide deletions, substitutions
or
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additions. Such modifications may be readily introduced using standard
mutagenesis
techniques, such as oligonucleotide-directed site-specific mutagenesis as
taught, for
example, by Adelman et al. (DNA, 2:183, 1983). Nucleotide variants may be
naturally
occurring allelic variants, or non-naturally occurring variants. Variant
nucleotide
sequences preferably exhibit at least about 70%, more preferably at least
about 80% and
most preferably at least about 90% identity (determined as described below) to
the
recited sequence.
The breast tumor antigens provided by the present invention include
variants that are encoded by DNA sequences which are substantially homologous
to one
or more of the DNA sequences specifically recited herein. "Substantial
homology," as
used herein, refers to DNA sequences that are capable of hybridizing under
moderately
stringent conditions. Suitable moderately stringent conditions include
prewashing in a
solution of 5X SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridizing at 50°C-
65°C, 5X
SSC, overnight or, in the event of cross-species homology, at 45°C with
0.5X SSC;
followed by washing twice at 65°C for 20 minutes with each of 2X, 0.5X
and 0.2X SSC
containing 0.1% SDS. Such hybridizing DNA sequences are also within the scope
of
this invention, as are nucleotide sequences that, due to code degeneracy,
encode an
immunogenic polypeptide that is encoded by a hybridizing DNA sequence.
Two nucleotide or polypeptide sequences are said to be "identical" if the
2o sequence of nucleotides or amino acid residues in the two sequences is the
same when
aligned for maximum correspondence as described below. Comparisons between two
sequences are typically performed by comparing the sequences over a comparison
window to identify and compare local regions of sequence similarity. A
"comparison
window" as used herein, refers to a segment of at least about 20 contiguous
positions,
usually 30 to about 75, 40 to about 50, in which a sequence may be compared to
a
reference sequence of the same number of contiguous positions after the two
sequences
are optimally aligned.
Optimal alignment of sequences for comparison may be conducted using
the Megalign program in the Lasergene suite of bioinformatics software
(DNASTAR,
3o Inc., Madison, WI), using default parameters. This program embodies several
alignment
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schemes described in the following references: Dayhoff, M.O. (1978) A model of
evolutionary change in proteins - Matrices for detecting distant
relationships. In
Dayhoff, M.O. (ed.) Atlas of Protein Sequence and Structure, National
Biomedical
Resarch Foundaiton, Washington DC Vol. 5, Suppl. 3, pp. 345-358; Hein J.
(1990)
Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology
vol. 183, Academic Press, Inc., San Diego, CA; Higgins, D.G. and Sharp, P.M.
(1989)
Fast and sensitive multiple sequence alignments on a microcomputer CABIOS
5:151-
153; Myers, E.W. and Muller W. (1988) Optimal alignments in linear space
CABIOS
4:11-17; Robinson, E.D. (1971) Comb. Theor 11:105; Santou, N. Nes, M. (1987)
The
to neighbor joining method. A new method for reconstructing phylogenetic trees
Mol. Biol.
Evol. 4:406-425; Sneath, P.H.A. and Sokal, R.R. (1973) Numerical Taxonomy -
the
Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco,
CA;
Wilbur, W.J. and Lipman, D.J. (1983) Rapid similarity searches of nucleic acid
and
protein data banks Proc. Natl. Acad., Sci. USA 80:726-730.
Preferably, the "percentage of sequence identity" is
determined by comparing two optimally aligned sequences over a window of
comparison
of at least 20 positions, wherein the portion of the polynucleotide sequence
in the
comparison window may comprise additions or deletions (i.e. gaps) of 20
percent or less,
usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference
sequences
(which does not comprise additions or deletions) for optimal alignment of the
two
sequences. The percentage is calculated by determining the number of positions
at which
the identical nucleic acid bases or amino acid residue occurs in both
sequences to yield
the number of matched positions, dividing the number of matched positions by
the total
number of positions in the reference sequence (i.e. the window size) and
multiplying the
results by 100 to yield the percentage of sequence identity. In general,
polynucleotides
encoding all or a portion of the polypeptides described herein may be prepared
using any
of several techniques. For example, cDNA molecules encoding such polypeptides
may
be cloned on the basis of the breast tumor-specific expression of the
corresponding
mRNAs, using differential display PCR. This technique compares the amplified
3o products from RNA template prepared from normal and breast tumor tissue.
cDNA may
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be prepared by reverse transcription of RNA using a (dT),ZAG primer. Following
amplification of the cDNA using a random primer, a band corresponding to an
amplified
product specific to the tumor RNA may- be cut out from a silver stained gel
and
subcloned into a suitable vector (e.g., the T-vector, Novagen, Madison, WI).
Polynucleotides encoding all or a portion of the breast tumor-specific
polypeptides
disclosed herein may be amplified from cDNA prepared as described above using
the
random primers shown in SEQ ID N0.:87-125.
Alternatively, a polynucleotide encoding a polypeptide as described
herein (or a portion thereof) may be amplified from human genomic DNA, or from
breast
i o tumor cDNA, via polymerase chain reaction. For this approach, B 18Ag 1
sequence-
specific primers may be designed based on the sequence provided in SEQ ID
NO:l, and
may be purchased or synthesized. One suitable primer pair for amplification
from breast
tumor cDNA is (5'ATG GCT ATT TTC GGG GGC TGA CA) (SEQ ID N0:126) and
(5'CCG GTA TCT CCT CGT GGG TAT T) (SEQ ID N0:127). An amplified portion of
B 18Ag 1 may then be used to isolate the full length gene from a human genomic
DNA
library or from a breast tumor cDNA library, using well known techniques, such
as those
described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold
Spring
Harbor Laboratories, Cold Spring Harbor, NY (1989). Other sequences within the
retroviral genome of which Bl8Agl is a part may be similarly prepared by
screening
2o human genomic libraries using B18Ag1-specific sequences as probes.
Nucleotides
translated into protein from the retroviral genome shown in SEQ ID NO: 141 may
then
be determined by cloning the corresponding cDNAs, predicting the open reading
frames
and cloning the appropriate cDNAs into a vector containing a viral promoter,
such as T7.
The resulting constructs can be employed in a translation reaction, using
techniques
known to those of skill in the art, to identify nucleotide sequences which
result in
expressed protein. Similarly, primers specific for the remaining breast tumor-
specific
polypeptides described herein may be designed based on the nucleotide
sequences
provided in SEQ ID NO:11-86, 142-298, 301-303, 307, 313, 314, 316 and 317.
Recombinant polypeptides encoded by the DNA sequences described
3o above may be readily prepared from the DNA sequences. For example,
supernatants
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14
from suitable host/vector systems which secrete recombinant protein or
polypeptide into
culture media may be first concentrated using a commercially available filter.
Following
concentration, the concentrate may be applied to a suitable purification
matrix such as an
affinity matrix or an ion exchange resin. Finally, one or more reverse phase
HPLC steps
can be employed to further purify a recombinant polypeptide.
In general, any of a variety of expression vectors known to those of
ordinary skill in the art may be employed to express recombinant polypeptides
of this
invention. Expression may be achieved in any appropriate host cell that has
been
transformed or transfected with an expression vector containing a
polynucleotide that
to encodes a recombinant polypeptide. Suitable host cells include prokaryotes,
yeast and
higher eukaryotic cells. Preferably, the host cells employed are E. coli,
yeast or a
mammalian cell line such as COS or CHO.
Such techniques may also be used to prepare polypeptides comprising
epitopes or variants of the native polypeptides. For example, variants of a
native
polypeptide may generally be prepared using standard mutagenesis techniques,
such as
oligonucleotide-directed site-specific mutagenesis, and sections of the DNA
sequence
may be removed to permit preparation of truncated polypeptides. Portions and
other
variants having fewer than about 100 amino acids, and generally fewer than
about 50
amino acids, may also be generated by synthetic means, using techniques well
known to
2o those of ordinary skill in the art. For example, such polypeptides may be
synthesized
using any of the commercially available solid-phase techniques, such as the
Merrifield
solid-phase synthesis method, where amino acids are sequentially added to a
growing
amino acid chain. See Merrifield, J. Am. Chem. Soc. 85:2149-2146 (1963).
Equipment
for automated synthesis of polypeptides is commercially available from
suppliers such as
Perkin Elmer/Applied BioSystems Division,, Foster City, CA, and may be
operated
according to the manufacturer's instructions.
In specific embodiments, polypeptides of the present invention encompass
amino acid sequences encoded by a polynucleotide having a sequence recited in
any one
of SEQ ID NO:1, 3-26, 28-77, 142, 143, 146-152, 154-166, 168-176, 178-192, 194-
198,
200-204, 206, 207, 209-214, 216, 218, 219, 221-240, 243-245, 247, 250, 251,
253, 255,
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257-266, 268, 269, 271-273, 275, 276, 278, 280, 281, 284, 288, 291-298, 301-
303, 307,
313, 314, 316 and 317, and variants of such polypeptides. Polypeptides within
the scope
of the present invention also include polypeptides (and epitopes thereof)
encoded by
DNA sequences that hybridize to a sequence recited in any one of SEQ ID NO:1,
3-26,
s 28-77, 142, 143, 146-152, 154-166, 168-176, 178-192, 194-198, 200-204, 206,
207, 209-
214, 216, 218, 219, 221-240, 243-245, 247, 250, 251, 253, 255, 257-266, 268,
269, 271-
273, 275, 276, 278, 280, 281, 284, 288, 291-298, 301-303, 307, 313, 314, 316
and 317
under stringent conditions, wherein the DNA sequences are at least 80%
identical in
overall sequence to a recited sequence and wherein RNA corresponding to the
nucleotide
to sequence is expressed at a greater level in human breast tumor tissue than
in normal
breast tissue. As used herein, "stringent conditions" refers to prewashing in
a solution of
6X SSC, 0.2% SDS; hybridizing at 65°C, 6X SSC, 0.2% SDS overnight;
followed by
two washes of 30 minutes each in 1X SSC, 0.1% SDS at 65°C and two
washes of 30
minutes each in 0.2 X SSC, 0.1% SDS at 65°C. Polynucleotides according
to the present
15 invention include molecules that encode any of the above polypeptides.
In another aspect of the present invention, antibodies are provided. Such
antibodies may be prepared by any of a variety of techniques known to those of
ordinary
skill in the art. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual,
Cold
Spring Harbor Laboratory, 1988. In one such technique, an immunogen comprising
the
2o polypeptide is initially injected into any of a wide variety of mammals
(e.g., mice, rats,
rabbits, sheep or goats). In this step, the polypeptides of this invention may
serve as the
immunogen without modification. Alternatively, particularly for relatively
short
polypeptides, a superior immune response may be elicited if the polypeptide is
joined to
a carrier protein, such as bovine serum albumin or keyhole limpet hemocyanin.
The
immunogen is injected into the animal host, preferably according to a
predetermined
schedule incorporating one or more booster immunizations, and the animals are
bled
periodically. Polyclonal antibodies specific for the polypeptide may then be
purified
from such antisera by, for example, affinity chromatography using the
polypeptide
coupled to a suitable solid support.
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16
Monoclonal antibodies specific for the antigenic polypeptide of interest
may be prepared, for example, using the technique of Kohler and Milstein, Eur.
J.
Immunol. 6:511-519 ( 1976), and improvements thereto. Briefly, these methods
involve
the preparation of immortal cell lines capable of producing antibodies having
the desired
specificity (i.e., reactivity with the polypeptide of interest). Such cell
lines may be
produced, for example, from spleen cells obtained from an animal immunized as
described above. The spleen cells are then immortalized by, for example,
fusion with a
myeloma cell fusion partner, preferably one that is syngeneic with the
immunized
animal. A variety of fusion techniques may be employed. For example, the
spleen cells
1 o and myeloma cells may be combined with a nonionic detergent for a few
minutes and
then plated at low density on a selective medium that supports the growth of
hybrid cells,
but not myeloma cells. A preferred selection technique uses HAT (hypoxanthine,
aminopterin, thymidine) selection. After a sufficient time, usually about 1 to
2 weeks,
colonies of hybrids are observed. Single colonies are selected and their
culture
supernatants tested for binding activity against the polypeptide. Hybridomas
having high
reactivity and specificity are preferred.
Monoclonal antibodies may be isolated from the supernatants of growing
hybridoma colonies. In addition, various techniques may be employed to enhance
the
yield, such as injection of the hybridoma cell line into the peritoneal cavity
of a suitable
2o vertebrate host, such as a mouse. Monoclonal antibodies may then be
harvested from the
ascites fluid or the blood. Contaminants may be removed from the antibodies by
conventional techniques, such as chromatography, gel filtration,
precipitation, and
extraction. The polypeptides of this invention may be used in the purification
process in,
for example, an affinity chromatography step.
Antibodies may be used, for example, in methods for detecting breast
cancer in a patient. Such methods involve using an antibody to detect the
presence or
absence of a breast tumor-specific polypeptide as described herein in a
suitable biological
sample. As used herein, suitable biological samples include tumor or normal
tissue
biopsy, mastectomy, blood, lymph node, serum or urine samples, or other
tissue,
3o homogenate, or extract thereof obtained from a patient.
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17
There are a variety of assay formats known to those of ordinary skill in
the art for using an antibody to detect polypeptide markers in a sample. See,
e.g., Harlow
and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory,
1988. For
example, the assay may be performed in a Western blot format, wherein a
protein
preparation from the biological sample is submitted to gel electrophoresis,
transferred to
a suitable membrane and allowed to react with the antibody. The presence of
the
antibody on the membrane may then be detected using a suitable detection
reagent, as
described below.
In another embodiment, the assay involves the use of antibody
1 o immobilized on a solid support to bind to the polypeptide and remove it
from the
remainder of the sample. The bound polypeptide may then be detected using a
second
antibody or reagent that contains a reporter group. Alternatively, a
competitive assay
may be utilized, in which a polypeptide is labeled with a reporter group and
allowed to
bind to the immobilized antibody after incubation of the antibody with the
sample. The
extent to which components of the sample inhibit the binding of the labeled
polypeptide
to the antibody is indicative of the reactivity of the sample with the
immobilized
antibody, and as a result, indicative of the concentration of polypeptide in
the sample.
The solid support may be any material known to those of ordinary skill in
the art to which the antibody may be attached. For example, the solid support
may be a
2o test well in a microtiter plate or a nitrocellulose filter or other
suitable membrane.
Alternatively, the support may be a bead or disc, such as glass, fiberglass,
latex or a
plastic material such as polystyrene or polyvinylchloride. The support may
also be a
magnetic particle or a fiber optic sensor, such as those disclosed, for
example, in U.S.
Patent No. 5,359,681.
The antibody may be immobilized on the solid support using a variety of
techniques known to those in the art, which are amply described in the patent
and
scientific literature. In the context of the present invention, the term
"immobilization"
refers to both noncovalent association, such as adsorption, and covalent
attachment
(which may be a direct linkage between the antigen and functional groups on
the support
or may be a linkage by way of a cross-linking agent). Immobilization by
adsorption to a
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18
well in a microtiter plate or to a membrane is preferred. In such cases,
adsorption may be
achieved by contacting the antibody, in a suitable buffer, with the solid
support for a
suitable amount of time. The contact time varies with temperature, but is
typically
between about 1 hour and 1 day. In general, contacting a well of a plastic
microtiter
plate (such as polystyrene or polyvinylchloride) with an amount of antibody
ranging
from about 10 ng to about 1 fig, and preferably about 100-200 ng, is
sufficient to
immobilize an adequate amount of polypeptide.
Covalent attachment of antibody to a solid support may also generally be
achieved by first reacting the support with a bifunctional reagent that will
react with both
1 o the support and a functional group, such as a hydroxyl or amino group, on
the antibody.
For example, the antibody may be covalently attached to supports having an
appropriate
polymer coating using benzoquinone or by condensation of an aldehyde group on
the
support with an amine and an active hydrogen on the binding partner (see,
e.g., Pierce
Immunotechnology Catalog and Handbook (1991) at A12-A13).
In certain embodiments, the assay for detection of polypeptide in a sample
is a two-antibody sandwich assay. This assay may be performed by first
contacting an
antibody that has been immobilized on a solid support, commonly the well of a
microtiter plate, with the biological sample, such that the polypeptide within
the sample
are allowed to bind to the immobilized antibody. Unbound sample is then
removed from
2o the immobilized polypeptide-antibody complexes and a second antibody
(containing a
reporter group) capable of binding to a different site on the polypeptide is
added. The
amount of second antibody that remains bound to the solid support is then
determined
using a method appropriate for the specific reporter group.
More specifically, once the antibody is immobilized on the support as
described above, the remaining protein binding sites on the support are
typically blocked.
Any suitable blocking agent known to those of ordinary skill in the art, such
as bovine
serum albumin or Tween 20TM (Sigma Chemical Co., St. Louis, MO). The
immobilized
antibody is then incubated with the sample, and polypeptide is allowed to bind
to the
antibody. The sample may be diluted with a suitable diluent, such as phosphate-
buffered
3o saline (PBS) prior to incubation. In general, an appropriate contact time
(i.e., incubation
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19
time) is that period of time that is sufficient to detect the presence of
polypeptide within a
sample obtained from an individual with breast cancer. Preferably, the contact
time is
sufficient to achieve a level of binding that is at least 95% of that achieved
at equilibrium
between bound and unbound polypeptide. Those of ordinary skill in the art will
recognize that the time necessary to achieve equilibrium may be readily
determined by
assaying the level of binding that occurs over a period of time. At room
temperature, an
incubation time of about 30 minutes is generally sufficient.
Unbound sample may then be removed by washing the solid support with
an appropriate buffer, such as PBS containing 0.1% Tween 20TM. The second
antibody,
1 o which contains a reporter group, may then be added to the solid support.
Preferred
reporter groups include enzymes (such as horseradish peroxidase), substrates,
cofactors,
inhibitors, dyes, radionuclides, luminescent groups, fluorescent groups and
biotin. The
conjugation of antibody to reporter group may be achieved using standard
methods
known to those of ordinary skill in the art.
The second antibody is then incubated with the immobilized antibody-
polypeptide complex for an amount of time sufficient to detect the bound
polypeptide.
An appropriate amount of time may generally be determined by assaying the
level of
binding that occurs over a period of time. Unbound second antibody is then
removed
and bound second antibody is detected using the reporter group. The method
employed
2o for detecting the reporter group depends upon the nature of the reporter
group. For
radioactive groups, scintillation counting or autoradiographic methods are
generally
appropriate. Spectroscopic methods may be used to detect dyes, luminescent
groups and
fluorescent groups. Biotin may be detected using avidin, coupled to a
different reporter
group (commonly a radioactive or fluorescent group or an enzyme). Enzyme
reporter
groups may generally be detected by the addition of substrate (generally for a
specific
period of time), followed by spectroscopic or other analysis of the reaction
products.
To determine the presence or absence of breast cancer, the signal detected
from the reporter group that remains bound to the solid support is generally
compared to
a signal that corresponds to a predetermined cut-off value established from
non-tumor
3o tissue. In one preferred embodiment, the cut-off value is the average mean
signal
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obtained when the immobilized antibody is incubated with samples from patients
without
breast cancer. In general, a sample generating a signal that is three standard
deviations
above the predetermined cut-off value may be considered positive for breast
cancer. In
an alternate preferred embodiment, the cut-off value is determined using a
Receiver
5 Operator Curve, according to the method of Sackett et al., Clinical
Epidemiology: A
Basic Science for Clinical Medicine, p. 106-7 (Little Brown and Co., 1985).
Briefly, in
this embodiment, the cut-off value may be determined from a plot of pairs of
true
positive rates (i.e., sensitivity) and false positive rates (100%-specificity)
that correspond
to each possible cut-off value for the diagnostic test result. The cut-off
value on the plot
to that is the closest to the upper left-hand corner (i.e., the value that
encloses the largest
area) is the most accurate cut-off value, and a sample generating a signal
that is higher
than the cut-off value determined by this method may be considered positive.
Alternatively, the cut-off value may be shifted to the left along the plot, to
minimize the
false positive rate, or to the right, to minimize the false negative rate. In
general, a sample
15 generating a signal that is higher than the cut-off value determined by
this method is
considered positive for breast cancer.
In a related embodiment, the assay is performed in a flow-through or strip
test format, wherein the antibody is immobilized on a membrane, such as
nitrocellulose.
In the flow-through test, the polypeptide within the sample bind to the
immobilized
2o antibody as the sample passes through the membrane. A second, labeled
antibody then
binds to the antibody-polypeptide complex as a solution containing the second
antibody
flows through the membrane. The detection of bound second antibody may then be
performed as described above. In the strip test format, one end of the
membrane to
which antibody is bound is immersed in a solution containing the sample. The
sample
migrates along the membrane through a region containing second antibody and to
the
area of immobilized antibody. Concentration of second antibody at the area of
immobilized antibody indicates the presence of breast cancer. Typically, the
concentration of second antibody at that site generates a pattern, such as a
line, that can
be read visually. The absence of such a pattern indicates a negative result.
In general,
3o the amount of antibody immobilized on the membrane is selected to generate
a visually
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21
discernible pattern when the biological sample contains a level of polypeptide
that would
be sufficient to generate a positive signal in the two-antibody sandwich
assay, in the
format discussed above. Preferably, the amount of antibody immobilized on the
membrane ranges from about 25 ng to about 1 fig, and more preferably from
about 50 ng
to about 1 ~,g. Such tests can typically be performed with a very small amount
of
biological sample.
The presence or absence of breast cancer in a patient may also be
determined by evaluating the level of mRNA encoding a breast tumor-specific
polypeptide as described herein within the biological sample (e.g., a biopsy,
mastectomy
1o and/or blood sample from a patient) relative to a predetermined cut-off
value. Such an
evaluation may be achieved using any of a variety of methods known to those of
ordinary
skill in the art such as, for example, in situ hybridization and amplification
by
polymerise chain reaction.
For example, polymerise chain reaction may be used to amplify
sequences from cDNA prepared from RNA that is isolated from one of the above
biological samples. Sequence-specific primers for use in such amplification
may be
designed based on the sequences provided in any one of SEQ ID NO: 1, 11-86,
142-298
301-303, 307, 313, 314, 316 and 317, and may be purchased or synthesized. In
the case
of B18Ag1, as noted herein, one suitable primer pair is B18Ag1-2 (5'ATG GCT
ATT
2o TTC GGG GGC TGA CA) (SEQ ID N0:126) and B18Ag1-3 (5'CCG GTA TCT CCT
CGT GGG TAT T) (SEQ ID N0:127). The PCR reaction products may then be
separated by gel electrophoresis and visualized according to methods well
known to
those of ordinary skill in the art. Amplification is typically performed on
samples
obtained from matched pairs of tissue (tumor and non-tumor tissue from the
same
individual) or from unmatched pairs of tissue (tumor and non-tumor tissue from
different
individuals). The amplification reaction is preferably performed on several
dilutions of
cDNA spanning two orders of magnitude. A two-fold or greater increase in
expression
in several dilutions of the tumor sample as compared to the same dilution of
the non-
tumor sample is considered positive.
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22
As used herein, the term "primer/probe specific for a polynucleotide"
means an oligonucleotide sequence that has at least about 80% identity,
preferably at
least about 90% and more preferably at least about 95%, identity to the
polynucleotide in
question, or an oligonucleotide sequence that is anti-sense to a sequence that
has at least
about 80% identity, preferably at least about 90% and more preferably at least
about
95%, identity to the polynucleotide in question. Primers and/or probes which
may be
usefully employed in the inventive diagnostic methods preferably have at least
about 10-
40 nucleotides. In a preferred embodiment, the polymerise chain reaction
primers
comprise at least about 10 contiguous nucleotides of a polynucleotide that
encodes one of
to the polypeptides disclosed herein or that is anti-sense to a sequence that
encodes one of
the polypeptides disclosed herein. Preferably, oligonucleotide probes for use
in the
inventive diagnostic methods comprise at least about 15 contiguous
oligonucleotides of a
polynucleotide that encodes one of the polypeptides disclosed herein or that
is anti-sense
to a sequence that encodes one of the polypeptides disclosed herein.
Techniques for both
PCR based assays and in situ hybridization assays are well known in the art.
Conventional RT-PCR protocols using agarose and ethidium bromide
staining, while important in defining gene specificity, do not lend themselves
to
diagnostic kit development because of the time and effort required in making
them
quantitative (i.e., construction of saturation and/or titration curves), and
their sample
2o throughput. This problem is overcome by the development of procedures such
as real
time RT-PCR which allows for assays to be performed in single tubes, and in
turn can be
modified for use in 96 well plate formats. Instrumentation to perform such
methodologies are available from Perkin Elmer/Applied Biosystems Division.
Alternatively, other high throughput assays using labeled probes (e.g.,
digoxygenin) in
combination with labeled (e.g., enzyme fluorescent, radioactive) antibodies to
such
probes can also be used in the development of 96 well plate assays.
In yet another method for determining the presence or absence of breast
cancer in a patient, one or more of the breast tumor-specific polypeptides
described may
be used in a skin test. As used herein, a "skin test" is any assay performed
directly on a
3o patient in which a delayed-type hypersensitivity (DTH) reaction (such as
swelling,
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23
reddening or dermatitis) is measured following intradermal injection of one or
more
polypeptides as described above. Such injection may be achieved using any
suitable
device sufficient to contact the polypeptide or polypeptides with dermal cells
of the
patient, such as a tuberculin syringe or 1 mL syringe. Preferably, the
reaction is
measured at least 48 hours after injection, more preferably 48-72 hours.
The DTH reaction is a cell-mediated immune response, which is greater in
patients that have been exposed previously to a test antigen (i. e., an
immunogenic portion
of a polypeptide employed, or a variant thereof). The response may measured
visually,
using a ruler. In general, a response that is greater than about 0.5 cm in
diameter,
1o preferably greater than about 5.0 cm in diameter, is a positive response,
indicative of
breast cancer.
The breast tumor-specific polypeptides described herein are preferably
formulated, for use in a skin test, as pharmaceutical compositions containing
at least one
polypeptide and a physiologically acceptable carrier, such as water, saline,
alcohol, or a
buffer. Such compositions typically contain one or more of the above
polypeptides in an
amount ranging from about 1 ~g to 100 fig, preferably from about 10 ~g to 50
~.g in a
volume of 0.1 mL. Preferably, the Garner employed in such pharmaceutical
compositions is a saline solution with appropriate preservatives, such as
phenol and/or
Tween 80TM
2o In other aspects of the present invention, the progression and/or response
to treatment of a breast cancer may be monitored by performing any of the
above assays
over a period of time, and evaluating the change in the level of the response
(i.e., the
amount of polypeptide or mRNA detected or, in the case of a skin test, the
extent of the
immune response detected). For example, the assays may be performed every
month to
every other month for a period of 1 to 2 years. In general, breast cancer is
progressing in
those patients in whom the level of the response increases over time. In
contrast, breast
cancer is not progressing when the signal detected either remains constant or
decreases
with time.
In further aspects of the present invention, the compounds described
3o herein may be used for the immunotherapy of breast cancer. In these
aspects, the
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24
compounds (which may be polypeptides, antibodies or polynucleotides) are
preferably
incorporated into pharmaceutical compositions or vaccines. Pharmaceutical
compositions comprise one or more such compounds and a physiologically
acceptable
carrier. Vaccines may comprise one or more such compounds in combination with
an
immunostimulant, such as an adjuvant or a liposome (into which the compound is
incorporated). An immunostimulant may be any substance that enhances or
potentiates
an immune response (antibody and/or cell-mediated) to an exogenous antigen.
Examples
of immunostimulants include adjuvants, biodegradable microspheres (e.g.,
polylactic
galactide) and liposomes (into which the compound is incorporated; see e.g.,
Fullerton,
to U.S. Patent No. 4,235,877). Vaccine preparation is generally described in,
for example,
M.F. Powell and M.J. Newman, eds., "Vaccine Design (the subunit and adjuvant
approach)," Plenum Press (NY, 1995). Pharmaceutical compositions and vaccines
within the scope of the present invention may also contain other compounds,
which may
be biologically active or inactive. For example, one or more immunogenic
portions of
other tumor antigens may be present, either incorporated into a fusion
polypeptide or as a
separate compound, within the composition or vaccine.
Alternatively, a vaccine may contain DNA encoding one or more of the
polypeptides as described above, such that the polypeptide is generated in
situ. In such
vaccines, the DNA may be present within any of a variety of delivery systems
known to
2o those of ordinary skill in the art, including nucleic acid expression
systems, bacteria and
viral expression systems. Appropriate nucleic acid expression systems contain
the
necessary DNA sequences for expression in the patient (such as a suitable
promoter and
terminating signal). Bacterial delivery systems involve the administration of
a bacterium
(such as Bacillus-Calmette-Guerrin) that expresses an immunogenic portion of
the
polypeptide on its cell surface. In a preferred embodiment, the DNA may be
introduced
using a viral expression system (e.g., vaccinia or other pox virus,
retrovirus, or
adenovirus), which may involve the use of a non-pathogenic (defective),
replication
competent virus. Techniques for incorporating DNA into such expression systems
are
well known to those of ordinary skill in the art. The DNA may also be "naked,"
as
3o described, for example, in Ulmer et al., Science 259:1745-1749 (1993), and
reviewed by
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Cohen, Science 259:1691-1692 (1993). The uptake of naked DNA may be increased
by
coating the DNA onto biodegradable beads, which are efficiently transported
into the
cells.
While any suitable carrier known to those of ordinary skill in the art may
5 be employed in the pharmaceutical compositions of this invention, the type
of carrier will
vary depending on the mode of administration. For parenteral administration,
such as
subcutaneous injection, the carrier preferably comprises water, saline,
alcohol, a fat, a
wax or a buffer. For oral administration, any of the above carriers or a solid
carrier, such
as mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum,
cellulose,
to glucose, sucrose, and magnesium carbonate, may be employed. Biodegradable
microspheres (e.g., polylactate polyglycolate) may also be employed as
carriers for the
pharmaceutical compositions of this invention.
Any of a variety of immunostimulants may be employed in the vaccines
of this invention. For example, an adjuvant may be included. Most adjuvants
contain a
15 substance designed to protect the antigen from rapid catabolism, such as
aluminum
hydroxide or mineral oil, and a stimulator of immune responses, such as lipid
A,
Bortadella pertussis or Mycobacterium tuberculosis derived proteins. Suitable
adjuvants
are commercially available as, for example, Freund's Incomplete Adjuvant and
Complete
Adjuvant (Difco Laboratories, Detroit, MI); Merck Adjuvant 65 (Merck and
Company,
2o Inc., Rahway, NJ); AS-2 (SmithKline Beecham, Philadelphia, PA); aluminum
salts such
as aluminum hydroxide gel (alum) or aluminum phosphate; salts of calcium, iron
or zinc;
an insoluble suspension of acylated tyrosine; acylated sugars; cationically or
anionically
derivatized polysaccharides; polyphosphazenes; biodegradable microspheres;
monophosphoryl lipid A and quil A. Cytokines, such as GM-CSF or interleukin-2,
-7, or
25 -12, may also be used as adjuvants.
Within the vaccines provided herein, the adjuvant composition is
preferably designed to induce an immune response predominantly of the Thl
type. High
levels of Thl-type cytokines (e.g., IFN-y, TNFa, IL-2 and IL-12) tend to favor
the
induction of cell mediated immune responses to an administered antigen. In
contrast,
3o high levels of Th2-type cytokines (e.g., IL-4, IL-~, IL-6 and IL-10) tend
to favor the
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26
induction of humoral immune responses. Following application of a vaccine as
provided
herein, a patient will support an immune response that includes Thl- and Th2-
type
responses. Within a preferred embodiment, in which a response is predominantly
Thl-
type, the level of Thl-type cytokines will increase to a greater extent than
the level of
Th2-type cytokines. The levels of these cytokines may be readily assessed
using
standard assays. For a review of the families of cytokines, see Mosmann and
Coffman,
Ann. Rev. Immunol. 7:145-173, 1989.
Preferred adjuvants for use in eliciting a predominantly Thl-type response
include, for example, a combination of monophosphoryl lipid A, preferably 3-de-
O-
1o acylated monophosphoryl lipid A (3D-MPL), together with an aluminum salt.
MPL
adjuvants are available from Corixa Corporation (Seattle, WA; see US Patent
Nos.
4,436,727; 4,877,611; 4,866,034 and 4,912,094). CpG-containing
oligonucleotides (in
which the CpG dinucleotide is unmethylated) also induce a predominantly Thl
response.
Such oligonucleotides are well known and are described, for example, in WO
96/02555
and WO 99/33488. Immunostimulatory DNA sequences are also described, for
example,
by Sato et al., Science 273:352, 1996. Another preferred adjuvant is a
saponin,
preferably QS21 (Aquila Biopharmaceuticals Inc., Framingham, MA), which may be
used alone or in combination with other adjuvants. For example, an enhanced
system
involves the combination of a monophosphoryl lipid A and saponin derivative,
such as
2o the combination of QS21 and 3D-MPL as described in WO 94/00153, or a less
reactogenic composition where the QS21 is quenched with cholesterol, as
described in
WO 96/33739. Other preferred formulations comprise an oil-in-water emulsion
and
tocopherol. A particularly potent adjuvant formulation involving QS21, 3D-MPL
and
tocopherol in an oil-in-water emulsion is described in WO 95/17210.
Other preferred adjuvants include Montanide ISA 720 (Seppic, France),
SAF (Chiron, California, United States), ISCOMS (CSL), MF-59 (Chiron), the
SBAS
series of adjuvants (e.g., SBAS-2 or SBAS-4, available from SmithKline
Beecham,
Rixensart, Belgium), Detox (Ribi ImmunoChem Research Inc., Hamilton, MT), RC-
529
(Ribi ImmunoChem Research Inc., Hamilton, MT) and Aminoalkyl glucosaminide 4-
3o phosphates (AGPs).
CA 02365909 2001-10-04
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27
Any vaccine provided herein may be prepared using well known methods
that result in a combination of antigen, immunostimulant and a suitable
carrier or
excipient. The compositions described herein may be administered as part of a
sustained
release formulation (i.e., a formulation such as a capsule, sponge or gel
(composed of
polysaccharides, for example) that effects a slow release of compound
following
administration). Such formulations may generally be prepared using well known
technology (see, e.g., Coombes et al., Vaccine 14:1429-1438, 1996) and
administered by,
for example, oral, rectal or subcutaneous implantation, or by implantation at
the desired
target site. Sustained-release formulations may contain a polypeptide,
polynucleotide or
1o antibody dispersed in a carrier matrix and/or contained within a reservoir
surrounded by
a rate controlling membrane.
Carriers for use within such formulations are biocompatible, and may also
be biodegradable; preferably the formulation provides a relatively constant
level of active
component release. Such carriers include microparticles of poly(lactide-co-
glycolide), as
well as polyacrylate, latex, starch, cellulose and dextran. Other delayed-
release carriers
include supramolecular biovectors, which comprise a non-liquid hydrophilic
core (e.g., a
cross-linked polysaccharide or oligosaccharide) and, optionally, an external
layer
comprising an amphiphilic compound, such as a phospholipid (see e.g., U.S.
Patent No.
5,151,254 and PCT applications WO 94/20078, WO/94/23701 and WO 96/06638). The
2o amount of active compound contained within a sustained release formulation
depends
upon the site of implantation, the rate and expected duration of release and
the nature of
the condition to be treated or prevented.
Any of a variety of delivery vehicles may be employed within
pharmaceutical compositions and vaccines to facilitate production of an
antigen-specific
immune response that targets tumor cells. Delivery vehicles include antigen
presenting
cells (APCs), such as dendritic cells, macrophages, B cells, monocytes and
other cells
that may be engineered to be efficient APCs. Such cells may, but need not, be
genetically modified to increase the capacity for presenting the antigen, to
improve
activation and/or maintenance of the T cell response, to have anti-tumor
effects per se
3o and/or to be immunologically compatible with the receiver (i.e., matched
HLA
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28
haplotype). APCs may generally be isolated from any of a variety of biological
fluids
and organs, including tumor and peritumoral tissues, and may be autologous,
allogeneic,
syngeneic or xenogeneic cells.
Certain preferred embodiments of the present invention use dendritic cells
or progenitors thereof as antigen-presenting cells. Dendritic cells are highly
potent APCs
(Banchereau and Steinman, Nature 392:245-251, 1998) and have been shown to be
effective as a physiological adjuvant for eliciting prophylactic or
therapeutic antitumor
immunity (see Timmerman and Levy, Ann. Rev. Med. 50:507-529, 1999). In
general,
dendritic cells may be identified based on their typical shape (stellate in
situ, with
to marked cytoplasmic processes (dendrites) visible in vitro), their ability
to take up,
process and present antigens with high efficiency and their ability to
activate naive T cell
responses. Dendritic cells may, of course, be engineered to express specific
cell-surface
receptors or ligands that are not commonly found on dendritic cells in vivo or
ex vivo,
and such modified dendritic cells are contemplated by the present invention.
As an
alternative to dendritic cells, secreted vesicles antigen-loaded dendritic
cells (called
exosomes) may be used within a vaccine (see Zitvogel et al., Nature Med. 4:594-
600,
1998).
Dendritic cells and progenitors may be obtained from peripheral blood,
bone marrow, tumor-infiltrating cells, peritumoral tissues-infiltrating cells,
lymph nodes,
2o spleen, skin, umbilical cord blood or any other suitable tissue or fluid.
For example,
dendritic cells may be differentiated ex vivo by adding a combination of
cytokines such
as GM-CSF, IL-4, IL-13 and/or TNFa to cultures of monocytes harvested from
peripheral blood. Alternatively, CD34 positive cells harvested from peripheral
blood,
umbilical cord blood or bone marrow may be differentiated into dendritic cells
by adding
to the culture medium combinations of GM-CSF, IL-3, TNFa, CD40 ligand, LPS,
flt3
ligand and/or other compounds) that induce differentiation, maturation and
proliferation
of dendritic cells.
Dendritic cells are conveniently categorized as "immature" and "mature"
cells, which allows a simple way to discriminate between two well
characterized
3o phenotypes. However, this nomenclature should not be construed to exclude
all possible
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intermediate stages of differentiation. Immature dendritic cells are
characterized as APC
with a high capacity for antigen uptake and processing, which correlates with
the high
expression of Fcy receptor and mannose receptor. The mature phenotype is
typically
characterized by a lower expression of these markers, but a high expression of
cell
surface molecules responsible for T cell activation such as class I and class
II MHC,
adhesion molecules (e.g., CD54 and CD11) and costimulatory molecules (e.g.,
CD40,
CD80, CD86 and 4-1BB).
APCs may generally be transfected with a polynucleotide encoding a
polypeptide of the present invention (or portion or other variant thereof)
such that the
to polypeptide, or an immunogenic portion thereof, is expressed on the cell
surface. Such
transfection may take place ex vivo, and a composition or vaccine comprising
such
transfected cells may then be used for therapeutic purposes, as described
herein.
Alternatively, a gene delivery vehicle that targets a dendritic or other
antigen presenting
cell may be administered to a patient, resulting in transfection that occurs
in vivo. In vivo
and ex vivo transfection of dendritic cells, for example, may generally be
performed
using any methods known in the art, such as those described in WO 97/24447, or
the
gene gun approach described by Mahvi et al., Immunology and cell Biology
75:456-460,
1997. Antigen loading of dendritic cells may be achieved by incubating
dendritic cells or
progenitor cells with the polypeptide, DNA (naked or within a plasmid vector)
or RNA;
or with antigen-expressing recombinant bacterium or viruses (e.g., vaccinia,
fowlpox,
adenovirus or lentivirus vectors). Prior to loading, the polypeptide may be
covalently
conjugated to an immunological partner that provides T cell help (e.g., a
carrier
molecule). Alternatively, a dendritic cell may be pulsed with a non-conjugated
immunological partner, separately or in the presence of the polypeptide.
Vaccines and pharmaceutical compositions may be presented in unit-dose
or mufti-dose containers, such as sealed ampoules or vials. Such containers
are
preferably hermetically sealed to preserve sterility of the formulation until
use. In
general, formulations may be stored as suspensions, solutions or emulsions in
oily or
aqueous vehicles. Alternatively, a vaccine or pharmaceutical composition may
be stored
3o in a freeze-dried condition requiring only the addition of a sterile liquid
carrier
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WO 00/61753 PCT/US00/09312
immediately prior to use.
The above pharmaceutical compositions and vaccines may be used, for
example, for the therapy of breast cancer in a patient. As used herein, a
"patient" refers
to any warm-blooded animal, preferably a human. A patient may or may not be
afflicted
5 with breast cancer. Accordingly, the above pharmaceutical compositions and
vaccines
may be used to prevent the development of breast cancer or to treat a patient
afflicted
with breast cancer. In a preferred embodiment, the compounds are administered
either
prior to or following surgical removal of primary tumors and/or treatment by
administration of radiotherapy and conventional chemotherapeutic drugs. To
prevent or
1o slow the development of breast cancer, a pharmaceutical composition or
vaccine
comprising one or more polypeptides as described herein may be administered to
a
patient. Alternatively, naked DNA or plasmid or viral vector encoding the
polypeptide
may be administered. For treating a patient with breast cancer, the
pharmaceutical
composition or vaccine may comprise one or more polypeptides, antibodies or
15 polynucleotides complementary to DNA encoding a polypeptide as described
herein
(e.g., antisense RNA or antisense deoxyribonucleotide oligonucleotides).
Routes and frequency of administration, as well as dosage, will vary from
individual to individual. In general, the pharmaceutical compositions and
vaccines may
be administered by injection (e.g., intracutaneous, intramuscular, intravenous
or
20 subcutaneous), intranasally (e.g., by aspiration) or orally. Between l and
10 doses may
be administered for a 52-week period. Preferably, 6 doses are administered, at
intervals
of 1 month, and booster vaccinations may be given periodically thereafter.
Alternate
protocols may be appropriate for individual patients. A suitable dose is an
amount of a
compound that, when administered as described above, is capable of promoting
an anti-
25 tumor immune response. Such response can be monitored by measuring the anti-
tumor
antibodies in a patient or by vaccine-dependent generation of cytolytic
effector cells
capable of killing the patient's tumor cells in vitro. Such vaccines should
also be capable
of causing an immune response that leads to an improved clinical outcome
(e.g., more
frequent remissions, complete or partial or longer disease-free survival) in
vaccinated
3o patients as compared to non-vaccinated patients. In general, for
pharmaceutical
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31
compositions and vaccines comprising one or more polypeptides, the amount of
each
polypeptide present in a dose ranges from about 100 qg to 5 mg. Suitable dose
sizes will
vary with the size of the patient, but will typically range from about 0.1 mL
to about 5
mL.
Polypeptides disclosed herein may also be employed in adoptive
immunotherapy for the treatment of cancer. Adoptive immunotherapy may be
broadly
classified into either active or passive immunotherapy. In active
immunotherapy,
treatment relies on the in vivo stimulation of the endogenous host immune
system to
react against tumors with the administration of immune response-modifying
agents (for
1o example, tumor vaccines, bacterial adjuvants, and/or cytokines).
In passive immunotherapy, treatment involves the delivery of biologic
reagents with established tumor-immune reactivity (such as effector cells or
antibodies)
that can directly or indirectly mediate antitumor effects and does not
necessarily depend
on an intact host immune system. Examples of effector cells include T
lymphocytes (for
example, CD8+ cytotoxic T-lymphocyte, CD4+ T-helper, tumor-infiltrating
lymphocytes), killer cells (Natural Killer cells, lymphokine-activated killer
cells), B
cells, or antigen presenting cells (such as dendritic cells and macrophages)
expressing the
disclosed antigens. The polypeptides disclosed herein may also be used to
generate
antibodies or anti-idiotypic antibodies (as in U.S. Patent No. 4,918,164), for
passive
2o immunotherapy.
The predominant method of procuring adequate numbers of T-cells for
adoptive immunotherapy is to grow immune T-cells in vitro. Culture conditions
for
expanding single antigen-specific T-cells to several billion in number with
retention of
antigen recognition in vivo are well known in the art. These in vitro culture
conditions
typically utilize intermittent stimulation with antigen, often in the presence
of cytokines,
such as IL-2, and non-dividing feeder cells. As noted above, the
immunoreactive
polypeptides described herein may be used to rapidly expand antigen-specific T
cell
cultures in order to generate sufficient number of cells for immunotherapy. In
particular,
antigen-presenting cells, such as dendritic, macrophage or B-cells, may be
pulsed with
3o immunoreactive polypeptides or transfected with a polynucleotide
sequence(s), using
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32
standard techniques well known in the art. For cultured T-cells to be
effective in
therapy, the cultured T-cells must be able to grow and distribute widely and
to survive
long term in vivo. Studies have demonstrated that cultured T-cells can be
induced to
grow in vivo and to survive long term in substantial numbers by repeated
stimulation
with antigen supplemented with IL-2 (see, for example, Cheever et al. Ibicl).
The polypeptides disclosed herein may also be employed to generate
and/or isolate tumor-reactive T-cells, which can then be administered to the
patient. In
one technique, antigen-specific T-cell lines may be generated by in vivo
immunization
with short peptides corresponding to immunogenic portions of the disclosed
to polypeptides. The resulting antigen specific CD8+ CTL clones may be
isolated from the
patient, expanded using standard tissue culture techniques, and returned to
the patient.
Alternatively, peptides corresponding to immunogenic portions of the
polypeptides may be employed to generate tumor reactive T cell subsets by
selective in
vitro stimulation and expansion of autologous T cells to provide antigen-
specific T cells
which may be subsequently transferred to the patient as described, for
example, by
Chang et al. (Crit. Rev. Oncol. Hematol., 22(3), 213, 1996).
In another embodiment, syngeneic or autologous dendritic cells may be
pulsed with peptides corresponding to at least an immunogenic portion of a
polypeptide
disclosed herein. The resulting antigen-specific dendritic cells may either be
transferred
2o into a patient, or employed to stimulate T cells to provide antigen-
specific T cells which
may, in turn, be administered to a patient. The use of peptide-pulsed
dendritic cells to
generate antigen-specific T cells and the subsequent use of such antigen-
specific T cells
to eradicate tumors in a marine model has been demonstrated by Cheever et al.
("Therapy With Cultured T Cells: Principles Revisited, " Irnmunological
Reviews,
2s 157:177, 1997).
Additionally vectors expressing the disclosed polynucleotides may be
introduced
into stem cells taken from the patient and clonally propagated in vitro for
autologous
transplant back into the same patient. In one embodiment, cells of the immune
system,
such as T cells, may be isolated from the peripheral blood of a patient, using
a
3o commercially available cell separation system, such as CellPro
Incorporated's (Bothell,
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33
WA) CEPRATE~ system (see U.S. Patent No. 5,240,856; U.S. Patent No. 5,215,926;
WO 89/06280; WO 91/16116 and WO 92/07243). The separated cells are stimulated
with one or more of the immunoreactive polypeptides contained within a
delivery
vehicle, such as a microsphere, to provide antigen-specific T cells. The
population of
tumor antigen-specific T cells is then expanded using standard techniques and
the cells
are administered back to the patient.
The following Examples are offered by way of illustration and not by way
of limitation.
to
EXAMPLES
EXAMPLE 1
PREPARATION OF BREAST TUMOR-SPECIFIC CDNAS USING
DIFFERENTIAL DISPLAY RT-PCR
This Example illustrates the preparation of cDNA molecules encoding
breast tumor-specific polypeptides using a differential display screen.
A. Preparation of B 18Ag 1 cDNA and Characterization of mRNA Expression
2o Tissue samples were prepared from breast tumor and normal tissue of a
patient with breast cancer that was confirmed by pathology after removal from
the
patient. Normal RNA and tumor RNA was extracted from the samples and mRNA was
isolated and converted into cDNA using a (dT),ZAG (SEQ ID N0:130) anchored 3'
primer. Differential display PCR was then executed using a randomly chosen
primer
(CTTCAACCTC) (SEQ ID N0:103). Amplification conditions were standard buffer
containing 1.5 mM MgCl2, 20 pmol of primer, 500 pmol dNTP, and 1 unit of Taq
DNA
polymerase (Perkin-Elmer, Branchburg, NJ). Forty cycles of amplification were
performed using 94°C denaturation for 30 seconds, 42°C annealing
for 1 minute, and 72°
C extension for 30 seconds. An RNA fingerprint containing 76 amplified
products was
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34
obtained. Although the RNA fingerprint of breast tumor tissue was over 98%
identical to
that of the normal breast tissue, a band was repeatedly observed to be
specific to the
RNA fingerprint pattern of the tumor. This band was cut out of a silver
stained gel,
subcloned into the T-vector (Novagen, Madison, WI) and sequenced.
The sequence of the cDNA, referred to as B l8Agl, is provided in SEQ ID
NO:1. A database search of GENBANK and EMBL revealed that the B 18Ag 1
fragment
initially cloned is 77% identical to the endogenous human retroviral element
571, which
is a truncated retroviral element homologous to the Simian Sarcoma Virus
(SSV). S71
contains an incomplete gag gene, a portion of the pol gene and an LTR-like
structure at
to the 3' terminus (see Werner et al., Virology 174:225-238 (1990)). B18Ag1 is
also 64%
identical to SSV in the region corresponding to the P30 (gag) locus. Bl8Agl
contains
three separate and incomplete reading frames covering a region which shares
considerable homology to a wide variety of gag proteins of retroviruses which
infect
mammals. In addition, the homology to S71 is not just within the gag gene, but
spans
several kb of sequence including an LTR.
B18Ag1-specific PCR primers were synthesized using computer analysis
guidelines. RT-PCR amplification (94°C, 30 seconds; 60°C -~
42°C, 30 seconds; 72°C,
30 seconds for 40 cycles) confirmed that B 18Ag 1 represents an actual mRNA
sequence
present at relatively high levels in the patient's breast tumor tissue. The
primers used in
2o amplification were B18Ag1-1 (CTG CCT GAG CCA CAA ATG) (SEQ ID N0:128) and
B18Ag1-4 (CCG GAG GAG GAA GCT AGA GGA ATA) (SEQ ID N0:129) at a
3.5 mM magnesium concentration and a pH of 8.5, and B18Ag1-2 (ATG GCT ATT TTC
GGG GCC TGA CA) (SEQ ID N0:126) and B18Ag1-3 (CCG GTA TCT CCT CGT
GGG TAT T) (SEQ ID N0:127) at 2 mM magnesium at pH 9.5. The same experiments
showed exceedingly low to nonexistent levels of expression in this patient's
normal
breast tissue (see Figure 1). RT-PCR experiments were then used to show that
B18Ag1
mRNA is present in nine other breast tumor samples (from Brazilian and
American
patients) but absent in, or at exceedingly low levels in, the normal breast
tissue
corresponding to each cancer patient. RT-PCR analysis has also shown that the
Bl8Agl
3o transcript is not present in various normal tissues (including lymph node,
myocardium
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
and liver) and present at relatively low levels in PBMC and lung tissue. The
presence of
B18Ag1 mRNA in breast tumor samples, and its absence from normal breast
tissue, has
been confirmed by Northern blot analysis, as shown in Figure 2.
The differential expression of B18Ag1 in breast tumor tissue was also
5 confirmed by RNase protection assays. Figure 3 shows the level of B18Ag1
mRNA in
various tissue types as determined in four different RNase protection assays.
Lanes 1-12
represent various normal breast tissue samples, lanes 13-25 represent various
breast
tumor samples; lanes 26-27 represent normal prostate samples; lanes 28-29
represent
prostate tumor samples; lanes 30-32 represent colon tumor samples; lane 33
represents
10 normal aorta; lane 34 represents normal small intestine; lane 35 represents
normal skin,
lane 36 represents normal lymph node; lane 37 represents normal ovary; lane 38
represents normal liver; lane 39 represents normal skeletal muscle; lane 40
represents a
first normal stomach sample, lane 41 represents a second normal stomach
sample; lane
42 represents a normal lung; lane 43 represents normal kidney; and lane 44
represents
15 normal pancreas. Interexperimental comparison was facilitated by including
a positive
control RNA of known (3-actin message abundance in each assay and normalizing
the
results of the different assays with respect to this positive control.
RT-PCR and Southern Blot analysis has shown the B 18Ag 1 locus to be
present in human genomic DNA as a single copy endogenous retroviral element. A
2o genomic clone of approximately 12-18 kb was isolated using the initial B
18Ag 1
sequence as a probe. Four additional subclones were also isolated by XbaI
digestion.
Additional retroviral sequences obtained from the ends of the XbaI digests of
these
clones (located as shown in Figure 4) are shown as SEQ ID N0:3 - SEQ ID NO:10,
where SEQ ID N0:3 shows the location of the sequence labeled 10 in Figure 4,
SEQ ID
25 N0:4 shows the location of the sequence labeled 11-29, SEQ ID NO:S shows
the
location of the sequence labeled 3, SEQ ID N0:6 shows the location of the
sequence
labeled 6, SEQ ID N0:7 shows the location of the sequence labeled 12, SEQ ID
N0:8
shows the location of the sequence labeled 13, SEQ ID N0:9 shows the location
of the
sequence labeled 14 and SEQ ID NO:10 shows the location of the sequence
labeled 11
30 22.
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36
Subsequent studies demonstrated that the 12-18 kb genomic clone
contains a retroviral element of about 7.75 kb, as shown in Figures SA and SB.
The
sequence of this retroviral element is shown in SEQ ID NO: 141. The numbered
line at
the top of Figure SA represents the sense strand sequence of the retroviral
genomic clone.
The box below this line shows the position of selected restriction sites. The
arrows
depict the different overlapping clones used to sequence the retroviral
element. The
direction of the arrow shows whether the single-pass subclone sequence
corresponded to
the sense or anti-sense strand. Figure SB is a schematic diagram of the
retroviral element
containing B18Ag1 depicting the organization of viral genes within the
element. The
open boxes correspond to predicted reading frames, starting with a methionine,
found
throughout the element. Each of the six likely reading frames is shown, as
indicated to
the left of the boxes, with frames 1-3 corresponding to those found on the
sense strand.
Using the cDNA of SEQ ID NO:1 as a probe, a longer cDNA was
obtained (SEQ ID N0:227) which contains minor nucleotide differences (less
than 1%)
compared to the genomic sequence shown in SEQ ID N0:141.
B. Preparation of cDNA Molecules Encoding~Other Breast Tumor-Specific
Polypeptides
Normal RNA and tumor RNA was prepared and mRNA was isolated and
converted into cDNA using a (dT),ZAG anchored 3' primer, as described above.
Differential display PCR was then executed using the randomly chosen primers
of SEQ
ID NO: 87-125. Amplification conditions were as noted above, and bands
observed to
be specific to the RNA fingerprint pattern of the tumor were cut out of a
silver stained
gel, subcloned into either the T-vector (Novagen, Madison, WI) or the pCRII
vector
(Invitrogen, San Diego, CA) and sequenced. The sequences are provided in SEQ
ID
NO:11 - SEQ ID N0:86. Of the 79 sequences isolated, 67 were found to be novel
(SEQ
ID NO:l 1-26 and 28-77) (see also Figures 6-20).
An extended DNA sequence (SEQ ID NO: 290) for the antigen B15Ag1
(originally identified partial sequence provided in SEQ ID NO: 27) was
obtained in
further studies. Comparison of the sequence of SEQ ID NO: 290 with those in
the gene
3o bank as described above, revealed homology to the known human (3-A activin
gene.
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37
Further studies led to the isolation of the full-length cDNA sequence for the
antigen
B21GT2 (also referred to as B311D; originally identified partial cDNA sequence
provided in SEQ ID NO: 56). The full-length sequence is provided in SEQ ID NO:
307,
with the corresponding amino acid sequence being provided in SEQ ID NO: 308.
Further studies led to the isolation of a splice variant of B311D. The B311D
clone of
SEQ ID NO: 316 was sequenced and a XhoI/NotI fragment from this clone was gel
purified and 32P-cDTP labeled by random priming for use as a probe for further
screening to obtain additional B311D gene sequence. Two fractions of a human
breast
tumor cDNA bacterial library were screened using standard techniques. One of
the
1o clones isolated in this manner yielded additional sequence which includes a
poly A+ tail.
The determined cDNA sequence of this clone (referred to as B311D BTl-lA) is
provided in SEQ ID NO: 317. The sequences of SEQ ID NO: 316 and 317 were found
to
share identity over a 464 by region, with the sequences diverging near the
poly A+
sequence of SEQ ID NO: 317.
Subsequent studies identified an additional 146 sequences (SEQ ID
NOS:142-289), of which 115 appeared to be novel (SEQ ID NOS:142, 143, 146-152,
154-166, 168-176, 178-192, 194-198, 200-204, 206, 207, 209-214, 216, 218, 219,
221-
240, 243-245, 247, 250, 251, 253, 255, 257-266, 268, 269, 271-273, 275, 276,
278, 280,
281, 284, 288 and 291). To the best of the inventors' knowledge none of the
previously
2o identified sequences have heretofore been shown to be expressed at a
greater level in
human breast tumor tissue than in normal breast tissue.
In further studies, several different splice forms of the antigen B 11 Ag 1
(also referred to as B305D) were isolated, with each of the various splice
forms
containing slightly different versions of the B 11 Ag 1 coding frame. Splice
junction
sequences define individual exons which, in various patterns and arrangements,
make up
the various splice forms. Primers were designed to examine the expression
pattern of
each of the exons using RT-PCR as described below. Each exon was found to show
the
same expression pattern as the original B 11 Ag 1 clone, with expression being
breast
tumor-, normal prostate- and normal testis-specific. The determined cDNA
sequences
3o for the isolated protein coding exons are provided in SEQ ID NO: 292-298,
respectively.
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38
The predicted amino acid sequences corresponding to the sequences of SEQ ID
NO: 292
and 298 are provided in SEQ ID NO: 299 and 300. Additional studies using rapid
amplification of cDNA ends (RACE), a 5' specific primer to one of the splice
forms of
B 11 Ag 1 provided above and a breast adenocarcinoma, led to the isolation of
three
additional, related, splice forms referred to as isoforms B 11 C-15, B 11 C-8
and B 11 C-
9,16. The determined cDNA sequences for these isoforms are provided in SEQ ID
NO:
301-303, with the corresponding predicted amino acid sequences being provided
in SEQ
ID NO: 304-306.
In subsequent studies on B305D isoform A (cDNA sequence provided in
1o SEQ ID NO: 292), the cDNA sequence (provided in SEQ ID NO: 313) was found
to
contain an additional guanine residue at position 884, leading to a frameshift
in the open
reading frame. The determined DNA sequence of this ORF is provided in SEQ ID
NO:
314. This frameshift generates a protein sequence (provided in SEQ ID NO: 315)
of 293
amino acids that contains the C-terminal domain common to the other isoforms
of
B305D but that differs in the N-terminal region.
EXAMPLE 2
PREPARATION OF B I SAG 1 DNA FROM HUMAN GENOMIC DNA
This Example illustrates the preparation of B 18Ag 1 DNA by
amplification from human genomic DNA.
B18Ag1 DNA may be prepared from 250 ng human genomic DNA using
20 pmol of B18Ag1 specific primers, 500 pmol dNTPS and 1 unit of Taq DNA
polymerase (Perkin Elmer, Branchburg, NJ) using the following amplification
parameters: 94°C for 30 seconds denaturing, 30 seconds 60°C to
42°C touchdown
annealing in 2°C increments every two cycles and 72°C extension
for 30 seconds. The
last increment (a 42°C annealing temperature) should cycle 25 times.
Primers were
selected using computer analysis. Primers synthesized were B 18Ag 1-1, B 18Ag
1-2,
B18Ag1-3, and B18Ag1-4. Primer pairs that may be used are 1+3, 1+4, 2+3, and
2+4
CA 02365909 2001-10-04
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39
Following gel electrophoresis, the band corresponding to B 18Ag 1 DNA
may be excised and cloned into a suitable vector.
EXAMPLE 3
PREPARATION OF B 1 BAG 1 DNA FROM BREAST TUMOR CDNA
This Example illustrates the preparation of B18Ag1 DNA by
amplification from human breast tumor cDNA.
First strand cDNA is synthesized from RNA prepared from human breast
1o tumor tissue in a reaction mixture containing 500 ng poly A+ RNA, 200 pmol
of the
primer (T),ZAG (i.e., TTT TTT TTT TTT AG) (SEQ ID NO: 130), 1X first strand
reverse
transcriptase buffer, 6.7 mM DTT, 500 mmol dNTPs, and 1 unit AMV or MMLV
reverse transcriptase (from any supplier, such as Gibco-BRL (Grand Island,
NY)) in a
final volume of 30 ~l. After first strand synthesis, the cDNA is diluted
approximately 25
fold and 1 ~.l is used for amplification as described in Example 2. While some
primer
pairs can result in a heterogeneous population of transcripts, the primers
B18Ag1-2
(5'ATG GCT ATT TTC GGG GGC TGA CA) (SEQ ID NO: 126) and Bl8Agl-3
(5'CCG GTA TCT CCT CGT GGG TAT T) (SEQ ID NO: 127) yield a single 151 by
amplification product.
EXAMPLE 4
IDENTIFICATION OF B-CELL AND T-CELL EPITOPES OF B 1 SAG 1
This Example illustrates the identification of B 18Ag 1 epitopes.
The B 18Ag 1 sequence can be screened using a variety of computer
algorithms. To determine B-cell epitopes, the sequence can be screened for
hydrophobicity and hydrophilicity values using the method of Hopp, Prog. Clin.
Biol.
Res. 172B:367-77 (1985) or, alternatively, Cease et al., J. Exp. Med. 164:1779-
84 (1986)
or Spouge et al., J. Immunol. 138:204-12 (1987). Additional Class II MHC
(antibody or
3o B-cell) epitopes can be predicted using programs such as AMPHI (e.g.,
Margalit et al., J.
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Immunol. 138:2213 (1987)) or the methods of Rothbard and Taylor (e.g., EMBO J.
7:93
(1988)).
Once peptides (15-20 amino -acids long) are identified using these
techniques, individual peptides can be synthesized using automated peptide
synthesis
5 equipment (available from manufacturers such as Perkin Elmer/Applied
Biosystems
Division, Foster City, CA) and techniques such as Merrifield synthesis.
Following
synthesis, the peptides can used to screen sera harvested from either normal
or breast
cancer patients to determine whether patients with breast cancer possess
antibodies
reactive with the peptides. Presence of such antibodies in breast cancer
patient would
1 o confirm the immunogenicity of the specific B-cell epitope in question. The
peptides can
also be tested for their ability to generate a serologic or humoral immune in
animals
(mice, rats, rabbits, chimps etc.) following immunization in vivo. Generation
of a
peptide-specific antiserum following such immunization further confirms the
immunogenicity of the specific B-cell epitope in question.
15 To identify T-cell epitopes, the B 18Ag 1 sequence can be screened using
different computer algorithms which are useful in identifying 8-10 amino acid
motifs
within the B 18Ag 1 sequence which are capable of binding to HLA Class I MHC
molecules. (see, e.g., Rammensee et al., Immunogenetics 41:178-228 (1995)).
Following
synthesis such peptides can be tested for their ability to bind to class I MHC
using
2o standard binding assays (e.g., Sette et al., J. Immunol. 153:5586-92
(1994)) and more
importantly can be tested for their ability to generate antigen reactive
cytotoxic T-cells
following in vitro stimulation of patient or normal peripheral mononuclear
cells using,
for example, the methods of Bakker et al., Cancer Res. 55:5330-34 (1995);
Visseren et
al., J. Immunol. 154:3991-98 (1995); Kawakami et al., J. Immunol. 154:3961-68
(1995);
25 and Kast et al., J. Immunol. 152:3904-12 (1994). Successful in vitro
generation of T-
cells capable of killing autologous (bearing the same Class I MHC molecules)
tumor
cells following in vitro peptide stimulation further confirms the
immunogenicity of the
B 18Ag 1 antigen. Furthermore, such peptides may be used to generate marine
peptide
and B18Ag1 reactive cytotoxic T-cells following in vivo immunization in mice
rendered
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41
transgenic for expression of a particular human MHC Class I haplotype
(Vitiello et al., J.
Exp. Med. 173:1007-15 (1991).
A representative list of predicted B18Ag1 B-cell and T-cell epitopes,
broken down according to predicted HLA Class I MHC binding antigen, is shown
below:
Predicted Th Motifs (B-cell epitopes) (SEQ ID NOS.: 131-133)
SSGGRTFDDFHRYLLVGI
QGAAQKPINLSKXIEVVQGHDE
SPGVFLEHLQEAYRIYTPFDLSA
Io
Predicted HLA A2.1 Motifs (T-cell epitopes) (SEQ ID NOS.: 134-140)
YLLVGIQGA
GAAQKPINL
NLSKXIEVV
EVVQGHDES
HLQEAYRIY
NLAFVAQAA
FVAQAAPDS
2o EXAMPLE 5
IDENTIFICATION OF T-CELL EPITOPES OF B 11 A~ 1
This Example illustrates the identification of B11Ag1 (also referred to as
B305D) epitopes. Four peptides, referred to as B11-8, B11-1, B11-5 and B11-12
(SEQ
ID NO: 309-312, respectfully) were derived from the B 11 Ag 1 gene.
Human CD8 T cells were primed in vitro to the peptide B11-8 using
dendritic cells according to the protocol of Van Tsai et al. (Critical Reviews
in
Immunology 18:65-75, 1998). The resulting CD8 T cell cultures were tested for
their
ability to recognize the B 11-8 peptide or a negative control peptide,
presented by the B-
LCL line, JY. Briefly, T cells were incubated with autologous monocytes in the
presence
of 10 ug/ml peptide, 10 ng/ml IL-7 and 10 ug/ml IL-2, and assayed for their
ability to
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specifically lyse target cells in a standard 51-Cr release assay. As shown in
Fig. 22, the
bulk culture line demonstrated strong recognition of the B 11-8 peptide with
weaker
recognition of the peptide B11-1.
A clone from this CTL line was isolated following rapid expansion using
the monoclonal antibody OKT3 and human IL-2. As shown in Fig. 23, this clone
(referred to as A1), in addition to being able to recognize specific peptide,
recognized JY
LCL transduced with the B 11 Ag 1 gene. This data demonstrates that B 11-8 is
a naturally
processed epitope of the B 11 Ag 1 gene. In addition these T cells were
further found to
recognize and lyre, in an HLA-~A2 restricted manner. an established tumor cell
line
1o naturally expressing B11Ag1 (Fig. 24). The T cells strongly recognize a
lung
adenocarcinoma (LT-140-22) naturally expressing B11Ag1 transduced with HLA-A2,
as
well as an A2+ breast carcinoma (CAMA-1 ) transduced with B 11 Ag 1, but not
untransduced lines or another negative tumor line (SW620).
These data clearly demonstrate that these human T cells recognize not
only B11-specific peptides but also transduced cells. as well as naturally
expressing
tumor lines.
CTL lines raised against the antigens B 11-5 and B 11-12, using the
procedures described above, were found to recognize corresponding peptide-
coated
targets.
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Example 6
CHARACTERIZATION OF BREAST TUMOR GENES DISCOVERED BY
DIFFERENTIAL DISPLAY PCR
The specificity and sensitivity of the breast tumor genes discovered by
differential display PCR were determined using RT-PCR. This procedure enabled
the
rapid evaluation of breast tumor gene mRNA expression semiquantitatively
without
using large amounts of RNA. Using gene specific primers, mRNA expression
levels in a
variety of tissues were examined, including 8 breast tumors, 5 normal breasts,
2 prostate
1o tumors, 2 colon tumors, 1 lung tumor, and 14 other normal adult human
tissues,
including normal prostate, colon, kidney, liver, lung, ovary, pancreas,
skeletal muscle,
skin, stomach and testes.
To ensure the semiquantitative nature of the RT-PCR, (3-actin was used as
internal control for each of the tissues examined. Serial dilutions of the
first strand
cDNAs were prepared and RT-PCR assays performed using (3-actin specific
primers. A
dilution was then selected that enabled the linear range amplification of (3-
actin template,
and which was sensitive enough to reflect the difference in the initial copy
number.
Using this condition, the (3-actin levels were determined for each reverse
transcription
reaction from each tissue. DNA contamination was minimized by DNase treatment
and
2o by assuring a negative result when using first strand cDNA that was
prepared without
adding reverse transcriptase.
Using gene specific primers, the mRNA expression levels were
determined in a variety of tissues. To date, 38 genes have been successfully
examined by
RT-PCR, five of which exhibit good specificity and sensitivity for breast
tumors
(B15AG-1, B3lGAlb, B38GA2a, BllAla and Bl8AGla). Figures 21A and 21B depict
the results for three of these genes: B15AG-1 (SEQ ID N0:27), B3lGAlb (SEQ ID
N0:148) and B38GA2a (SEQ ID NO. 157). Table I summarizes the expression level
of
all the genes tested in normal breast tissue and breast tumors, and also in
other tissues.
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TABLEI
Percentage of Breast Cancer Antigens that are Expressed in Various Tissues
Over-expressed in Breast Tumors 84%
Breast Tissues
Equally Expressed in Normals and Tumor 16%
1 o Over-expressed in Breast Tumors but
not in any Normal Tissues 9%
Other Tissues Over-expressed in Breast Tumors but
Expressed in Some Normal Tissues 30%
Over-expressed in Breast Tumors but
Equally Expressed in All Other Tissues 61
2o From the foregoing, it will be appreciated that, although specific
embodiments of the invention have been described herein for the purpose of
illustration,
various modifications may be made without deviating from the spirit and scope
of the
invention.
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SEQUENCE LISTING
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<120> COMPOSITIONS AND METHODS FOR THE
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2
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tctagagctgcgcctggatcccgccacagtgaggagacctgaagaccagagaaaacacag 60
caagtaggccctttaaactactcacctgtgttgtcttctaatttattctgttttattttg 120
tttccatcattttaaggggttaaaatcatcttgttcagacctcagcatataaaatgaccc 180
atctgtagacctcaggctccaaccataccccaagagttgtctggttttgtttaaattact 240
gccaggtttcagctgcagatatccctggaaggaatattccagattccctgagtagtttcc 300
aggttaaaatcctataggcttcttctgttttgaggaagagttcctgtcagagaaaaacat 360
gattttggatttttaactttaatgcttgtgaaacgctataaaaaaaattttctaccccta 420
gctttaaagtactgttagtgagaaattaaaattccttcaggaggattaaactgccatttc 480
agttaccctaattccaaatgttttggtggttagaatcttctttaatgttcttgaagaagt 540
gttttatattttcccatcnagataaattctctcncnccttnnttttntntctnntttttt 600
aaaacggantcttgctccgttgtccangetgggaattttnttttggccaatctccgctnc 660
cttgcaanaatnctgcntcccaaaattaccncctttttcccacctccaccccnnggaatt 720
acctggaattanaggcccccnccccccccccggctaatttgtttttgtttttagtaaaaa 780
acgggtttcctgttttagttaggatggcccanntctgaccccntnatcntccccctcngc 840
cctcnaatnttnggnntanggcttaccccccccngnngtttttcctccattnaaattttc 900
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tntggantct tgaatnncgg gttttccctt ttaaaccnat tttttttttn nnncccccan 960
ttttncctcc cccntntnta angggggttt cccaanccgg gtccnccccc angtccccaa 1020
tttttctccc cccccctctt ttttctttnc cccaaaantc ctatcttttc ctnnaaatat 1080
cnantnt 1087
<210> 5
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<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(1010)
<223> n = A,T,C or G
<400> 5
tctagaccaagaaatgggaggattttagagtgactgatgatttctctatcatctgcagtt 60
agtaaacattctccacagtttatgcaaaaagtaacaaaaccactgcagatgacaaacact 120
aggtaacacacatactatctcccaaatacctacccacaagctcaacaattttaaactgtt 180
aggatcactggctctaatcaccatgacatgaggtcaccaccaaaccatcaagcgctaaac 240
agacagaatgtttccactcctgatccactgtgtgggaagaagcaccgaacttacccactg 300
gggggcctgcntcanaanaaaagcccatgcccccgggtntncctttnaaccggaacgaat 360
naacccaccatccccacanctcctctgttcntgggccctgcatcttgtggcctcntntnc 420
tttngggganacntggggaaggtaccccatttcnttgaccccncnanaaaaccccngtgg 480
ccctttgccctgattcncntgggccttttctcttttcccttttgggttgtttaaattccc 540
aatgtccccngaaccctctccntnctgcccaaaacctacctaaattnctcnctangnntt 600
ttcttggtgttncttttcaaaggtnaccttncctgttcanncccnacnaaaatttnttcc 660
ntatnntggncccnnaaaaannnatcnncccnaattgcccgaattggttnggtttttcct 720
nctgggggaaaccctttaaatttcccccttggccggccccccttttttcccccctttnga 780
aggcaggnggttcttcccgaacttccaattncaacagccntgcccattgntgaaaccctt 840
ttcctaaaattaaaaaatanccggttnnggnnggcctctttcccctccnggngggnngng 900
aaantccttaccccnaaaaaggttgcttagcccccngtccccactcccccnggaaaaatn 960
aaccttttcnaaaaaaggaatataantttnccactccttngttctcttcc 1010
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<213> Homo sapien
<220>
<221> misc_feature
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<223> n = A,T,C or G
<400> 6
tctagagctcgcggccgcgagctctaatacgactcactatagggcgtcgactcgatctca 60
gctcactgcaatctctgcccccggggtcatgcgattctcctgcctcagccttccaagtag 120
ctgggattacaggcgtgcaacaccacacccggctaattttgtatttttaatagagatggg 180
gttttcccttgttggccannatggtctcnaacccctgacctcnngtgatccccccncccn 240
nganctcnnactgctggggatnnccgnnnnnnncctcccnncncnnnnnnncncnntccn 300
tnntccttnctcnnnnnnnncnntcnntccnncttctcnccnnntnttntcnncnnccnn 360
cnnnccncntncccncnnnttcncntncnntntccnncnnnntcnncnnncnnnncntnn 420
ccnntacntcntnnncnnntccntctntnncctcnncnntcnctncncnttntctcctcn 480
ntnnnnnnctccnnnnntctcntcncnncntncctcnntnnccncnccccncctcncnnc 540
ctnntttnnncnncnnntccntnccnttcnnntccnntnncnncntcncnnncnttnttc 600
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ccnccnnttccttncncntnnnntntcnnncncntcnntcntttnctcctnnntcccnnc 660
tcnnttcncccnnntccnccccccncctntctctcncccnnntnnntntnnnncntccnc 720
tntcncnttcntcnntncnttnctntcnncnncnntncnctnccntntntctnnntcncn 780
tcncntntcnccntccnttnctntctcctntntccttcccctcncctnctcnttcnccnc 840
ccnntntntntnncnccnntnctnnncnnccntcntttcntctctnctnnnnntnncctc 900
nncccntnccctnntncnctnctnntaccntnctnctccntcttccttcc 950
<210> 7
<211> 1086
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(1086)
<223> n = A,T,C or G
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tctagagctcgcggccgcgagctcaattaaccctcactaaagggagtcgactcgatcaga 60
ctgttactgtgtctatgtagaaagaagtagacataagagattccattttgttctgtacta 120
agaaaaattcttctgccttgagatgctgttaatctgtaaccctagccccaaccctgtgct 180
cacagagacatgtgctgtgttgactcaaggttcaatggatttagggctatgctttgttaa 240
aaaagtgcttgaagataatatgcttgttaaaagtcatcaccattctctaatctcaagtac 300
ccagggacacaatacactgcggaaggccgcagggacctctgtctaggaaagccaggtatt 360
gtccaagatttctccccatgtgatagcctgagatatggcctcatgggaagggtaagacct 420
gactgtcccccagcccgacatcccccagcccgacatcccccagcccgacacccgaaaagg 480
gtctgtgctgaggaagattantaaaagaggaaggctctttgcattgaagtaagaagaagg 540
ctctgtctcctgctcgtccctgggcaataaaatgtcttggtgttaaacccgaatgtatgt 600
tctacttactgagaataggagaaaacatccttagggctggaggtgagacaccctggcggc 660
atactgctctttaatgcacgagatgtttgtntaattgccatccagggccancccctttcc 720
ttaactttttatganacaaaaactttgttcncttttcctgcgaacctctccccctattan 780
cctattggcctgcccatcccctccccaaanggtgaaaanatgttcntaaatncgagggaa 840
tccaaaacnttttcccgttggtcccctttccaaccccgtccctgggccnntttcctcccc 900
aacntgtcccggntccttcnttcccncccccttcccnganaaaaaaccccgtntganggn 960
gccccctcaaattataacctttccnaaacaaannggttcnaaggtggtttgnttccggtg 1020
cggctggccttgaggtcccccctncaccccaatttggaanccngttttttttattgcccn 1080
ntcccc 1086
<210> 8
<211> 1177
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(1177)
<223> n = A,T,C or G
<400> 8
nccntttaga tgttgacaan ntaaacaagc ngctcaggca gctgaaaaaa gccactgata 60
aagcatcctg gagtatcaga gtttactgtt agatcagcct catttgactt cccctcccac 120
atggtgttta aatccagcta cactacttcc tgactcaaac tccactattc ctgttcatga 180
ctgtcaggaa ctgttggaaa ctactgaaac tggccgacct gatcttcaaa atgtgcccct 240
aggaaaggtg gatgccaccg tgttcacaga cagtaccncc ttcctcgaga agggactacg 300
aggggccggt gcanctgtta ccaaggagac tnatgtgttg tgggctcagg ctttaccanc 360
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aaacacctcancncnnaaggctgaattgatcgccctcactcaggctctcggatggggtaa 420
gggatattaacgttaacactgacagcaggtacgcctttgctactgtgcatgtacgtggag 480
ccatctaccaggagcgtgggctactcactcggcaggtggctgtnatccactgtaaangga 540
catcaaaaggaaaacnnggctgttgcccgtggtaaccanaaanctgatcnncagctcnaa 600
gatgctgtgttgactttcactcncncctcttaaacttgctgcccacantctcctttccca 660
accagatctgcctgacaatccccatactcaaaaaaaaaanaanactggccccgaacccna 720
accaataaaaacgggganggtnggtngancnncctgacccaaaaataatggatcccccgg 780
gctgcaggaattcaattcanccttatcnatacccccaacnnggnggggggggccngtncc 840
cattncccctntattnattctttnnccccccccccggcntcctttttnaactcgtgaaag 900
ggaaaacctgncttaccaanttatcncctggaccntccccttccncggtngnttanaaaa 960
aaaagcccncantcccntccnaaatttgcacngaaaggnaaggaatttaacctttatttt 1020
ttnntcctttantttgtnnncccccttttacccaggcgaacngccatcntttaanaaaaa 1080
aaanagaangtttatttttccttngaaccatcccaatanaaancacccgcnggggaacgg 1140
ggnggnaggccnctcaccccctttntgtnggngggnc 1177
<210> 9
<211> 1146
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (1146)
<223> n = A,T,C or G
<400>
9
nccnnttnntgatgttgtctttttggcctctctttggatactttccctctcttcagaggt 60
gaaaagggtcaaaaggagctgttgacagtcatcccaggtgggccaatgtgtccagagtac 120
agactccatcagtgaggtcaaagcctggggcttttcagagaagggaggattatgggtttt 180
ccaattatacaagtcagaagtagaaagaagggacataaaccaggaagggggtggagcact 240
catcacccagagggacttgtgcctctctcagtggtagtagaggggctacttcctcccacc 300
acggttgcaaccaagaggcaatgggtgatgagcctacaggggacatanccgaggagacat 360
gggatgaccctaagggagtaggctggttttaaggcggtgggactgggtgagggaaactct 420
cctcttcttcagagagaagcagtacagggcgagctgaaccggctgaaggtcgaggcgaaa 480
acacggtctggctcaggaagaccttggaagtaaaattatgaatggtgcatgaatggagcc 540
atggaaggggtgctcctgaccaaactcagccattgatcaatgttagggaaactgatcagg 600
gaagccgggaatttcattaacaacccgccacacagcttgaacattgtgaggttcagtgac 660
ccttcaaggggccactccactccaactttggccattctactttgcnaaatttccaaaact 720
tccttttttaaggccgaatccntantccctnaaaaacnaaaaaaaatctgcncctattct 780
ggaaaaggcccancccttaccaggctggaagaaattttnccttttttttttttttgaagg 840
cntttnttaaattgaacctnaattcncccccccaaaaaaaaacccnccnggggggcggat 900
ttccaaaaacnaattcccttaccaaaaaacaaaaacccncccttnttcccttccnccctn 960
ttcttttaattagggagagatnaagccccccaatttccnggnctngatnngtttcccccc 1020
cccccattttccnaaactttttcccancnaggaanccnccctttttttnggtcngattna 1080
ncaaccttccaaaccatttttccnnaaaaantttgntnggngggaaaaanacctnntttt 1140
atagan 1146
<210> 10
<211> 545
<212> DNA
<213> Homo sapien
<400> 10
cttcattggg tacgggcccc ctcgaggtcg acggtatcga taagcttgat atcgaattcc 60
tgcagcccgg gggatccact agttctagag tcaggaagaa ccaccaacct tcctgatttt 120
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
6
tattggctctgagttctgaggccagttttcttcttctgttgagtatgcgggattgtcagg 180
cagatctggctgtggaaaggagactgtgggcagcaagtttagaggcgtgactgaaagtca 240
cactgcatcttgagctgctgaatcagctttctggttaccacgggcaacagccgtgttttc 300
cttttgatgtcctttacagtggattacagccacctgctgaggtgagtagcccacgctcct 360
ggtagatggctccacgtacatgcacagtagcaaaggcgtacctgctgtcagtgttaacgt 420
taatatccttaccccatcggagagcctgagtgagggcgatcaattcagcccttttgtgct 480
gaggtgtttgctggttaagccctgaacccacaacacatctgtctccatggtaacagctgc 540
accgg 545
<210> 11
<211> 196
<212> DNA
<213> Homo sapien
<400> 11
tctcctaggc tgggcacagt ggctcatacc tgtaatcctg accgtttcag aggctcaggt 60
ggggggatcg cttgagccca agatttcaag actagtctgg gtaacatagt gagaccctat 120
ctctacgaaa aaataaaaaa atgagcctgg tgtagtggca cacaccagct gaggagggag 180
aatcgagcct aggaga 196
<210> 12
<211> 388
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (388)
<223> n = A,T,C or G
<400> 12
tctcctaggc ttgggggctc tgactagaaa ttcaaggaac ctgggattca agtccaactg 60
tgacaccaac ttacactgtg gnctccaata aactgcttct ttcctattcc ctctctatta 120
aataaaataa ggaaaacgat gtctgtgtat agccaagtca gntatcctaa aaggagatac 180
taagtgacat taaatatcag aatgtaaaac ctgggaacca ggttcccagc ctgggattaa 240
actgacagca agaagactga acagtactac tgtgaaaagc ccgaagnggc aatatgttca 300
ctctaccgtt gaaggatggc tgggagaatg aatgctctgt cccccagtcc caagctcact 360
tactatacct cctttatagc ctaggaga 388
<210> 13
<211> 337
<212> DNA
<213> Homo sapien
<400> 13
tagtagttgcctataatcatgtttctcattattttcacattttattaaccaatttctgtt60
taccctgaaaaatatgagggaaatatatgaaacagggaggcaatgttcagataattgatc120
acaagatatgatttctacatcagatgctctttcctttcctgtttatttcctttttatttc180
ggttgtggggtcgaatgtaatagctttgtttcaagagagagttttggcagtttctgtagc240
ttctgacactgctcatgtctccaggcatctatttgcactttaggaggtgtcgtgggagac300
tgagaggtctattttttccatatttgggcaactacta 337
<210> 14
<211> 571
<212> DNA
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
7
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(571)
<223> n = A,T,C or G
<400> 14
tagtagttgccatacagtgcctttccatttatttaacccccacctgaacggcataaactg 60
agtgttcagctggtgttttttactgtaaacaataaggagactttgctcttcatttaaacc 120
aaaatcatatttcatattttacgctcgagggtttttaccggttcctttttacactcctta 180
aaacagtttttaagtcgtttggaacaagatattttttctttcctggcagcttttaacatt 240
atagcaaatttgtgtctgggggactgctggtcactgtttctcacagttgcaaatcaaggc 300
atttgcaaccaagaaaaaaaaatttttttgttttatttgaaactggaccggataaacggt 360
gtttggagcggctgctgtatatagttttaaatggtttattgcacctccttaagttgcact 420
tatgtgggggggggnttttgnatagaaagtntttantcacanagtcacagggacttttnt 480
cttttggnnactgagctaaaaagggctgnttttcgggtgggggcagatgaaggctcacag 540
gaggcctttctcttagaggggggaactncta 571
<210> 15
<211> 548
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(548)
<223> n = A,T,C or G
<400> 15
tatatatttaataacttaaatatattttgatcacccactggggtgataagacaatagata 60
taaaagtatttccaaaaagcataaaaccaaagtatcataccaaaccaaattcatactgct 120
tcccccacccgcactgaaacttcaccttctaactgtctacctaaccaaattctacccttc 180
aagtctttggtgcgtgctcactactctttttttttttttttttnttttggagatggagtc 240
tggctgtgcagcccaggggtggagtacaatggcacaacctcagctcactgnaacctccgc 300
ctcccaggttcatgagattctcctgnttcagccttcccagtagctgggactacaggtgtg 360
catcaccatgcctggntaatcttttttngttttngggtagagatgggggttttacatgtt 420
ggccaggntggtntcgaactcctgacctcaagtgatccacccacctcaggctcccaaagt 480
gctaggattacagacatgagccactgngcccagncctggtgcatgctcacttctctaggc 540
aactacta 548
<210> 16
<211> 638
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(638)
<223> n = A,T,C or G
<400> 16
ttccgttatg cacatgcaga atattctatc ggtacttcag ctattactca ttttgatggc 60
gcaatccgag cctatcctca agatgagtat ttagaaagaa ttgatttagc gatagaccaa 120
gctggtaagc actctgacta cacgaaattg ttcagatgtg atggatttat gacagttgat 180
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
8
ctttggaagagattattaagtgattattttaaagggaatccattaattccagaatatctt240
ggtttagctcaagatgatatagaaatagaacagaaagagactacaaatgaagatgtatca300
ccaactgatattgaagagcctatagtagaaaatgaattagctgcatttattagccttaca360
catagcgattttcctgatgaatcttatattcagccatcgacatagcattacctgatgggc420
aaccttacgaataatagaaactgggtgcggggctattgatgaattcatccncagtaaatt480
tggatatnacaaaatataactcgattgcatttggatgatggaatactaaatctggcaaaa540
gtaactttggagctactagtaacctctctttttgagatgcaaaattttcttttagggttt600
cttattctctactttacggatattggagcataacggga 638
<210> 17
<211> 286
<212> DNA
<213> Homo sapien
<400> 17
actgatggat gtcgccggag gcgaggggcc ttatctgatg ctcggctgcc tgttcgtgat 60
gtgcgcggcg attgggctgt ttatctcaaa caccgccacg gcggtgctga tggcgcctat 120
tgccttagcg gcggcgaagt caatgggcgt ctcaccctat ccttttgcca tggtggtggc 180
gatggcggct tcggcggcgt ttatgacccc ggtctcctcg ccggttaaca ccctggtgct 240
tggccctggc aagtactcat ttagcgattt tgtcaaaata ggcgtg 286
<210> 18
<211> 262
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(262)
<223> n = A,T,C or G
<400> 18
tcggtcatagcagccccttcttctcaatttcatctgtcactaccctggtgtagtatctca 60
tagccttacatttttatagcctcctccctggtctgtcttttgattttcctgcctgtaatc 120
catatcacacataactgcaagtaaacatttctaaagtgtggttatgctcatgtcactcct 180
gtgncaagaaatagtttccattaccgtcttaataaaattcggatttgttctttnctattn 240
tcactcttcacctatgaccgas 262
<210> 19
<211> 261
<212> DNA
<213> Homo sapien
<400> 19
tcggtcatagcaaagccagtggtttgagctctctactgtgtaaactcctaaaccaaggcc 60
atttatgataaatggtggcaggatttttattataaacatgtacccatgcaaatttcctat 120
aactctgagatatattcttctacatttaaacaataaaaataatctatttttaaaagccta 180
atttgcgtagttaggtaagagtgtttaatgagagggtataaggtataaatcaccagtcaa 240
cgtttctctgcctatgaccga 261
<210> 20
<211> 294
<212> DNA
<213> Homo sapien
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
9
<220>
<221> misc_feature
<222> (1) . . (294)
<223> n = A,T,C or G
<400> 20
tacaacgagg cgacgtcggt aaaatcggac atgaagccac cgctggtctt ttcgtccgag 60
cgataggcgc cggccagcca gcggaacggt tgcccggatg gcgaagcgag ccggagttct 120
tcggactgag tatgaatctt gttgtgaaaa tactcgccgc cttcgttcga cgacgtcgcg 180
tcgaaatctt cganctcctt acgatcgaag tcttcgtggg cgacgatcgc ggtcagttcc 240
gccccaccga aatcatggtt gagccggatg ctgnccccga agncctcgtt tgtn 294
<210> 21
<211> 208
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(208)
<223> n = A,T,C or G
<400> 21
ttggtaaagg gcatggacgc agacgcctga cgtttggctg aaaatctttc attgattcgt 60
atcaatgaat aggaaaattc ccaaagaggg aatgtcctgt tgctcgccag tttttntgtt 120
gttctcatgg anaaggcaan gagctcttca gactattggn attntcgttc ggtcttctgc 180
caactagtcg ncttgcnang atcttcat 208
<210> 22
<211> 287
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (287)
<223> n = A,T,C or G
<400> 22
nccnttgagc tgagtgattg agatntgtaa tggttgtaag ggtgattcag gcggattagg 60
gtggcgggtc acccggcagt gggtctcccg acaggccagc aggatttggg gcaggtacgg 120
ngtgcgcatc gctcgactat atgctatggc aggcgagccg tggaaggngg atcaggtcac 180
ggcgctggag ctttccacgg tccatgnatt gngatggctg ttctaggcgg ctgttgccaa 240
gcgtgatggt acgctggctg gagcattgat ttctggtgcc aaggtgg 287
<210> 23
<211> 204
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (204)
<223> n = A,T,C or G
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
<400> 23
ttgggtaaag ggagcaagga gaaggcatgg agaggctcan gctggtcctg gcctacgact 60
gggccaagct gtcgccgggg atggtggaga actgaagcgg gacctcctcg aggtcctccg 120
ncgttacttc nccgtccagg aggagggtct ttccgtggtc tnggaggagc ggggggagaa 180
gatnctcctc atggtcnaca tccc 204
<210> 24
<211> 264
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (264)
<223> n = A,T,C or G
<400> 24
tggattggtcaggagcgggtagagtggcaccattgaggggatattcaaaaatattatttt 60
gtcctaaatgatagttgctgagtttttctttgacccatgagttatattggagtttatttt 120
ttaactttccaatcgcatggacatgttagacttattttctgttaatgattnctattttta 180
ttaaattggatttgagaaattggttnttattatatcaatttttggtatttgttgagtttg 240
acattatagcttagtatgtgacca 264
<210> 25
<211> 376
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(376)
<223> n = A,T,C or G
<400> 25
ttacaacgaggggaaactccgtctctacaaaaattaaaaaattagccaggtgtggtggtg 60
tgcacccgcaatcccagctacttgggaggttgagacacaagantcacctanatgtgggag 120
gtcaaggttgcatgagtcatgattgtgccactgcactccagcctgggtgacagaccgaga 180
ccctgcctcaanaganaangaataggaagttcagaaatcntggntgtggngcccagcaat 240
ctgcatctatncaacccctgcaggcaangctgatgcagcctangttcaagagctgctgtt 300
tctggaggcagcagttngggcttccatccagtatcacggccacactcgcacnagccatct 360
gtcctccgtntgtnac 376
<210> 26
<211> 372
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (372)
<223> n = A,T,C or G
<400> 26
ttacaacgag gggaaactcc gtctctacaa aaattaaaaa attagccagg tgtggtggtg 60
tgcacctgta atcccagcta cttgggcggc tgagacacaa gaaccaccta aatgtgggag 120
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
11
ggtcaaggttgcatgagtcatgatcgcgccactgcactccagcctgggtgacagactgag 180
accctgcctcaaaagaaaaagaataggaagttcagaaaccctgggtgtggngcccagcaa 240
tctgcatttaaacaatccctgcaggcaatgctgatgcagcctaagttcaagagctgctgt 300
tctggaggcagnagtaagggcttccatccagcatcacggncaacactgcaaaagcacctg 360
tcctcgttggto 372
<210> 27
<211> 477
<212> DNA
<213> Homo sapien
<400>
27
ttctgtccacatctacaagttttatttattttgtgggttttcagggtgactaagtttttc 60
cctacattgaaaagagaagttgctaaaaggtgcacaggaaatcatttttttaagtgaata 120
tgataatatgggtccgtgcttaatacaactgagacatatttgttctctgtttttttagag 180
tcacctcttaaagtccaatcccacaatggtgaaaaaaaaatagaaagtatttgttctacc 240
tttaaggagactgcagggattctccttgaaaacggagtatggaatcaatcttaaataaat 300
atgaaattggttggtcttctgggataagaaattcccaactcagtgtgctgaaattcacct 360
gactttttttgggaaaaaatagtcgaaaatgtcaatttggtccataaaatacatgttact 420
attaaaagatatttaaagacaaattctttcagagctctaagattggtgtggacagaa 477
<210> 28
<211> 438
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(438)
<223> n = A,T,C or G
<400> 28
tctncaacctcttgantgtcaaaaaccttntaggctatctctaaaagctgactggtattc 60
attccagcaaaatccctctagtttttggagtttccttttactatctggggctgcctgagc 120
cacaaatgccaaattaagagcatggctattttcgggggctgacaggtcaaaaggggtgta 180
aatccgataagcctcctggaggtgctctaaaaacactcctggtgactcatcatgcccctg 240
gacgacttcaatcgncttagacaagtttataggtttctgggcagctccctgaatacccac 300
gaggagataccggtggaaatcgtcaaaagttctccctccacttgagaaatttgggtccca 360
attaggtcccaattgggtctctaatcactattcctctagcttcctcctccggnctattgg 420
ttgatgtgaggttgaaga 438
<210> 29
<211> 620
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (620)
<223> n = A,T,C or G
<400> 29
aagagggtac cagccccaag ccttgacaac ttccataggg tgtcaagcct gtgggtgcac 60
agaagtcaaa aattgagttt tgggatcctc agcctagatt tcagaggata taaagaaaca 120
cctaacacct agatattcag acaaaagttt actacaggga tgaagctttc acggaaaacc 180
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
12
tctactaggaaagtacagaagagaaatgtgggtttggagcccccaaacagaatcccctct 240
agaacactgcctaatgaaactgtgagaagatggccactgtcatccagacaccagaatgat 300
agacccaccaaaaacttatgccatattgcctataaaacctacagacactcaatgccagcc 360
ccatgaaaaaaaaactgagaagaagactgtnccctacaatgccaccggagcagaactgcc 420
ccaggccatggaagcacagctcttatatcaatgtgacctggatgttgagacatggaatcc 480
nangaaatcnttttaanacttccacggttnaatgactgccctattanattcngaacttan 540
atccnggcctgtgacctctttgctttggccattccccctttttggaatggctnttttttt 600
cccatgcctgtnccctctta 620
<210> 30
<211> 100
<212> DNA
<213> Homo sapien
<400> 30
ttacaacgag ggggtcaatg tcataaatgt cacaataaaa caatctcttc tttttttttt 60
tttttttttt tttttttttt tttttttttt tttttttttt 100
<210> 31
<211> 762
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(762)
<223> n = A,T,C or G
<400> 31
tagtctatgcgccggacagagcagaattaaattggaagttgccctccggactttctaccc 60
acactcttcctgaaaagagaaagaaaagaggcaggaaagaggttaggatttcattttcaa 120
gagtcagctaattaggagagcagagtttagacagcagtaggcaccccatgatacaaacca 180
tggacaaagtccctgtttagtaactgccagacatgatcctgctcaggttttgaaatctct 240
ctgcccataaaagatggagagcaggagtgccatccacatcaacacgtgtccaagaaagag 300
tctcagggagacaagggtatcaaaaaacaagattcttaatgggaaggaaatcaaaccaaa 360
aaattagatttttctctacatatatataatatacagatatttaacacattattccagagg 420
tggctccagtccttggggcttgagagatggtgaaaacttttgttccacattaacttctgc 480
tctcaaattctgaagtatatcagaatgggacaggcaatgttttgctccacactggggcac 540
agacccaaatggttctgtgcccgaagaagagaagcccgaaagacatgaaggatgcttaag 600
gggggttgggaaagccaaattggtantatcttttcctcctgcctgtgttccngaagtctc 660
cnctgaaggaattcttaaaaccctttgtgaggaaatgcccccttaccatgacaantggtc 720
ccattgcttttagggngatggaaacaccaagggttttgatcc 762
<210> 32
<211> 276
<212> DNA
<213> Homo sapien
<400> 32
tagtctatgcgtgtattaacctcccctccctcagtaacaaccaaagaggcaggagctgtt 60
attaccaaccccattttacagatgcatcaataatgacagagaagtgaagtgacttgcgca 120
cacaaccagtaaattggcagagtcagatttgaatccatggagtctggtctgcactttcaa 180
tcaccgaataccctttctaagaaacgtgtgctgaatgagtgcatggataaatcagtgtct 240
actcaacatctttgcctagatatcccgcatagacta 276
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
13
<210> 33
<211> 477
<212> DNA
<213> Homo sapien
<400> 33
tagtagttgccaaatatttgaaaatttacccagaagtgattgaaaactttttggaaacaa 60
aaacaaataaagccaaaaggtaaaataaaaatatctttgcactctcgttattacctatcc 120
ataactttttcaccgtaagctctcctgcttgttagtgtagtgtggttatattaaactttt 180
tagttattattttttattcacttttccactagaaagtcattattgatttagcacacatgt 240
tgatctcatttcattttttctttttataggcaaaatttgatgctatgcaacaaaaatact 300
caagcccattatcttttttccccccgaaatctgaaaattgcaggggacagagggaagtta 360
tcccattaaaaaattgtaaatatgttcagtttatgtttaaaaatgcacaaaacataagaa 420
aattgtgtttacttgagctgctgattgtaagcagttttatctcaggggcaactacta 477
<210> 34
<211> 631
<212> DNA
<213> Homo sapien
<400> 34
tagtagttgccaattcagatgatcagaaatgctgctttcctcagcattgtcttgttaaac 60
cgcatgccatttggaactttggcagtgagaagccaaaaggaagaggtgaatgacatatat 120
atatatatatattcaatgaaagtaaaatgtatatgctcatatactttctagttatcagaa 180
tgagttaagctttatgccattgggctgctgcatattttaatcagaagataaaagaaaatc 240
tgggcatttttagaatgtgatacatgtttttttaaaactgttaaatattatttcgatatt 300
tgtctaagaaccggaatgttcttaaaatttactaaaacagtattgtttgaggaagagaaa 360
actgtactgtttgccattattacagtcgtacaagtgcatgtcaagtcacccactctctca 420
ggcatcagtatccacctcatagctttacacattttgacggggaatattgcagcatcctca 480
ggcctgacatetgggaaaggctcagatccacctactgctccttgctcgttgatttgtttt 540
aaaatattgtgcctggtgtcacttttaagccacagccctgcctaaaagccagcagagaac 600
agaacccgcaccattctataggcaactacta 631
<210> 35
<211> 578
<212> DNA
<213> Homo sapien
<400> 35
tagtagttgccatcccatattacagaaggctctgtatacatgacttatttggaagtgatc 60
tgttttctctccaaacccatttatcgtaatttcaccagtcttggatcaatcttggtttcc 120
actgataccatgaaacctacttggagcagacattgcacagttttctgtggtaaaaactaa 180
aggtttatttgctaagctgtcatcttatgcttagtattttttttttacagtggggaattg 240
ctgagattacattttgttattcattagatactttgggataacttgacactgtcttctttt 300
tttcgcttttaattgctatcatcatgcttttgaaacaagaacacattagtcctcaagtat 360
tacataagcttgcttgttacgcctggtggtttaaaggactatctttggcctcaggttcac 420
aagaatgggcaaagtgtttccttatgttctgtagttctcaataaaagattgccaggggcc 480
gggtactgtggctcgcactgtaatcccagcactttgggaagctgaggctggcggatcatg 540
ttagggcaggtgttcgaaaccagcctgggcaactacta 578
<210> 36
<211> 583
<212> DNA
<213> Homo sapien
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
14
<400> 36
tagtagttgcctgtaatcccagcaactcaggaggctggggcaggagaatcagttgaacct 60
gggaggcagaagttgtaattagcaaagatcgcaccattgcacttcagcctgggcaacaag 120
agtgagattccatctcaaaaacaaaaaaaagaaaaagaaaagaaaaggaaaaaacgtata 180
aacccagccaaaacaaaatgatcattcttttaataagcaagactaatttaatgtgtttat 240
ttaatcaaagcagttgaatcttctgagttattggtgaaaatacccatgtagttaatttag 300
ggttcttacttgggtgaacgtttgatgttcacaggttataaaatggttaacaaggaaaat 360
gatgcataaagaatcttataaactactaaaaataaataaaatataaatggataggtgcta 420
tggatggagtttttgtgtaatttaaaatcttgaagtcattttggatgctcattggttgtc 480
tggtaatttccattaggaaaaggttatgatatggggaaactgtttctggaaattgcggaa 540
tgtttctcatctgtaaaatgctagtatctcagggcaactacta 583
<210> 37
<211> 716
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (716)
<223> n = A,T,C or G
<400> 37
gatctactagtcatntggattctatccatggcagctaagcctttctgaatggattctact 60
gctttcttgttctttaatccagacccttatatatgtttatgttcacaggcagggcaatgt 120
ttagtgaaaacaattctaaattttttattttgcattttcatgctaatttccgtcacactc 180
cagcaggcttcctgggagaataaggagaaatacagctaaagacattgtccctgcttactt 240
acagcctaatggtatgcaaaaccacttcaataaagtaacaggaaaagtactaaccaggta 300
gaatggaccaaaactgatatagaaaaatcagaggaagagaggaacaaatatttactgagt 360
cctagaatgtacaaggctttttaattacatattttatgtaaggcctgcaaaaaacaggtg 420
agtaatcaacatttgtcccattttacatataaggaaactgaagcttaaattgaataattt 480
aatgcatagattttatagttagaccatgttcaggtccctatgttatacttactagctgta 540
tgaatatgagaaaataattttgttattttcttggcatcagtattttcatctgcaaaataa 600
agctaaagttatttagcaaacagtcagcatagtgcctgatacatagtaggtgctccaaac 660
atgattacnctantattnggtattanaaaaatccaatataggcntggataaaaccg 716
<210> 38
<211> 688
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(688)
<223> n = A,T,C or G
<400> 38
ttctgtccacatatcatcccactttaattgttaatcagcaaaactttcaatgaaaaatca 60
tccattttaaccaggatcacaccaggaaactgaaggtgtatttttttttaccttaaaaaa 120
aaaaaaaaaaaccaaacaaaccaaaacagattaacagcaaagagttctaaaaaatttaca 180
tttctcttacaactgtcattcagagaacaatagttcttaagtctgttaaatcttggcatt 240
aacagagaaacttgatgaanagttgtacttggaatattgtggatttttttttttgtctaa 300
tctccccctattgttttgccaacagtaatttaagtttgtgtggaacatccccgtagttga 360
agtgtaaacaatgtataggaaggaatatatgataagatgatgcatcacatatgcattaca 420
tgtagggaccttcacaacttcatgcactcagaaaacatgcttgaagaggaggagaggacg 480
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
gcccagggtc accatccagg tgccttgagg acagagaatg cagaagtggc actgttgaaa 540
tttagaagac catgtgtgaa tggtttcagg cctgggatgt ttgccaccaa gaagtgcctc 600
cgagaaattt ctttcccatt tggaatacag ggtggcttga.tgggtacggt gggtgaccca 660
acgaagaaaa tgaaattctg ccctttcc 688
<210> 39
<211> 585
<212> DNA
<.213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(585)
<223> n = A,T,C or G
<400> 39
tagtagttgccgcnnacctaaaanttggaaagcatgatgtctaggaaacatantaaaata 60
gggtatgcctatgtgctacagagagatgttagcatttaaagtgcatanttttatgtattt 120
tgacaaatgcatatncctctataatccacaactgattacgaagctattacaattaaaaag 180
tttggccgggcgtggtgggcggtggctgacgcctgtaatcccagcactttgggaggccga 240
ggcacgcggatcacgaggtcgggagttcaagaccatcctggctaacacggtgaaagtcca 300
tctctactaaaaatacgaaaaaattaccccggcgtggtggcgggcgcctgtagtcccagc 360
tactccggaggctgaggcaggagaatggcgtgaacccaggacacggagcttgcagtgtgc 420
caacatcacgtcactgccctccagcctgggggacaggaacaagantcccgtcctcanaaa 480
agaaaaatactactnatantttcnactttattttaanttacacagaactncctcttggta 540
cccccttaccattcatctcacccacctcctatagggcacnnctaa 585
<210> 40
<211> 475
<212> DNA
<213> Homo sapien
<400> 40
tctgtccacaccaatcttagaagctctgaaaagaatttgtctttaaatatcttttaatag60
taacatgtattttatggaccaaattgacattttcgactgttttttccaaaaaagtcaggt120
gaatttcagcacactgagttgggaatttcttatcccagaagaccaaccaatttcatattt180
atttaagattgattccatactccgttttcaaggagaatccctgcagtctccttaaaggta240
gaacaaatacttcctatttttttttcaccattgtgggattggactttaagaggtgactct300
aaaaaaacagagaacaaatatgtctcagttgtattaagcacggacccatattatcatatt360
cacttaaaaaaatgatttcctgtgcaccttttggcaacttctcttttcaatgtagggaaa420
aacttagtcaccctgaaaacccacaaaataaataaaacttgtagatgtggacaga 475
<210> 41
<211> 423
<212> DNA
<213> Homo sapien
<400> 41
taagagggta catcgggtaa gaacgtaggc acatctagag cttagagaag tctggggtag 60
gaaaaaaatc taagtattta taagggtata ggtaacattt aaaagtaggg ctagctgaca 120
ttatttagaa agaacacata cggagagata agggcaaagg actaagacca gaggaacact 180
aatatttagt gatcacttcc attcttggta aaaatagtaa cttttaagtt agcttcaagg 240
aagatttttg gccatgatta gttgtcaaaa gttagttctc ttgggtttat attactaatt 300
ttgttttaag atccttgtta gtgctttaat aaagtcatgt tatatcaaac gctctaaaac 360
attgtagcat gttaaatgtc acaatatact taccatttgt tgtatatggc tgtaccctct 420
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
16
cta 423
<210> 42
<211> 527
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(527)
<223> n = A,T,C or G
<400> 42
tctcctaggctaatgtgtgtgtttctgtaaaagtaaaaagttaaaaattttaaaaataga 60
aaaaagcttatagaataagaatatgaagaaagaaaatatttttgtacatttgcacaatga 120
gtttatgttttaagctaagtgttattacaaaagagccaaaaaggttttaaaaattaaaac 180
gtttgtaaagttacagtacccttatgttaatttataattgaagaaagaaaaacttttttt 240
tataaatgtagtgtagcctaagcatacagtatttataaagtctggcagtgttcaataatg 300
tcctaggccttcacattcactcactgactcacccagagcaacttccagtcctgtaagctc 360
cattcgtggtaagtgccctatacaggtgcaccatttattttacagtatttttactgtacc 420
ttctctatgtttccatatgtttcgatatacaaataccactggttactatngcccnacagg 480
taattccagtaacacggcctgtatacgtctggtanccctagngaaga 527
<210> 43
<211> 331
<212> DNA
<213> Homo sapien
<400> 43
tcttcaacct cgtaggacaa ctctcatatg cctgggcact atttttaggt tactaccttg 60
gctgcccttc tttaagaaaa aaaaaagaag aaaaaagaac ttttccacaa gtttctcttc 120
ctctagttgg aaaattagag aaatcatgtt tttaattttg tgttatttca gatcacaaat 180
tcaaacactt gtaaacatta agcttctgtt caatcccctg ggaagaggat tcattctgat 240
atttacggtt caaaagaagt tgtaatattg tgcttggaac acagagaacc agttattaac 300
ttcctactac tattatataa taaataataa c 331
<210> 44
<211> 592
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(592)
<223> n = A,T,C or G
<400> 44
ggcttagtagttgccaggcaaaatarcgttgattctcctcaggagccacccccaacaccc 60
ctgtttgcttctagacctatacctagactaaagtcccagcagacccctagaggtgaggtt 120
cagagtgacccttgaggagatgtgctacactagaaaagaactgcttgagttttctaattt 180
atataagcagaaatctggagaagagtcataggaatggatattaagggtgtgagataatgg 240
cggaaggaatatagagttggatcaggctggacttattgatttgaacccactaagtagaga 300
ttctgcttttgatgttgcagctcagggagttaaaaaaggttttaatggttctaatagttt 360
atttgcttggttagctgaaatatggataaaagatggcccactgtgagcaagctggaaatg 420
cctgatctctctcagtttaatgtagaggaagggatccaaaagtttagggaganttggatg 480
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
17
ctggraktgg attggtcact ttgrgaccta cccwtcccag ctgggagggt ccagaagata 540
cacccttgac caacgctttg cgaaatggat ttgtgatggc ggcaactact as 592
<210> 45
<211> 567
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(567)
<223> n = A,T,C or G
<400>
45
ggcttagtagttgccattgcgagtgcttgctcaacgagcgttgaacatggcggattgtct 60
agattcaacggatttgagttttaccagcaaagcgaaccaagcgcggcccagagaattatg 120
ggttggttggctttgaaaagatggaaatcctgtaggcctagtcagaaaag~ccttcttgca180
gaacagttggttctcgggcgaacgctcatcaagatgcccattggaaaggctagcgtgtat 240
ttgggagagcctgatagcgtgtcttctgatgatgtttgtgcttggacagtgacaaaagat 300
atgcaaagcaagtccgaactagacgtcaagcttcgtgagcaaattattgtagactcctac 360
ttatactgtgaggaatgatagccaagggtggggactttaagactaaggtggtttgtactt 420
gcgccgatgatcccaggcagaaagamctgatcgctagttttatacgggcaactactaagc 480
cgaattccagcacactggcggccgttactaattggatccganctcggtaccagcttgatg 540
catascttgagttwtctatantgtcnc 567
<210> 46
<211> 908
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(908)
<223> n = A,T,C or G
<400> 46
gagcgaaagaccgagggcagngnntangngcgangaagcggagagggccaaaaagcaacc 60
gctttccccggggggtgccgattcattaaggcaggtggaggacaggtttcccgatggaag 120
gcggcaggggcgcaagcaattaatgtgagtaggccattcattagcacccgggcttaacat 180
ttaagcttcgggttggtatgtggtgggaattgtgagcggataacaatttcacacaggaaa 240
cagctatgaccatgattacgccaagctatttaggtgacattatagaataactcaagttat 300
gcatcaagcttggtaccgagttcggatccactagtaacggccgccagtgtgtggaattcg 360
gcttagtagttgccgaccatggagtgctacctaggctagaatacctgagytcctccctag 420
cctcactcacattaaattgtatcttttctacattagatgtcctcagcgccttatttctgc 480
tggacwatcgataaattaatcctgataggatgatagcagcagattaattactgagagtat 540
gttaatgtgtcatccctcctatataacgtatttgcattttaatggagcaattctggagat 600
aatccctgaaggcaaaggaatgaatcttgagggtgagaaagccagaatcagtgtccagct 660
gcagttgtgggagaaggtgatattatgtatgtctcagaagtgacaccatatgggcaacta 720
ctaagcccgaattccagcacactggcgggcgttactaatggatccgagctcggtaccaag 780
cttgatgcatagcttgagtatctatagtgtcactaaatagcctggcgttatcatggtcat 840
agctgtttcctgtgtgaaattgttatccgctcccaattccccccaccatacgagccggaa 900
cataaagt 908
<210> 47
<211> 480
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
18
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(480)
<223> n = A,T,C or G
<.400> 47
tgccaacaaggaaagttttaaatttccccttgaggattcttggtgatcatcaaattcagt 60
ggtttttaaggttgttttctgtcaaataactctaactttaagccaaacagtatatggaag 120
cacagatakaatattacacagataaaagaggagttgatctaaagtaragatagttggggg 180
ctttaatttctggaacctaggtctccccatcttcttctgtgctgaggaacttcttggaag 240
cggggattctaaagttctttggaagacagtttgaaaaccaccatgttgttctcagtacct 300
ttatttttaaaaagtaggtgaacattttgagagagaaaagggcttggttgagatgaagtc 360
ccccccccccctttttttttttttagctgaaatagataccctatgttnaargaarggatt 420
attatttaccatgccaytarscacatgctctttgatgggcnyctccstaccctccttaag 480
<210> 48
<211> 591
<212> DNA
<213> Homo sapien
<400>
48
aagagggtaccgagtggaatttccgcttcactagtctggtgtggctagtcggtttcgtgg 60
tggccaacattacgaacttccaactcaaccgttcttggacgttcaagcgggagtaccggc 120
gaggatggtggcgtgaattctggcctttctttgccgtgggatcggtagccgccatcatcg 180
gtatgtttatcaagatcttctttactaacccgacctctccgatttacctgcccgagccgt 240
ggtttaacgaggggagggggatccagtcacgcgagtactggtcccagatcttcgccatcg 300
tcgtgacaatgcctatcaacttcgtcgtcaataagttgtggaccttccgaacggtgaagc 360
actccgaaaacgtccggtggctgctgtgcggtgactcccaaaatcttgataacaacaagg 420
taaccgaatcgcgctaaggaaccccggcatctcgggtactctgcatatgcgtacccctta 480
agccgaattccagcacactggcggccgttactaattggatccgaactccgtaaccaagcc 540
tgatgcgtaacttgagttattctatagtgtccctaaaataacctggcgtta 591
<210> 49
<211> 454
<212> DNA
<213> Homo sapien
<400> 49
aagagggtacctgccttgaaatttaaatgtctaaggaaartgggagatgattaagagttg 60
gtgtggcytagtcacaccaaaatgtatttattacatcctgctcctttctagttgacagga 120
aagaaagctgctgtggggaaaggagggataaatactgaagggatttactaaacaaatgtc 180
catcacagagttttcctttttttttttttgagacagagtcttgctctgtcacccaggctg 240
gaatgaagwggtatgatctcagttgaatgcaacctctacctcctaggttcaagcgattct 300
catgcctcagcctcctgagcagctgggactataggcgcatgctaccatgccaggctaatt 360
tttatatttttattagagacggggtgttgccatgttggccaggcaggtctcgaactcctg 420
ggcctcagatgatctgccccaccgtaccctctta 454
<210> 50
<211> 463
<212> DNA
<213> Homo sapien
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
19
<400> 50
aagagggtaccaaaaaaaagaaaaaggaaaaaaagaaaaacaacttgtataaggctttct 60
gctgcatacagctttttttttttaaataaatggtgccaacaaatgtttttgcattcacac 120
caattgctggttttgaaatcgtactcttcaaaggtatttgtgcagatcaatccaatagtg 180
atgccccgtaggttttgtggactgcccacgttgtctaccttctcatgtaggagccattga 240
gagactgtttggacatgcctgtgttcatgtagccgtgatgtccgggggccgtgtacatca 300
tgttaccgtggggtggggtctgcattggctgctgggcatatggctgggtgcccatcatgc 360
ccatctgcatctgcatagggtattggggcgtttgatccatatagccatgattgctgtggt 420
agccactgttcatcattggctgggacatgctgttaccctctta 463
<210> 51
<211> 399
<212> DNA
<213> Homo sapien
<400> 51
cttcaacctcccaaagtgctgggattacaggactgagccaccacgctcagcctaagcctc 60
tttttcactaccctctaagcgatctaccacagtgatgaggggctaaagagcagtgcaatt 120
tgattacaataatggaacttagatttattaattaacaatttttccttagcatgttggttc 180
cataattattaagagtatggacttacttagaaatgagctttcattttaagaatttcatct 240
ttgaccttctctattagtctgagcagtatgacactatacgtattttatttaactaaccta 300
ccttgagctattactttttaaaaggctatatacatgaatgtgtattgtcaactgtaaagc 360
cccacagtatttaattatatcatgatgtctttgaggttg 399
<210> 52
<211> 392
<212> DNA
<213> Homo sapien
<400> 52
cttcaacctc aatcaacctt ggtaattgat aaaatcatca cttaactttc tgatataatg 60
gcaataatta tctgagaaaa aaaagtggtg aaagattaaa cttgcatttc tctcagaatc 120
ttgaaggata tttgaataat tcaaaagcgg aatcagtagt atcagccgaa gaaactcact 180
tagctagaac gttggaccca tggatctaag tccctgccct tccactaacc agctgattgg 240
ttttgtgtaa acctcctaca cgcttgggct tggtcgcctc atttgtcaaa gtaaaggctg 300
aaataggaag ataatgaacc gtgtcttttt ggtctctttt ccatccatta ctctgatttt 360
acaaagaggc ctgtattccc ctggtgaggt tg 392
<210> 53
<211> 179
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (179)
<223> n = A,T,C or G
<400> 53
ttcgggtgat gcctcctcag gctacagtga agactggatt acagaaaggt gccagcgaga 60
tttcagattc ctgtaaacct ctaaagaaaa ggagtcgcgc ctcaactgat gtagaaatga 120
ctagttcagc atacngagac acntctgact ccgattctag aggactgagt gacctgcan 179
<210> 54
<211> 112
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(112)
<223> n = A,T,C or G
<400> 54
ttcgggtgat gcctcctcag gctacatcat natagaagca aagtagaana atcnngtttg 60
tgcattttcc cacanacaaa attcaaatga ntggaagaaa ttggganagt at 112
<210> 55
<211> 225
<212> DNA
<213> Homo sapien
<400> 55
tgagcttccg cttctgacaa ctcaatagat aatcaaagga caactttaac agggattcac 60
aaaggagtat atccaaatgc caataaacat ataaaaagga attcagcttc atcatcatca 120
gaagwatgca aattaaaacc ataatgagaa accactatgt cccactagaa tagataaaat 180
cttaaaagac tggtaaaacc aagtgttggt aaggcaagag gagca 225
<210> 56
<211> 175
<212> DNA
<213> Homo sapien
<400> 56
gctcctcttg ccttaccaac acattctcaa aaacctgtta gagtcctaag cattctcctg 60
ttagtattgg gattttaccc ctgtcctata aagatgttat gtaccaaaaa tgaagtggag 120
ggccataccc tgagggaggg gagggatctc tagtgttgtc agaagcggaa gctca 175
<210> 57
<211> 223
<212> DNA
<213> Homo sapien
<400> 57
agccatttac cacccatgga tgaatggatt ttgtaattct agctgttgta ttttgtgaat 60
ttgttaattt tgttgttttt ctgtgaaaca catacattgg atatgggagg taaaggagtg 120
tcccagttgc tcctggtcac tccctttata gccattactg tcttgtttct tgtaactcag 180
gttaggtttt ggtctctctt gctccactgc aaaaaaaaaa aaa 223
<210> 58
<211> 211
<212> DNA
<213> Homo sapien
<400> 58
gttcgaaggt gaacgtgtag gtagcggatc tcacaactgg ggaactgtca aagacgaatt 60
aactgacttg gatcaatcaa atgtgactga ggaaacacct gaaggtgaag aacatcatcc 120
agtggcagac actgaaaata aggagaatga agttgaagag gtaaaagagg agggtccaaa 180
agagatgact ttggatgggt ggtaaatggc t 211
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
21
<210> 59
<211> 208
<212> DNA
<213> Homo sapien
<400> 59
gctcctcttg ccttaccaac tttgcaccca tcatcaacca tgtggccagg tttgcagccc 60
aggctgcaca tcaggggact gcctcgcaat acttcatgct gttgctgctg actgatggtg
120ctgtgacgga tgtggaagcc acacgtgagg ctgtggtgcg tgcctcgaac ctgcccatgt
180
cagtgatcat tatgggtggt aaatggct 208
<210> 60
<211> 171
<212> DNA
<213> Homo sapien
<400> 60
agccatttac cacccatact aaattctagt tcaaactcca acttcttcca taaaacatct 60
aaccactgac accagttggc aatagcttct tccttcttta acctcttaga gtatttatgg 120
tcaatgccac acatttctgc aactgaataa agttggtaag gcaagaggag c 171
<210> 61
<211> 134
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(134)
<223> n = A,T,C or G
<400> 61
cgggtgatgc ctcctcaggc tttggtgtgt ccactcnact cactggcctc ttctccagca 60
actggtgaan atgtcctcan gaaaancncc acacgcngct cagggtgggg tgggaancat 120
canaatcatc nggc 134
<210> 62
<211> 145
<212> DNA
<213> Homo sapien
<400> 62
agagggtaca tatgcaacag tatataaagg aagaagtgca ctgagaggaa cttcatcaag 60
gccatttaat caataagtga tagagtcaag gctcaaccca ggtgtgacgg attccaggtc 120
ccaagctcct tactggtacc ctctt 145
<210> 63
<211> 297
<212> DNA
<213> Homo sapien
<400> 63
tgcactgaga ggaattcaaa gggtttatgc caaagaacaa accagtcctc tgcagcctaa 60
ctcatttgtt tttgggctgc gaagccatgt agagggcgat caggcagtag atggtccctc 120
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
22
ccacagtcag cgccatggtg gtccggtaaa gcatttggtc aggcaggcct cgtttcaggt 180
agacgggcac acatcagctt tctggaaaaa cttttgtagc tctggagctt tgtttttccc 240
agcataatca tacactgtgg aatcggaggt cagtttagtt ggtaaggcaa gaggagc 297
<210> 64
<211> 300
<212> DNA
<213> Homo sapien
<400> 64
gcactgagaggaacttccaatactatgttgaataggagtggtgagagagggcatccttgt 60
cttgtgccggttttcaaagggaatgcttccagcttttgcccattcagtataatattaaag 120
aatgttttaccattttctgtcttgcctgtttttctgtgtttttgttggtctcttcattct 180
ccatttttaggcctttacatgttaggaatatatttcttttaatgatacttcacctttggt 240
atcttttgtgagactctactcatagtgtgataagcactgggttggtaaggcaagaggagc 300
<210> 65
<211> 203
<212> DNA
<213> Homo sapien
<400> 65
gctcctcttg ccttaccaac tcacccagta tgtcagcaat tttatcrgct ttacctacga 60
aacagcctgt atccaaacac ttaacacact cacctgaaaa gttcaggcaa caatcgcctt 120
ctcatgggtc tctctgctcc agttctgaac ctttctcttt tcctagaaca tgcatttarg 180
tcgatagaag ttcctctcag tgc 203
<210> 66
<211> 344
<212> DNA
<213> Homo sapien
<400>
66
tacggggacccctgcattgagaaagcgagactcactctgaagctgaaatgctgttgccct 60
tgcagtgctggtagcaggagttctgtgctttgtgggctaaggctcctggatgacccctga 120
catggagaaggcagagttgtgtgccccttctcatggcctcgtcaaggcatcatggactgc 180
cacacacaaaatgccgtttttattaacgacatgaaattgaaggagagaacacaattcact 240
gatgtggctcgtaaccatggatatggtcacatacagaggtgtgattatgtaaaggttaat 300
tccacccacctcatgtggaaactagcctcaatgcaggggtccca 344
<210> 67
<211> 157
<212> DNA
<213> Homo sapien
<400> 67
gcactgagag gaacttcgta gggaggttga actggctgct gaggaggggg aacaacaggg 60
taaccagact gatagccatt ggatggataa tatggtggtt gaggagggac actacttata 120
gcagagggtt gtgtatagcc tgaggaggca tcacccg 157
<210> 68
<211> 137
<212> DNA
<213> Homo sapien
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
23
<400> 68
gcactgagag gaacttctag aaagtgaaag tctagacata aaataaaata aaaatttaaa 60
actcaggaga gacagcccag cacggtggct cacgcctgta atcccagaac tttgggagcc 120
tgaggaggca tcacccg 137
<210> 69
<211> 137
<212> DNA
<213> Homo sapien
<400> 69
cgggtgatgc ctcctcaggc tgtattttga agactatcga ctggacttct tatcaactga 60
agaatccgtt aaaaatacca gttgtattat ttctacctgt caaaatccat ttcaaatgtt 120
gaagttcctc tcagtgc 137
<210> 70
<211> 220
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(220)
<223> n = A,T,C or G
<400> 70
agcatgttga gcccagacac gcaatctgaa tgagtgtgca cctcaagtaa atgtctacac 60
gctgcctggt ctgacatggc acaccatcnc gtggagggca casctctgct cngcctacwa 120
cgagggcant ctcatwgaca ggttccaccc accaaactgc aagaggctca nnaagtactr 180
ccagggtmya sggacmasgg tgggaytyca ycacwcatct 220
<210> 71
<211> 353
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(353)
<223> n = A,T,C or G
<400> 71
cgttagggtctctatccactgctaaaccatacacctgggtaaacagggaccatttaacat60
tcccanctaaatatgccaagtgacttcacatgtttatcttaaagatgtccaaaacgcaac120
tgattttctcccctaaacctgtgatggtgggatgattaancctgagtggtctacagcaag180
ttaagtgcaaggtgctaaatgaangtgacctgagatacagcatctacaaggcagtacctc240
tcaacncagggcaactttgcttctcanagggcatttagcagtgtctgaagtaatttctgt300
attacaactcacggggcggggggtgaatatctantgganagnagaccctaacg 353
<210> 72
<211> 343
<212> DNA
<213> Homo sapien
<400> 72
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
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gcactgagaggaacttccaatacyatkatcagagtgaacargcarccyacagaacaggag 60
aaaatgttygcaatctctccatctgacaaaaggctaatatccagawtctaawaggaactt 120
aaacaaatttatgagaaaagaacaracaacctcawcaaaaagtgggtgaaggawatgcts 180
aaargaagacatytattcagccagtaaacayatgaaaaaaaggctcatsatcactgawca 240
ttagagaaatgcaaatcaaaaccacaatgagataccatctyayrccagttagaayggtga 300
tcattaaaarstcaggaaacaacagatgctggacaaggtgtca 343
<210> 73
<211> 321
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(321)
<223> n = A,T,C or G
<400> 73
gcactgagaggaacttcagagagagagagagagttccaccctgtacttggggagagaaac 60
agaaggtgagaaagtctttggttctgaagcagcttctaagatcttttcatttgcttcatt 120
tcaaagttcccatgctgccaaagtgccatcctttggggtactgttttctgagctccagtg 180
ataactcatttatacaagggagatacccagaaaaaaagtgagcaaatcttaaaaaggtgg 240
cttgagttcagccttaaataccatcttgaaatgacacagagaaagaangatgttgggtgg 300
gagtggatagagaccctaacg 321
<210> 74
<211> 321
<212> DNA
<213> Homo sapien
<400> 74
gcactgagaggaacttcagagagagagagagagttccaccctgtacttggggagagaaac 60
agaaggtgagaaagtctttggttctgaagcagcttctaagatcttttcatttgcttcatt 120
tcaaagttcccatgctgccaaagtgccatcctttggggtactgttttctgagctccagtg 180
ataactcatttatacaagggagatacccagaaaaaaagtgagcaaatcttaaaaaggtgg 240
cttgagttcagycttaaataccatcttgaaatgamacagagaaagaaggatgttgggtgg 300
gagtggatagagaccctaacg 321
<210> 75
<211> 317
<212> DNA
<213> Homo sapien
<400>
75
gcactgagaggaacttccacatgcactgagaaatgcatgttcacaaggactgaagtctgg 60
aactcagtttctcagttccaatcctgattcaggtgtttaccagctacacaaccttaagca 120
agtcagataaccttagcttcctcatatgcaaaatgagaatgaaaagtactcatcgctgaa 180
ttgttttgaggattagaaaaacatctggcatgcagtagaaattcaattagtattcatttt 240
cattcttctaaattaaacaaataggatttttagtggtggaacttcagacaecagaaatgg 300
gagtggatagagaccct 317
<210> 76
<211> 244
<212> DNA
<213> Homo sapien
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
<400> 76
cgttagggtctctatccactcccactactgatcaaactctatttatttaattatttttat 60
catactttaagttctgggatacacgtgcagcatgcgcaggtttgttgcataggtatacac 120
ttgccatggtggtttgctgcacccatcagtccatcatctacattaggtatttctcctaat 180
gctatccctcccctagccccttacacccccaacaggctctagtgtgtgaagttcctctca 240
gtgc 244
<210> 77
<211> 254
<212> DNA
<213> Homo sapien
<400> 77
cgttagggtctctatccactgaaatctgaagcacaggaggaagagaagcagtyctagtga 60
gatggcaagttcwtttaccacactctttaacatttygtttagttttaacctttatttatg 120
gataataaaggttaatattaataatgatttattttaaggcattcccraatttgcataatt 180
ctccttttggagatacccttttatctccagtgcaagtctggatcaaagtgatasamagaa 240
gttcctctcagtgc 254
<210> 78
<211> 355
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (355)
<223> n = A,T,C or G
<400> 78
ttcgatacaggcaaacatgaactgcaggagggtggtgacgatcatgatgttgccgatggt 60
ccggatggncacgaagacgcactggancacgtgcttacgtccttttgctctgttgatggc 120
cctgaggggacgcaggacccttatgaccctcagaatcttcacaacgggagatggcactgg 180
attgantcccantgacaccagagacaccccaaccaccagnatatcantatattgatgtag 240
ttcctgtaganggcccccttgtggaggaaagctccatnagttggtcatcttcaacaggat 300
ctcaacagtttccgatggctgtgatgggcatagtcatanttaaccntgtntcgaa 355
<210> 79
<211> 406
<212> DNA
<213> Homo sapien
<400> 79
taagagggtaccagcagaaaggttagtatcatcagatagcatcttatacgagtaatatgc60
ctgctatttgaagtgtaattgagaaggaaaattttagcgtgctcactgacctgcctgtag120
ccccagtgacagctaggatgtgcattctccagccatcaagagactgagtcaagttgttcc180
ttaagtcagaacagcagactcagctctgacattctgattcgaatgacactgttcaggaat240
cggaatcctgtcgattagactggacagcttgtggcaagtgaatttgcctgtaacaagcca300
gattttttaaaatttatattgtaaataatgtgtgtgtgtgtgtgtgtatatatatatata360
tgtacagttatctaagttaatttaaaagttgtttggtaccctctta 406
<210> 80
<211> 327
<212> DNA
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
26
<213> Homo sapien
<400> 80
tttttttttttttactcggctcagtctaatcctttttgtagtcactcataggccagactt 60
agggctaggatgatgattaataagagggatgacataactattagtggcaggttagttgtt 120
tgtagggctcatggtaggggtaaaaggagggcaatttctagatcaaataataagaaggta 180
atagctactaagaagaattttatggagaaagggacgcgggcgggggatatagggtcgaag 240
ccgcactcgtaaggggtggatttttctatgtagccgttgagttgtggtagtcaaaatgta 300
ataattattagtagtaagcctaggaga 327
<210> 81
<211> 318
<212> DNA
<213> Homo sapien
<400> 81
tagtctatgc ggttgattcg gcaatccatt atttgctgga ttttgtcatg tgttttgcca 60
attgcattca taatttatta tgcatttatg cttgtatctc ctaagtcatg gtatataatc 120
catgcttttt atgttttgtc tgacataaac tcttatcaga gccctttgca cacagggatt 180
caataaatat taacacagtc tacatttatt tggtgaatat tgcatatctg ctgtactgaa 240
agcacattaa gtaacaaagg caagtgagaa gaatgaaaag cactactcac aacagttatc 300
atgattgcgc atagacta 318
<210> 82
<211> 338
<212> DNA
<213> Homo sapien
<400> 82
tcttcaacctctactcccactaatagctttttgatgacttctagcaagcctcgctaacct 60
cgccttaccccccactattaacctactgggagaactctctgtgctagtaaccacgttctc 120
ctgatcaaatatcactctcctacttacaggactcaacatactagtcacagccctatactc 180
cctctacatatttaccacaacacaatggggctcactcacccaccacattaacaacataaa 240
accctcattcacacgagaaaacaccctcatgttcatacacctatcccccattctcctcct 300
atccctcaaccccgacatcattaccgggttttcctctt 338
<210> 83
<211> 111
<212> DNA
<213> Homo sapien
<400> 83
agccatttac cacccatcca caaaaaaaaa aaaaaaaaag aaaaatatca aggaataaaa 60
atagactttg aacaaaaagg aacatttgct ggcctgagga ggcatcaccc g 111
<210> 84
<211> 224
<212> DNA
<213> Homo sapien
<400> 84
tcgggtgatg cctcctcagg ccaagaagat aaagcttcag acccctaaca catttccaaa 60
aaggaagaaa ggagaaaaaa gggcatcatc cccgttccga agggtcaggg aggaggaaat 120
tgaggtggat tcacgagttg cggacaactc ctttgatgcc aagcgaggtg cagccggaga 180
ctggggagag cgagccaatc aggttttgaa gttcctctca gtgc 224
CA 02365909 2001-10-04
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27
<210> 85
<211> 348
<212> DNA
<213> Homo sapien
<400> 85
gcactgagag gaacttcgtt ggaaacgggt ttttttcatg taaggctaga cagaagaatt 60
ctcagtaact tccttgtgtt gtgtgtattc aactcacasa gttgaacgat cctttacaca 120
gagcagactt gtaacactct twttgtggaa tttgcaagtg gagatttcag scgctttgaa 180
gtsaaaggta gaaaaggaaa tatcttccta taaaaactag acagaatgat tctcagaaac 240
tcctttgtga tgtgtgcgtt caactcacag agtttaacct ttcwtttcat agaagcagtt 300
aggaaacact ctgtttgtaa agtctgcaag tggatagaga ccctaacg 348
<210> 86
<211> 293
<212> DNA
<213> Homo sapien
<400> 86
gcactgagag gaacttcyttgtgwtgtktgyattcaactcacagagttgaasswtsmttt 60
acabagwkca ggcttkcaaacactctttttgtmgaatytgcaagwggakatttsrrccrc 120
tttgwggycw wysktmgaawmggrwatatcttcwyatmraamctagacagaaksattctc 180
akaawstyyy ytgtgawgwstgcrttcaactcacagagktkaacmwtyctkytsatrgag 240
cagttwkgaa actctmtttctttggattctgcaagtggatagagaccctaacg 293
<210> 87
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 87
ctcctaggct 10
<210> 88
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 88
agtagttgcc 10
<210> 89
<211> 11
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
CA 02365909 2001-10-04
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28
<400> 89
ttccgttatg c 11
<210> 90
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 90
tggtaaaggg 10
<210> 91
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 91
tcggtcatag 10
<210> 92
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 92
tacaacgagg 10
<210> 93
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 93
tggattggtc 10
<210> 94
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
CA 02365909 2001-10-04
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<400> 94
ctttctaccc 10
<210> 95
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 95
ttttggctcc 10
<210> 96
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 96
ggaaccaatc 10
<210> 97
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 97
tcgatacagg 10
<210> 98
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 98
ggtactaagg 10
<210> 99
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
<400> 99
agtctatgcg 10
<210> 100
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 100
ctatccatgg 10
<210> 101
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 101
tctgtccaca 10
<210> 102
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 102
aagagggtac - 10
<210> 103
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 103
cttcaacctc 10
<210> 104
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
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<400> 104
gctcctcttg ccttaccaac 20
<210> 105
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 105
gtaagtcgag cagtgtgatg 20
<210> 106
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 106
gtaagtcgag cagtctgatg 20
<210> 107
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer.for amplification from breast tumor cDNA
<400> 107
gacttagtgg aaagaatgta 20
<210> 108
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 108
gtaattccgc caaccgtagt 20
<210> 109
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
CA 02365909 2001-10-04
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<400> 109
atggttgatc gatagtggaa 20
<210> 110
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 110
acggggaccc ctgcattgag 20
<210> 111
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 111
tattctagac cattcgctac 20
<210> 112
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 112
acataaccac tttagcgttc 20
<210> 113
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 113
cgggtgatgc ctcctcaggc 20
<210> 114
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
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<400> 114
agcatgttga gcccagacac 20
<210> 115
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 115
gacaccttgt ccagcatctg 20
<210> 116
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 116
tacgctgcaa cactgtggag 20
<210> 117
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 117
cgttagggtc tctatccact 20
<210> 118
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 118
agactgactc atgtccccta 20
<210> 119
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
CA 02365909 2001-10-04
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<400> 119
tcatcgctcg gtgactcaag 20
<210> 120
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 120
caagattcca taggctgacc 20
<210> 121
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 121
acgtactggt cttgaaggtc 20
<210> 122
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 122
gacgcttggc cacttgacac 20
<210> 123
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 123
gtatcgacgt agtggtctcc 20
<210> 124
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
CA 02365909 2001-10-04
VSO 00/61753 PCT/US00/09312
<400> 124
tagtgacatt acgacgctgg 20
<210> 125
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 125
cgggtgatgc ctcctcaggc 20
<210> 126
<211> 23
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 126
atggctattt tcgggggctg aca 23
<210> 127
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 127
ccggtatctc ctcgtgggta tt 22
<210> 128
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
<400> 128
ctgcctgagc cacaaatg 18
<210> 129
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer for amplification from breast tumor cDNA
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36
<400> 129
ccggaggagg aagctagagg aata 24
<210> 130
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer
<400> 130
tttttttttt ttag 14
<210> 131
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Predicited Th Motifs (B-cell epitopes)
<400> 131
Ser Ser Gly Gly Arg Thr Phe Asp Asp Phe His Arg Tyr Leu Leu Val
1 5 10 15
Gly Ile
<210> 132
<211> 22
<212> PRT
<213> Artificial Sequence
<220>
<223> Predicited Th Motifs (B-cell epitopes)
<221> VARIANT
<222> (1) . . . (22)
<223> Xaa = Any Amino Acid
<400> 132
Gln Gly Ala Ala Gln Lys Pro Ile Asn Leu Ser Lys Xaa Ile Glu Val
1 5 10 15
Val Gln Gly His Asp Glu
<210> 133
<211> 23
<212> PRT
<213> Artificial Sequence
<220>
<223> Predicited Th Motifs (B-cell epitopes)
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<400> 133
Ser Pro Gly Val Phe Leu Glu His Leu Gln Glu Ala Tyr Arg Ile Tyr
1 5 10 15
Thr Pro Phe Asp Leu Ser Ala
<210> 134
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Predicited HLA A2.1 Motifs (T-cell epitopes)
<400> 134
Tyr Leu Leu Val Gly Ile Gln Gly Ala
1 5
<210> 135
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Predicited HLA A2.1 Motifs (T-cell epitopes)
<400> 135
Gly Ala Ala Gln Lys Pro Ile Asn Leu
1 5
<210> 136
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Predicited HLA A2.1 Motifs (T-cell epitopes)
<221> VARIANT
<222> (1) . . . (9)
<223> Xaa = Any Amino Acid
<400> 136
Asn Leu Ser Lys Xaa Ile Glu Val Val
1 5
<210> 137
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Predicited HLA A2.1 Motifs (T-cell epitopes)
<400> 137
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38
Glu Val Val Gln Gly His Asp Glu Ser
1 5
<210> 138
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Predicited HLA A2.1 Motifs (T-cell epitopes)
<400> 138
His Leu Gln Glu Ala Tyr Arg Ile Tyr
1 5
<210> 139
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Predicited HLA A2.1 Motifs (T-cell epitopes)
<400> 139
Asn Leu Ala Phe Val Ala Gln Ala Ala
1 5
<210> 140
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Predicited HLA A2.1 Motifs (T-cell epitopes)
<400> 140
Phe Val Ala Gln Ala Ala Pro Asp Ser
1 5
<210> 141
<211> 9388
<212> DNA
<213> Homo sapien
<400>
141
gctcgcggccgcgagctcaattaaccctcactaaagggagtcgactcgatcagactgtta 60
ctgtgtctatgtagaaagaagtagacataagagattccattttgttctgtactaagaaaa 120
attcttctgccttgagatgctgttaatctgtaaccctagccccaaccctgtgctcacaga 180
gacatgtgctgtgttgactcaaggttcaatggatttagggctatgctttgttaaaaaagt 240
gcttgaagataatatgcttgttaaaagtcatcaccattctctaatctcaagtacccaggg 300
acacaatacactgcggaaggccgcagggacctctgtctaggaaagccaggtattgtccaa 360
gatttctccccatgtgatagcctgagatatggcctcatgggaagggtaagacctgactgt 420
cccccagcccgacatcccccagcccgacatcccccagcccgacacccgaaaagggtctgt 480
gctgaggaggattagtaaaagaggaaggcctctttgcagttgaggtaagaggaaggcatc 540
tgtctcctgctcgtccctgggcaatagaatgtcttggtgtaaaacccgattgtatgttct 600
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39
acttactgagataggagaaaacatccttagggctggaggtgagacacgctggcggcaata660
ctgctctttaatgcaccgagatgtttgtataagtgcacatcaaggcacagcacctttcct720
taaacttatttatgacacagagacctttgttcacgttttcctgctgaccctctccccact780
attaccctattggcctgccacatccccctctccgagatggtagagataatgatcaataaa840
tactgagggaactcagagaccagtgtccctgtaggtcctccgtgtgctgagcgccggtcc900
cttgggctcacttttctttctctatactttgtctctgtgtctctttcttttctcagtctc960
tcgttccacctgacgagaaatacccacaggtgtggaggggcaggccaccccttcaataat1020
ttactagcctgttcgctgacaacaagactggtggtgcagaaggttgggtcttggtgttca1080
ccgggtggcaggcatgggccaggtgggagggtctecagcgcctggtgcaaatctccaaga1140
aagtgcaggaaacagcaccaagggtgattgtaaattttgatttggcgcggcaggtagcca1200
ttccagcgcaaaaatgcgcaggaaagcttttgctgtgcttgtaggcaggtaggccccaag1260
cacttcttattggctaatgtggagggaacctgcacatccattggctgaaatctccgtcta1320
tttgaggctgactgagcgcgttcctttcttctgtgttgcctggaaacggactgtctgcct1380
agtaacatctgatcacgtttcccattggccgccgtttccggaagcccgccctcccatttc1440
cggaagcctggcgcaaggttggtctgcaggtggcctccaggtgcaaagtgggaagtgtga1500
gtcctcagtcttgggctattcggccacgtgcctgccggacatgggacgctggagggtcag1560
cagcgtggagtcctggccttttgcgtccacgggtgggaaattggccattgccacggcggg1620
aactgggactcaggctgccccccggccgtttctcatccgtccaccggactcgtgggcgct1680
cgcactggcgctgatgtagtttcctgacctctgacccgtattgtctccagattaaaggta1740
aaaacggggctttttcagcccactcgggtaaaacgccttttgatttctaggcaggtgttt1800
tgttgcacgcctgggagggagtgacccgcaggttgaggtttattaaaatacattcctggt1860
ttatgttatgtttataataaagcaccccaacctttacaaaatctcactttttgccagttg1920
tattatttagtggactgtctctgataaggacagccagttaaaatggaattttgttgttgc1980
taattaaaccaatttttagttttggtgtttgtcctaatagcaacaacttctcaggcttta2040
taaaaccatatttcttgggggaaatttctgtgtaaggcacagcgagttagtttggaattg2100
ttttaaaggaagtaagttcctggttttgatatcttagtagtgtaatgcccaacctggttt2160
ttactaaccctgtttttagactctccctttccttaaatcacctagccttgtttccacctg2220
aattgactctcccttagctaagagcgccagatggactccatcttggctctttcactggca2280
gccccttcctcaaggacttaacttgtgcaagctgactcccagcacatccaagaatgcaat2340
taactgttaagatactgtggcaagctatatccgcagttccgaggaattcatccgattgat2400
tatgcccaaaagccccgcgtctatcaccttgtaataatcttaaagcccctgcacctggaa2460
ctattaactttcctgtaaccatttatccttttaacttttttgcttactttatttctgtaa2520
aattgttttaactagacctcccctcccctttctaaaccaaagtataaaagaagatctagc2580
cccttcttcagagcggagagaattttgagcattagccatctcttggcggccagctaaata2640
aatggacttttaatttgtctcaaagtgtggcgttttctctaactcgctcaggtacgacat2700
ttggaggccccagcgagaaacgtcaccgggagaaacgtcaccgggcgagagccgggcccg2760
ctgtgtgctcccccggaaggacagccagcttgtaggggggagtgccacctgaaaaaaaaa2820
tttccaggtccccaaagggtgaccgtcttccggaggacagcggatcgactaccatgcggg2880
tgcccaccaaaattccacctctgagtcctcaactgctgaccccggggtcaggtaggtcag2940
atttgactttggttctggcagagggaagcgaccctgatgagggtgtccctcttttgactc3000
tgcccatttctctaggatgctagagggtagagccctggttttctgttagacgcctctgtg3060
tctctgtctgggagggaagtggccctgacaggggccatcccttgagtcagtccacatccc3120
aggatgctgggggactgagtcctggtttctggcagactggtctctctctctctctttttc3180
tatctetaatctttccttgttcaggtttcttggagaatctctgggaaagaaaaaagaaaa3240
actgttataaactctgtgtgaatggtgaatgaatgggggaggacaagggcttgcgcttgt3300
cctccagtttgtagctccacggcgaaagctacggagttcaagtgggccctcacctgcggt3360
tccgtggcgacctcataaggcttaaggcagcatccggcatagctcgatccgagccggggg3420
tttataccggcctgtcaatgctaagaggagcccaagtcccctaagggggagcggccaggc3480
gggcatctgactgatcccatcacgggaccccctccccttgtttgtctaaaaaaaaaaaaa3540
gaagaaactgtcataactgtttacatgccctagggtcaactgtttgttttatgtttattg3600
ttctgttcggtgtctattgtcttgtttagtggttgtcaaggttttgcatgtcaggacgtc3660
gatattgcccaagacgtctgggtaagaacttctgcaaggtccttagtgctgattttttgt3720
cacaggaggttaaatttctcatcaatcatttaggctggccaccacagtcctgtcttttct3780
gccagaagcaagtcaggtgttgttacgggaatgagtgtaaaaaaacattcgcctgattgg3840
gatttctggcaccatgatggttgtatttagattgtcataccccacatccaggttgattgg3900
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
acctcctctaaactaaactggtggtgggttcaaaacagccaccctgcagatttccttgct3960
cacctctttggtcattctgtaacttttcctgtgcccttaaatagcacactgtgtagggaa4020
acctaccctcgtactgctttacttcgtttagattcttactctgttcctctgtggctactc4080
tcccatcttaaaaacgatccaagtggtccttttcctcctccctgccccctaccccacaca4140
tctcgttttccagtgcgacagcaagttcagcgtctccaggacttggctctgctctcactc4200
cttgaacccttaaaagaaaaagctgggtttgagctatttgcctttgagtcatggagacac4260
aaaaggtatttagggtacagatctagaagaagagagagaacacctagatccaactgaccc4320
aggagatctcgggctggcctctagtcctcctccctcaatcttaaagctacagtgatgtgg4380
caagtggtatttagctgttgtggtttttctgctctttctggtcatgttgattctgttctt4440
tcgatactccagccccccagggagtgagtttctctgtctgtgctgggtttgatatctatg4500
ttcaaatcttattaaattgccttcaaaaaaaaaaaaaaaagggaaacacttcctcccagc4560
cttgtaagggttggagccctctccagtatatgctgcagaatttttctctcggtttctcag4620
aggattatggagtccgccttaaaaaaggcaagctctggacactctgcaaagtagaatggc4680
caaagtttggagttgagtggccccttgaagggtcactgaacctcacaattgttcaagctg4740
tgtggcgggttgttactgaaactcccggcctccctgatcagtttccctacattgatcaat4800
ggctgagtttggtcaggagcaccccttccatggctccactcatgcaccattcataatttt4860
acctccaaggtcctcctgagccagaccgtgttttcgcctcgaccctcagccggttcagct4920
cgccctgtactgcctctctctgaagaagaggagagtctccctcacccagtcccaccgcct4980
taaaaccagcctactcccttagggtcatcccatgtctcctcggctatgtcccctgtaggc5040
tcatcacccattgcctcttggttgcaaccgtggtgggaggaagtagcccctctactacca5100
ctgagagaggcacaagtccctctgggtgatgagtgctccacccccttcctggtttatgtc5160
ccttctttctacttctgacttgtataattggaaaacccataatcctcccttctctgaaaa5220
.
gccccaggctttgacctcactgatggagtctgtactctggacacattggcccacctggga5280
tgactgtcaacagctccttttgacccttttcacctctgaagagagggaaagtatccaaag5340
agaggccaaaaagtacaacctcacatcaaccaataggccggaggaggaagctagaggaat5400
agtgattagagacccaattgggacctaattgggacccaaatttctcaagtggagggagaa5460
cttttgacgatttccaccggtatctcctcgtgggtattcagggagctgctcagaaaccta5520
taaacttgtctaaggcgactgaagtcgtccaggggcatgatgagtcaccaggagtgtttt5580
tagagcacctcCaggaggcttatcggatttacaccccttttgacctggcagcccccgaaa5640
atagccatgctcttaatttggcatttgtggctcaggcagccccagatagtaaaaggaaac5700
tccaaaaactagagggattttgctggaatgaataccagtcagcttttagagatagcctaa5760
aaggtttttgacagtcaagaggttgaaaaacaaaaacaagcagctcaggcagctgaaaaa5820
agccactgataaagcatcctggagtatcagagtttactgttagatcagcctcatttgact5880
tcccctcccacatggtgtttaaatccagctacactacttcctgactcaaactccactatt5940
cctgttcatgactgtcaggaactgttggaaactactgaaactggccgacctgatcttcaa6000
aatgtgcccctaggaaaggtggatgccaccgtgttcacagacagtagcagcttcctcgag6060
aagggactacgaaaggccggtgcagctgttaccatggagacagatgtgttgtgggctcag6120
gctttaccagcaaacacctcagcacaaaaggctgaattgatcgccctcactcaggctctc6180
cgatggggtaaggatattaacgttaacactgacagcaggtacgcctttgctactgtgcat6240
gtacgtggagccatctaccaggagcgtgggctactcacctcagcaggtggctgtaatcca6300
ctgtaaaggacatcaaaaggaaaacacggctgttgcccgtggtaaccagaaagctgattc6360
agcagctcaagatgcagtgtgactttcagtcacgcctctaaacttgctgcccacagtctc6420
ctttccacagccagatctgcctgacaatcccgcatactcaacagaagaagaaaactggcc6480
tcagaactcagagccaataaaaatcaggaaggttggtggattcttcctgactctagaatc6540
ttcataccccgaactcttgggaaaactttaatcagtcacctacagtctaccacccattta6600
ggaggagcaaagctacctcagctcctccggagccgttttaagatcccccatcttcaaagc6660
ctaacagatcaagcagctctccggtgcacaacctgcgcccaggtaaatgccaaaaaaggt6720
cctaaacccagcccaggccaccgtctccaagaaaactcaccaggagaaaagtgggaaatt6780
gactttacagaagtaaaaccacaccgggctgggtacaaataccttctagtactggtagac6840
accttctctggatggactgaagcatttgctaccaaaaacgaaactgtcaatatggtagtt6900
aagtttttactcaatgaaatcatccctcgacgtgggctgcctgttgccatagggtctgat6960
aatggaccggccttcgccttgtctatagtttagtcagtcagtaaggcgttaaacattcaa7020
tggaagctccattgtgcctatcgaccccagagctctgggcaagtagaacgcatgaactgc7080
accctaaaaaacactcttacaaaattaatcttagaaaccggtgtaaattgtgtaagtctc7140
cttcctttagccctacttagagtaaggtgcaccccttactgggctgggttcttacctttt7200
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
41
gaaatcatgtatgggagggcgctgcctatcttgcctaagctaagagatgcccaattggca 7260
aaaatatcacaaactaatttattacagtacctacagtctccccaacaggtacaagatatc 7320
atcctgccacttgttcgaggaacccatcccaatccaattcctgaacagacagggccctgc 7380
cattcattcccgccaggtgacctgttgtttgttaaaaagttccagagagaaggactccct 7440
cctgcttggaagagacctcacaccgtcatcacgatgccaacggctctgaaggtggatggc 7500
attcctgcgtggattcatcactcccgcatcaaaaaggccaacggagcccaactagaaaca 7560
tgggtccccagggctgggtcaggccccttaaaactgcacctaagttgggtgaagccatta 7620
gattaattctttttcttaattttgtaaaacaatgcatagcttctgtcaaacttatgtatc 7680
ttaagactcaatataacccccttgttataactgaggaatcaatgatttgattccccaaaa 7740
acacaagtggggaatgtagtgtccaacctggtttttactaaccctgtttttagactctcc 7800
ctttcctttaatcactcagccttgtttccacctgaattgactctcccttagctaagagcg 7860
ccagatggactccatcttggctctttcactggcagccgcttcctcaaggacttaacttgt 7920
gcaagctgactcccagcacatccaagaatgcaattaactgataagatactgtggcaagct 7980
atatccgcagttcccaggaattcgtccaattgattacacccaaaagccccgcgtctatca 8040
ccttgtaataatcttaaagcccctgcacctggaactattaacgttcctgtaaccatttat 8100
ccttttaacttttttgcctactttatttctgtaaaattgttttaactagaccccccctct 8160
cctttctaaaccaaagtataaaagcaaatctagccccttcttcaggccgagagaatttcg 8220
agcgttagccgtctcttggccaccagctaaataaacggattcttcatgtgtctcaaagtg 8280
tggcgttttctctaactcgctcaggtacgaccgtggtagtattttccccaacgtcttatt 8340
tttagggcacgtatgtagagtaacttttatgaaagaaaccagttaaggaggttttgggat 8400
ttcctttatcaactgtaatactggttttgattatttatttatttatttattttttttgag 8460
aaggagtttcactcttgttgcccaggctggagtgcaatggtgcgatcttggctcactgca 8520
acttccgcctcccaggttcaagcgattctcctgcctcagcctcgagagtagctgggatta 8580
taggcatgcgccaccacacccagctaattttgtatttttagtaaagatggggtttcttca 8640
tgttggtcaagctggtctggaactccccgcctcgggtgatctgcccgcctcggcctccga 8700
aagtgctgggattacaggtgtgatccaccacacccagccgatttatatgtatataaatca 8760
cattcctctaaccaaaatgtagtgtttccttccatcttgaatataggctgtagaccccgt 8820
gggtatgggacattgttaacagtgagaccacagcagtttttatgtcatctgacagcatct 8880
ccaaatagccttcatggttgtcactgcttcccaagacaattccaaataacacttcccagt 8940
gatgacttgctacttgctattgttacttaatgtgttaaggtggctgttacagacactatt 9000
agtatgtcaggaattacaccaaaatttagtggctcaaacaatcattttattatgtatgtg 9060
gattctcatggtcaggtcaggatttcagacagggcacaagggtagcccacttgtctctgt 9120
ctatgatgtctggcctcagcacaggagactcaacagctggggtctgggaccatttggagg 9180
cttgttccctcacatctgatacctggcttgggatgttggaagagggggtgagctgagact 9240
gagtgcctatatgtagtgtttccatatggccttgacttccttacagcctggcagcctcag 9300
ggtagtcagaattcttaggaggcacagggctccagggcagatgctgaggggtcttttatg 9360
aggtagcacagcaaatccacccaggatc 9388
<210> 142
<211> 419
<212> DNA
<213> Homo sapien
<400> 142
tgtaagtcgagcagtgtgatggaaggaatggtctttggagagagcatatccatctcctcc 60
tcactgcctcctaatgtcatgaggtacactgagcagaattaaacagggtagtcttaacca 120
cactatttttagctaccttgtcaagctaatggttaaagaacacttttggtttacacttgt 180
tgggtcatagaagttgctttccgccatcacgcaataagtttgtgtgtaatcagaaggagt 240
taccttatggtttcagtgtcattctttagttaacttgggagctgtgtaatttaggctttg 300
cgtattatttcacttctgttctccacttatgaagtgattgtgtgttcgcgtgtgtgtgcg 360
tgcgcatgtgcttccggcagttaacataagcaaatacccaacatcacactgctcgactt 419
<210> 143
<211> 402
<212> DNA
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
42
<213> Homo sapien
<400> 143
tgtaagtcgagcagtgtgatgtccactgcagtgtgttgctgggaacagttaatgagcaaa 60
ttgtatacaatggctagtacattgaccgggatttgttgaagctggtgagtgttatgactt 120
agcctgttagactagtctatgcacatggctctggtcaactaccgctctctcatttctcca 180
gataaatcccccatgctttatattctcttccaaacatactatcctcatcaccacatagtt 240
cctttgttaatgctttgttctagactttcccttttctgttttcttattcaaacctatatc 300
tctttgcatagattgtaaattcaaatgccctcagggtgcaggcagttcatgtaagggagg 360
gaggctagccagtgagatctgcatcacactgctcgacttaca 402
<210> 144
<211> 224
<212> DNA
<213> Homo sapien
<400> 144
tcgggtgatg cctcctcagg ccaagaagat aaagcttcag acccctaaca catttccaaa 60
aaggaagaaa ggagaaaaaa gggcatcatc cccgttccga agggtcaggg aggaggaaat 120
tgaggtggat tcacgagttg cggacaactc ctttgatgcc aagcgaggtg cagccggaga 180
ctggggagag cgagccaatc aggttttgaa gttcctctca gtgc 224
<210> 145
<211> 111
<212> DNA
<213> Homo sapien
<400> 145
agccatttac cacccatcca caaaaaaaaa aaaaaaaaag aaaaatatca aggaataaaa 60
atagactttg aacaaaaagg aacatttgct ggcctgagga ggcatcaccc g 111
<210> 146
<211> 585
<212> DNA
<213> Homo sapien
<400> 146
tagcatgttgagcccagacacttgtagagagaggaggacagttagaagaagaagaaaagt60
ttttaaatgctgaaagttactataagaaagctttggctttggatgagacttttaaagatg120
cagaggatgctttgcagaaacttcataaatatatgcaggtgattccttatttcctcctag180
aaatttagtgatatttgaaataatgcccaaacttaattttctcctgaggaaaactattct240
acattacttaagtaaggcattatgaaaagtttctttttaggtatagtttttcctaattgg300
gtttgacattgcttcatagtgcctctgtttttgtccataatcgaaagtaaagatagctgt360
gagaaaactattacctaaatttggtatgttgttttgagaaatgtccttatagggagctca420
cctggtggtttttaaattattgttgctactataattgagctaattataaaaacctttttg480
agacatattttaaattgtcttttcctgtaatactgatgatgatgttttctcatgcatttt540
cttctgaattgggaccattgctgctgtgtctgggctcacatgcta 585
<210> 147
<211> 579
<212> DNA
<213> Homo sapien
<220>
<221> misc feature
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
43
<222> (1)...(579)
<223> n = A,T,C or G
<400> 147
tagcatgttgagcccagacactgggcagcgggggtggccacggcagctcctgccgagccc 60
aagcgtgtttgtctgtgaaggaccctgacgtcacctgccaggctagggaggggtcaatgt 120
ggagtgaatgttcaccgactttcgcaggagtgtgcagaagccaggtgcaacttggtttgc 180
ttgtgttcatcacccctcaagatatgcacactgctttccaaataaagcatcaactgtcat 240
ctccagatggggaagactttttctccaaccagcaggcaggtccccatccactcagacacc 300
agcacgtccaccttctcgggcagcaccacgtcctccaccttctgctggtacacggtgatg 360
atgtcagcaaagccgttctgcangaccagctgccccgtgtgctgtgccatctcactggcc 420
tccaccgcgtacaccgctctaggccgcgcatantgtgcacagaanaaatgatgatccagt 480
cccacagcccacgtccaagangactttatccgtcagggattctttattctgcaggatgac 540
ctgtggtattaattgttcgtgtctgggctcaacatgcta 579
<210> 148
<211> 249
<212> DNA
<213> Homo sapien
<400> 148
tgacaccttg tccagcatct gcaagccagg aagagagtcc tcaccaagat ccccaccccg 60
ttggcaccag gatcttggac ttccaatctc cagaactgtg agaaataagt atttgtcgct 120
aaataaatct ttgtggtttc agatatttag ctatagcaga tcaggctgac taagagaaac 180
ccca.taagag ttacatactc attaatctcc gtctctatcc ccaggtctca gatgctggac 240
aaggtgtca 249
<210> 149
<211> 255
<212> DNA
<213> Homo sapien
<400> 149
tgacaccttg tccagcatct gctattttgt gactttttaa taatagccat tctgactggt 60
gtgagatggt aactcattgt gggtttggtc tgcatttctc taatgatcag tgatattaag 120
ctttttttaa atatgcttgt tgaccacatg tatatcatct tttgagaagt gtctgttcat 180
atcctttgcc cactttttaa tttttttatc ttgtaaattt gtttaatttc cttacagatg 240
ctggacaagg tgtca 255
<210> 150
<211> 318
<212> DNA
<213> Homo sapien
<400>
150
ttacgctgcaacactgtggaggccaagctgggatcacttcttcattctaactggagagga 60
gggaagttcaagtccagcagagggtgggtgggtagacagtggcactcagaaatgtcagct 120
ggacccctgtccccgcataggcaggacagcaaggctgtggctctccagggccagctgaag 180
aacaggacactgtctccgctgccacaaagcgtcagagactcccatctttgaagcacggcc 240
ttcttggtcttcctgcacttccctgttctgttagagacctggttatagacaaggcttctc 300
cacagtgttgcagcgtaa 318
<210> 151
<211> 323
<212> DNA
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
44
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(323)
<223> n = A,T,C or G
<400> 151tnacgcngcn
acnntgtaga
ganggnaagg
cnttccccac
attncccctt
catnanagaa60
ttattcnaccaagnntgaccnatgccntttatgacttacatgcnnactncntaatctgtn 120
tcnngccttaaaagcnnntccactacatgcntcancactgtntgtgtnacntcatnaact 180
gtcngnaataggggcncataactacagaaatgcanttcatactgcttccantgccatcng 240
cgtgtggccttncctactcttcttntattccaagtagcatctctggantgcttccccact 300
ctccacattgttgcagcnataat 323
<210> 152
<211> 311
<212> DNA
<213> Homo sapien
<400> 152
tcaagattcc ataggctgac cagtccaagg agagttgaaa tcatgaagga gagtctatct 60
ggagagagct gtagttttga gggttgcaaa gacttaggat ggagttggtg ggtgtggtta 120
gtctctaagg ttgattttgt tcataaattt catgccctga atgccttgct tgcctcaccc 180
tggtccaagc cttagtgaac acctaaaagt ctctgtcttc ttgctctcca aacttctcct 240
gaggatttcc tcagattgtc tacattcaga tcgaagccag ttggcaaaca agatgcagtc 300
cagagggtca g 311
<210> 153
<211> 332
<212> DNA
<213> Homo sapien
<400> 153
caagattccataggctgaccaggaggctattcaagatctctggcagttgaggaagtctct 60
ttaagaaaatagtttaaacaatttgttaaaatttttctgtcttacttcatttctgtagca 120
gttgatatctggctgtcctttttataatgcagagtgggaactttccctaccatgtttgat 180
aaatgttgtccaggctccattgccaataatgtgttgtccaaaatgcctgtttagttttta 240
aagacggaactccaccctttgcttggtcttaagtatgtatggaatgttatgataggacat 300
agtagtagcggtggtcagcctatggaatcttg 332
<210> 154
<211> 345
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (345)
<223> n = A,T,C or G
<400> 154
tcaagattcc ataggctgac ctggacagag atctcctggg tctggcccag gacagcaggc 60
tcaagctcag tggagaaggt ttccatgacc ctcagattcc cccaaacctt ggattgggtg 120
acattgcatc tectcagaga gggaggagat gtangtctgg gcttccacag ggacctggta 180
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
ttttaggatc agggtaccgc tggcctgagg cttggatcat tcanagcctg ggggtggaat 240
ggctggcagc ctgtggcccc attgaaatag gctctggggc actccctctg ttcctanttg 300
aacttgggta aggaacagga atgtggtcan cctatggaat cttga 345
<210> 155
<211> 295
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(295)
<223> n = A,T,C or G
<400> 155
gacgcttggc cacttgacac attaaacagt tttgcataat cactancatg tatttctagt 60
ttgctgtctg ctgtgatgcc ctgccctgat tctctggcgt taatgatggc aagcataatc 120
aaacgctgtt ctgttaattc caagttataa ctggcattga ttaaagcatt atctttcaca 180
actaaactgt tcttcatana acagcccata ttattatcaa attaagagac aatgtattcc 240
aatatccttt anggccaata tatttnatgt cccttaatta agagctactg tccgt 295
<210> 156
<211> 406
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (406)
<223> n = A,T,C or G
<400> 156
gacgcttggccacttgacactgcagtgggaaaaccagcatgagccgctgcccccaaggaa 60
cctcgaagcccaggcagaggaccagccatcccagcctgcaggtaaagtgtgtcacctgtc 120
aggtgggcttggggtgagtgggtgggggaagtgtgtgtgcaaagggggtgtnaatgtnta 180
tgcgtgtgagcatgagtgatggctagtgtgactgcatgtcagggagtgtgaacaagcgtg 240
cgggggtgtgtgtgcaagtgcgtatgcatatgagaatatgtgtctgtggatgagtgcatt 300
tgaaagtctgtgtgtgtgcgtgtggtcatganggtaanttantgactgcgcaggatgtgt 360
gagtgtgcatggaacactcantgtgtgtgtcaagtggccnancgtc 406
<210> 157
<211> 208
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (208)
<223> n = A,T,C or G
<400> 157
tgacgcttgg ccacttgaca cactaaaggg tgttactcat cactttcttc tctcctcggt 60
ggcatgtgag tgcatctatt cacttggcac tcatttgttt ggcagtgact gtaanccana 120
tctgatgcat acaccagctt gtaaattgaa taaatgtctc taatactatg tgctcacaat 180
anggtanggg tgaggagaag gggagaga 208
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
46
<210> 158
<211> 547
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (547)
<223> n = A,T,C or G
<400> 158
cttcaacctccttcaacctccttcaacctcctggattcaaacaatcatcccacctcagac 60
tccttagtagctgagactacagactcacgccactacatctggctaaatttttgtagagat 120
agggtttcatcatgttgccctggctggtetcaaactcctgacctcaagcaatgtgcccac 180
ctcagcctcccaaagtgctgggattacaggcataagccaccatgcccagtccatntttaa 240
tctttcctaccacattcttaccacactttcttttatgtttagatacataaatgcttacca 300
ttatgatacaattgcccacagtattaagacagtaacatgctgcacaggtttgtagcctag 360
gaacagtaggcaataccacatagcttaggtgtgtggtagactataccatctaggtttgtg 420
taagttacactttatgctgtttacacaatgacaaaaccatctaatgatgcatttctcaga 480
atgtatccttgtcagtaagctatgatgtacagggaacactgcccaaggacacagatattg 540
tacctgt 547
<210> 159
<211> 203
<212> DNA
<213> Homo sapien
<400> 159
gctcctcttg ccttaccaac tcacccagta tgtcagcaat tttatcrgct ttacctacga 60
aacagcctgt atccaaacac ttaacacact cacctgaaaa gttcaggcaa caatcgcctt 120
ctcatgggtc tctctgctcc agttctgaac ctttctcttt tcctagaaca tgcatttarg 180
tcgatagaag ttcctctcag tgc 203
<210> 160
<211> 402
<212> DNA
<213> Homo sapien
<400> 160
tgtaagtcgagcagtgtgatgggtggaacagggttgtaagcagtaattgcaaactgtatt 60
taaacaataataataatatttagcatttatagagcactttatatcttcaaagtacttgca 120
aacattayctaattaaataccctctctgattataatctggatacaaatgcacttaaactc 180
aggacagggtcatgagaraagtatgcatttgaaagttggtgctagctatgctttaaaaac 240
ctatacaatgatgggraagttagagttcagattctgttggactgtttttgtgcatttcag 300
ttcagcctgatggcagaattagatcatatctgcactcgatgactytgcttgataacttat 360
cactgaaatctgagtgttgatcatcacactgctcgacttaca 402
<210> 161
<211> 193
<212> DNA
<213> Homo sapien
<400> 161
agcatgttga gcccagacac tgaccaggag aaaaaccaac caatagaaac acgcccagac 60
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
47
actgaccagg agaaaaacca accaataaaa acaggcccgg acataagaca aataataaaa 120
ttagcggaca aggacatgaa aacagctatt gtaagagcgg atatagtggt gtgtgtctgg 180
gctcaacatg cta 193
<210> 162
<211> 147
<212> DNA
<213> Homo sapien
<400> 162
tgttgagccc agacactgac caggagaaaa accaaccaat aaaaacaggc ccggacataa 60
gacaaataat aaaattagcg gacaaggaca tgaaaacagc tattgtaaga gcggatatag 120
tggtgtgtgt ctgggctcaa catgcta 147
<210> 163
<211> 294
<212> DNA
<213> Homo sapien
<400>
163
tagcatgttgagcccagacacaaatctttccttaagcaataaatcatttctgcatatgtt 60
tttaaaaccacagctaagccatgattattcaaaaggactattgtattgggtattttgatt 120
tgggttcttatctccctcacattatcttcatttctatcattgacctcttatcccagagac 180
tctcaaacttttatgttatacaaatcacattctgtctcaaaaaatatctcacccacttct 240
cttctgtttctgcgtgtgtatgtgtgtgtgtgtgtgtctgggctcaacatgcta 294
<210> 164
<211> 412
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(412)
<223> n = A,T,C or G
<400> 164
cgggattggctttgagctgcagatgctgcctgtgaccgcacccggcgtggaacagaaagc 60
cacctggctgcaagtgcgccagagccgccctgactacgtgctgctgtggggctggggcgt 120
gatgaactccaccgccctgaaggaagcccaggccaccggatacccccgcgacaagatgta 180
cggcgtgtggtgggccggtgcggagcccgatgtgcgtgacgtgggcgaaggcgccaaggg 240
ctacaacgcgctggctctgaacggctacggcacgcagtccaaggtgatccangacatcct 300
gaaacacgtgcacgacaagggccagggcacggggcccaaagacgaagtgggctcggtgct 360
gtacacccgcggcgtgatcatccagatgctggacaaggtgtcaatcactaat 412
<210> 165
<211> 361
<212> DNA
<213> Homo sapien
<400> 165
ttgacacctt gtccagcatc tgcatctgat gagagcctca gatggctacc actaatggca 60
gaaggcaaag gagaacaggc attgtatggc aagaaaggaa gaaagagaga ggggagaaag 120
gtgctaggtt cttttcaaca accagttctt gatggaactg agagtaagag ctcaaggcca 180
ggtgtggtga ctccaaccag taatcccaac attttaggag gctgaggcag gcagatgtct 240
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
48
tgaccccatg agtttgtgac cagcctgaac aacatcatga gactccatct ctacaataat 300
tacaaaaatt aatcaggcat tgtggtatgc cctgtagtcc cagatgctgg acaaggtgtc 360
a 361
<210> 166
<211> 427
<212> DNA
<213> Homo sapien
<400> 166
twgactgactcatgtcccctacacccaactatcttctccaggtggccaggcatgatagaa 60
tctgatcctgacttaggggaatattttctttttacttcccatcttgattccctgccggtg 120
agtttcctggttcagggtaagaaaggagctcaggccaaagtaatgaacaaatccatcctc 180
acagacgtacagaataagagaacwtggacwtagccagcagaacmcaaktgaaamcagaac 240
mcttamctaggatracaamcmcrraratarktgcycmcmcwtataatagaaaccaaactt 300
gtatctaattaaatatttatccacygtcagggcattagtggttttgataa.atacgctttg360
gctaggattcctgaggttagaatggaaraacaattgcamcgagggtaggggacatgagtc 420
aktctaa 427
<210> 167
<211> 500
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (500)
<223> n = A,T,C or G
<400> 167
aacgtcgcatgctcccggccgccatggccgcgggatagactgactcatgtcccctaagat 60
agaggagacacctgctaggtgtaaggagaagatggttaggtctacggaggctccagggtg 120
.
ggagtagttccctgctaagggagggtagactgttcaacctgttcctgctccggcctccac 180
tatagcagatgcgagcaggagtaggagagagggaggtaagagtcagaagcttatgttgtt 240
tatgcggggaaacgccrtatcgggggcagccragttattaggggacantrtagwyartcw 300
agntagcatccaaagcgngggagttntcccatatggttggacctgcaggcggccgcatta 360
gtgattagcatgtgagccccagacacgcatagcaacaaggacctaaactcagatcctgtg 420
ctgattacttaacatgaattattgtatttatttaacaactttgagttatgaggcatatta 480
ttaggtccatattacctgga 500
<210> 168
<211> 358
<212> DNA
<213> Homo sapien
<400> 168
ttcatcgctcggtgactcaagcctgtaatcccagaactttgggaggccgaggggagcaga 60
tcacctgaggttgggagtttgagaccagcctggccaacatggtgacaacccgtctctgct 120
aaaaatacaaaaattagccaagcatggtggcatgcacttgtaatcccagctactcgggag 180
gctgaggcaggagaatcacttgaggccaggaggcagaggttgcagtgaggcagaggttga 240
gatcatgccactgcactccagcctgggcaacagagtaagactccatctcaaaaaaaaaaa 300
aaaaaaagaatgatcagagccacaaatacagaaaaccttgagtcaccgagcgatgaaa 358
<210> 169
<211> 1265
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
49
<212> DNA
<213> Homo sapien
<400> 169
ttctgtccacaccaatcttagagctctgaaagaatttgtctttaaatatcttttaatagt 60
aacatgtattttatggaccaaattgacattttcgactattttttcccaaaaaaagtcagg 120
tgaatttcagcacactgagttgggaatttcttatcccagaagwcggcacgagcaatttca 180
tatttatttaagattgattccatactccgttttcaaggagaatccctgcagtctccttaa 240
aggtagaacaaatactttctatttttttttcaccattgtgggattggactttaagaggtg 300
actctaaaaaaacagagaacaaatatgtctcagttgtattaagcacggacccatattatc 360
atattcacttaaaaaaatgatttcctgtgcaccttttggcaacttctcttttcaatgtag 420
ggaaaaacttagtcaccctgaaaacccacaaaataaataaaacttgtagatgtgggcaga 480
argtttgggggtggacattgtatgtgtttaaattaaaccctgtatcactgagaagctgtt 540
gtatgggtcagagaaaatgaatgcttagaagctgttcacatcttcaagagcagaagcaaa 600
ccacatgtctcagctatattattatttattttttatgcataaagtgaatcatttcttctg 660
tattaatttccaaagggttttaccctctatttaaatgctttgaaaaacagtgcattgaca 720
atgggttgatatttttctt.taaaagaaaaatataattatgaaagccaaga~taatctgaag780
cctgttttattttaaaactttttatgttctgtggttgatgttgtttgtttgtttgtttct 840
attttgttggttttttactttgttttttgttttgttttgttttggtttdgcatactacat 900
gcagtttctttaaccaatgtctgtttggctaatgtaattaaagttgttaatttatatgag 960
tgcatttcaactatgtcaatggtttcttaatatttattgtgtagaagtactggtaatttt 1020
tttatttacaatatgtttaaagagataacagtttgatatgttttcatgtgtttatagcag 1080
aagttatttatttctatggcattccagcggatattttggtgtttgcgaggcatgcagtca 1140
atattttgtacagttagtggacagtattcagcaacgcctgatagcttctttggccttatg 1200
ttaaataaaaagacctgtttgggatgtaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa 1260
aaaaa 1265
<210> 170
<211> 383
<212> DNA
<213> Homo sapien
<400> 170
tgtaagtcgagcagtgtgatgacgatattcttcttattaatgtggtaattgaacaaatga 60
tctgtgatactgatcctgagctaggaggcgctgttcagttaatgggacttcttcgtactc 120
taattgatccagagaacatgctggctacaactaataaaaccgaaaaaagtgaatttctaa 180
attttttctacaaccattgtatgcatgttctcacagcaccacttttgaccaatacttcag 240
aagacaaatgtgaaaaggataatatagttggatcaaacaaaaacaacacaatttgtcccg 300
ataattatcaaacagcacagctacttgccttaattttagagttactcacattttgtgtgg 360
aacatcacactgctcgacttaca 383
<210> 171
<211> 383
<212> DNA
<213> Homo sapien
<400> 171
tgggcaccttcaatatcgcaagttaaaaataatgttgagtttattatacttttgacctgt60
ttagctcaacagggtgaaggcatgtaaagaatgtggacttctgaggaattttcttttaaa120
aagaacataatgaagtaacattttaattactcaaggactacttttggttgaagtttataa180
tctagatacctctactttttgtttttgctgttcgacagttcacaaagaccttcagcaatt240
tacagggtaaaatcgttgaagtagtggaggtgaaactgaaatttaaaattattctgtaaa300
tactatagggaaagaggctgagcttagaatcttttggttgttcatgtgttctgtgctctt360
atcatcacactgctcgacttaca 383
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
<210> 172
<211> 699
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(699)
<223> n = A,T,C or G
<400> 172
tcgggtgatgcctcctcaggcttgtcgttagtgtacacagagctgctcatgaagcgacag 60
cggctgcccctggcacttcagaacctcttcctctacacttttggtgcgcttctgaatcta 120
ggtctgcatgctggcggcggctctggcccaggcctcctggaaagtttctcaggatgggca 180
gcactcgtggtgctgagccaggcactaaatggactgctcatgtctgctgtcatggagcat 240
ggcagcagcatcacacgcctctttgtggtgtcctgctcgctggtggtcaacgccgtgctc 300
tcagcagtcctgctacggctgcagctcacagccgccttcttcctggccacattgctcatt 360
ggcctggccatgcgcctgtactatggcagccgctagtccctgacaacttccaccctgatt 420
ccggaccctgtagattgggcgccaccaccagatccccctcccaggccttcctccctctcc 480
catcagcggccctgtaacaagtgccttgtgagaaaagctggagaagtgagggcagccagg 540
ttattctctggaggttggtggatgaaggggtacccctaggagatgtgaagtgtgggtttg 600
gttaaggaaatgcttaccatcccccacccccaaccaagttnttccagactaaagaattaa 660
ggtaacatcaatacctaggcctgaggaggcatcacccga 699
<210> 173
<211> 701
<212> DNA
<213> Homo sapien
<400>
173
tcgggtgatgcctcctcaggccagatcaaacttggggttgaaaactgtgcaaagaaatca60
atgtcggagaaagaattttgcaaaagaaaaatgcctaatcagtactaatttaataggtca120
cattagcagtggaagaagaaatgttgatattttatgtcagctattttataatcaccagag180
tgcttagcttcatgtaagccatctcgtattcattagaaataagaacaattttattcgtcg240
gaaagaacttttcaatttatagcatcttaattgctcaggattttaaattttgataaagaa300
agctccacttttggcaggagtagggggcagggagagaggaggctccatccacaaggacag360
agacaccagggccagtagggtagctggtggctggatcagtcacaacggactgacttatgc420
catgagaagaaacaacctccaaatctcagttgcttaatacaacacaagctcatttcttgc480
tcacgttacatgtcctatgtagatcaacagcaggtgactcagggacccaggctccatctc540
catatgagcttccatagtcaccaggacacgggctctgaaagtgtcctccatgcagggaca600
catgcctcttcctttcattgggcagagcaagtcacttatggccagaagtcacactgcagg660
gcagtgccatcctgctgtatgcctgaggaggcatcacccga 701
<210> 174
<211> 700
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(700)
<223> n = A,T,C or G
<400> 174
tcgggtgatg cctcctcang cccctaaatc agagtccagg gtcagagcca caggagacag 60
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
51
ggaaagacatagattttaaccggcccccttcaggagattctgaggctcagttcactttgt 120
tgcagtttgaacagaggcagcaaggctagtggttaggggcacggtctctaaagctgcact 180
gectggatctgcctcccagctctgccaggaaccagctgcgtggccttgagctgctgacac 240
gcagaaagccccctgtggacccagtctcctcgtctgtaagatgaggacaggactctagga 300
accctttcccttggtttggcctcactttcacaggctcccatcttgaactctatctactct 360
tttcctgaaaccttgtaaaagaaaaaagtgctagcctgggcaacatggcaaaaccctgtc 420
tctacaaaaaatacaaaaattagttgggtgtggtggcatgtgcctgtagtcccagccact 480
tgggaggtgctgaggtgggaggatcacttgagcccgggaggtggaggttgcagtgagcca 540
agatcatgccactgcactccagcctgagtaatagagtaagactctgtctcaaaaacaaca 600
acaacaacagtgagtgtgcctctgtttccgggttggatggggcaccacatttatgcatct 660
ctcagatttggacgctgcagcctgaggaggcatcacccga 700
<210> 175
<211> 484
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (484)
<223> n = A,T,C or G
<400> 175
tatagggcgaattgggcccgagttgcatgntcccggccgccatggccgcgggattcgggt 60
gatgcctcctcaggcttgtctgccacaagctacttctctgagctcagaaagtgccccttg 120
atgagggaaaatgtcctactgcactgcgaatttctcagttccattttacctcccagtcct 180
ccttctaaaccagttaataaattcattccacaagtatttactgattacctgcttgtgcca 240
gggactattctcaggctgaagaaggtgggaggggagggcggaacctgaggagccacctga 300
gccagctttatatttcaaccatggctggcccatctgagagcatctccccactctcgccaa 360
cctatcggggcatagcccagggatgcccccaggcggcccaggttagatgcgtccctttgg 420
cttgtcagtgatgacatacaccttagctgcttagctggtgctggcctgaggaggcatcac 480
ccga 484
<210> 176
<211> 432
<212> DNA
<213> Homo sapien
<400> 176
tcgggtgatgcctcctcagggctcaagggatgagaagtgacttctttctggagggaccgt 60
tcatgccacccaggatgaaaatggatagggacccacttggaggacttgctgatatgtttg 120
gacaaatgccaggtagcggaattggtactggtccaggagttatccaggatagattttcac 180
ccaccatgggacgtcatcgttcaaatcaactcttcaatggccatgggggacacatcatgc 240
ctcccacacaatcgcagtttggagagatgggaggcaagtttatgaaaagccaggggctaa 300
gccagctctaccataaccagagtcagggactcttatcccagctgcaaggacagtcgaagg 360
atatgccacctcggttttctaagaaaggacagcttaatgcagatgagattagcctgagga 420
ggcatcacccga 432
<210> 177
<211> 788
<212> DNA
<213> Homo sapien
<400> 177
tagcatgttg agcccagaca cagtagcatt tgtgccaatt tctggttgga atggtgacaa 60
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
52
catgctggagccaagtgctaacatgccttggttcaagggatggaaagtcacccgtaagga 120
tggcaatgccagtggaaccacgctgcttgaggctctggactgcatcctaccaccaactcg 180
cccaactgacaagcccttgcgcctgcctctccaggatgtctacaaaattggtggtattgg 240
tactgttcctgttggccgagtggagactggtgttctcaaacccggtatggtggtcacctt 300
tgctccagtcaacgttacaacggaagtaaaatctgtcgaaatgcaccatgaagctttgag 360
tgaagctcttcctggggacaatgtgggcttcaatgtcaagaatgtgtctgtcaaggatgt 420
tcgtcgtggcaacgttgctggtgacagcaaaaatgacccaccaatggaagcagctggctt 480
cactgctcaggtgattatcctgaaccatccaggccaaataagtgccggctatgcccctgt 540
attggattgccacacggctcacattgcatgcaagtttgctgagctgaaggaaaagattga 600
tcgccgttctggtaaaaagctggaagatggccctaaattcttgaagtctggtgatgctgc 660
cattgttgatatggttcctggcaagcccatgtgtgttgagagcttctcagactatccacc 720
tttgggtcgctttgctgttcgtgatatgagacagacagttgcggtgggtgtctgggctca 780
acatgcta 788
<210> 178
<211> 786
<212> DNA
<213> Homo sapien
<400>
178
tagcatgttgagcccagacacctgtgtttctgggagctctggcagtggcggattcatagg 60
cacttgggctgcactttgaatgacacacttggctttattagattcactagtttttaaaaa 120
attgttgttcgtttcttttcattaaaggtttaatcagacagatcagacagcataattttg 180
tatttaatgacagaaacgttggtacatttcttcatgaatgagcttgcattctgaagcaag 240
agcctacaaaaggcacttgttataaatgaaagttctggctctagaggccagtactctgga 300
gtttcagagcagccagtgattgttccagtcagtgatgcctagttatatagaggaggagta 360
cactgtgcactcttctaggtgtaagggtatgcaactttggatcttaaaattctgtacaca 420
tacacactttatatatatgtatgtatgtatgaaaacatgaaattagtttgtcaaatatgt 480
gtgtgtttagtattttagcttagtgcaactatttccacattatttattaaattgatctaa 540
gacactttcttgttgacaccttgaatattaatgttcaagggtgcaatgtgt.attccttta600
gattgttaaagcttaattactatgatttgtagtaaattaacttttaaaatgtatttgagc 660
ccttctgtagtgtcgtagggctcttacagggtgggaaagattttaattttccagttgcta 720
attgaacagtatggcctcattatatattttgatttataggagtttgtgtctgggctcaac 780
atgcta 786
<210> 179
<211> 796
<212> DNA
<213> Homo sapien
<400> 179
tagcatgttgagcccagacactggttacaagaccagacctgcttcctccatatgtaaaca 60
gcttttaaaaagccagtgaacctttttaatactttggcaaccttctttcacaggcaaaga 120
acacccccatccgccccttgtttggagtgcagagtttggctttggttctttgccttgcct 180
ggagtatacttctaattcctgttgtcctgcacaagctgaataccgagctacccaccgcca 240
cccaggccaggtttccactcatttattactttatgtttctgttccattgctggtccacag 300
aaataagttttcctttggaggaatgtgattatacccctttaatttcctccttttgctttt 360
ttttaatatcattggtatgtgtttggcccagaggaaactgaaattcaccatcatcttgac 420
tggcaatcccattaccatgctttttttaaaaaacgtaatttttcttgccttacattggca 480
gagtagcccttcctggctactggcttaatgtagtcactcagtttctaggtggcattaggc 540
atgagacctgaagcacagactgtcttaccacaaaaggtgacaagatctcaaaccttagcc 600
aaagggctatgtcaggtttcaatgctatctgcttctgttcctgctcactgttctggattt 660
tgtecttcttcatccctagcaccagaatttcccagtctccctccctaccttcccttgttt 720
taattctaatctatcagcaaaataacttttcaaatgttttaaccggtatctccatgtgtc 780
tgggctcaacatgcta 796
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
53
<210> 180
<211> 488
<212> DNA
<213> Homo sapien
<400> 180
ggatgtgctgcaaggcgattaagttgggtaacgccagggttttcccagtcacgacgttgt 60
aaaacgacggccagtgaattgtaatacgactcactatagggcgaattgggcccgacgtcg 120
catgctcccggccgccatggccgcgggatagcatgttgagcccagacacctgcaggtcat 180
ttggagagatttttcacgttaccagcttgatggtctttttcaggaggagagacactgagc 240
actcccaaggtgaggttgaagatttcctctagatagccggataagaagactaggagggat 300
gcctagaaaatgattagcatgcaaatttctacctgccatttcagaactgtgtgtcagccc 360
acattcagctgcttcttgtgaactgaaaagagagaggtattgagacttttctgatggccg 420
ctctaacattgtaacacagtaatctgtgtgtgtgtgggtgtgtgtgtgtgtctgggctca 480
acatgcta 488
<210> 181
<211> 317
<212> DNA
<213> Homo sapien
<400> 181
tagcatgttgagcccagacacggcgacggtacctgatgagtggggtgatggcacctgtga 60
aaaggaggaacgtcatcccccatgatattggggacccagatgatgaaccatggctccgcg 120
tcaatgcatatttaatccatgatactgctgattggaaggacctgaacctgaagtttgtgc 180
tgcaggtttatcgggactattacctcacgggtgatcaaaacttcctgaaggacatgtggc 240
ctgtgtgtctagtaagggatgcacatgcagtggccagtgtgccaggggtatggttggtgt 300
ctgggctcaacatgcta 317
<210> 182
<211> 507
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(507)
<223> n = A,T,C or G
<400> 182
tagcatgttgagcccagacactggctgttagccaaatcctctctcagctgctccctgtgg 60
tttggtgactcaggattacagaggcatcctgtttcagggaacaaaaagattttagctgcc 120
agcagagagcaccacatacattagaatggtaaggactgccacctccttcaagaacaggag 180
tgagggtggtggtgaatgggaatggaagcctgcattccct,gatgcatttgtgctctctca 240
aatcctgtcttagtcttaggaaaggaagtaaagtttcaaggacggttccgaactgctttt 300
tgtgtctgggctcaacatgctatcccgcggccatggcggccgggagcatgcgacgtcggg 360
cccaattcgccctatagtgagtcgtattacaattcactggccgtcgttttacaacgtcgt 420
gactgggaaaaccctggcgttacccaacttaatcgccttgcagcacatccccctttccca 480
gctggcgtaatancgaaaaggcccgca 507
<210> 183
<211> 227
<212> DNA
<213> Homo sapien
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
54
<400> 183
gatttacgct gcaacactgt ggaggtagcc ctggagcaag gcaggcatgg atgcttctgc 60
aatccccaaa tggagcctgg tatttcagcc aggaatctga gcagagcccc ctctaattgt 120
agcaatgata agttattctc tttgttcttc aaccttccaa tagccttgag cttccagggg 180
agtgtcgtta atcattacag cctggtctcc acagtgttgc agcgtaa 227
<210> 184
<211> 225
<212> DNA
<213> Homo sapien
<400> 184
ttacgctgca acactgtgga gcagattaac atcagacttt tctatcaaca tgactggggt 60
tactaaaaag acaacaaatc aatggcttca aaagtctaag gaataatttc gatacttcaa 120
ctttataaaa cctgacaaaa ctatcaatca agcataaaga cagatgaaga acatttccag 180
attttggcca atcagatatt ttacctccac agtgttgcag cgtaa 225
<210> 185
<211> 597
<212> DNA
<213> Homo sapien
<400>
185
ggcccgacgtcgcatgctcccggccgccatggccgcgggattcgttagggtctctatcca 60
ctgggacccataggctagtcagagtatttagagttgagttcctttctgcttcccagaatt 120
tgaaagaaaaggagtgaggtgatagagctgagagatcagatttgcctctgaagcctgttc 180
aagatgtatgtgctcagaccccaccactggggcctgtgggtgaggtcctgggcatctatt 240
tgaatgaattgctgaaggggagcactatgccaaggaaggggaacccatcctggcactggc 300
acaggggtcaccttatccagtgctcagtgcttctttgctgctacctggttttctctcata 360
tgtgaggggcaggtaagaagaagtgcccrgtgttgtgcgagttttagaacatctaccagt 420
aagtggggaagtttcacaaagcagcagctttgttttgtgtattttcaccttcagttagaa 480
gaggaaggctgtgagatgaatgttagttgagtggaaaagacgggtaagcttagtggatag 540
agaccctaacgaatcactagtgcggccgccttgcaggtcgaccatatgggagagctc 597
<210> 186
<211> 597
<212> DNA
<213> Homo sapien
<400> 186
ggcccgaagttgcatgttcccggccgccatggccgcgggattcgttagggtctctatcca 60
ctacctaaaaaatcccaaacatataactgaactcctcacacccaattggaccaatccatc 120
accccagaggcctacagatcctcctttgatacataagaaaatttccccaaactacctaac 180
tatatcattttgcaagatttgttttaccaaattttgatggcctttctgagcttgtcagtg 240
tgaaccactattacgaacgatcggatattaactgcccctcaccgtccaggtgtagctggc 300
aacatcaagtgcagtaaatattcattaagttttcacctactaaggtgcttaaacacccta 360
gggtgccatgtcggtagcagatcttttgatttgtttttatttcccataagggtcctgttc 420
aaggtcaatcatacatgtagtgtgagcagctagtcactatcgcatgacttggagggtgat 480
aatagaggcctcctttgctgttaaagaactcttgtcccagcctgtcaaagtggatagaga 540
ccctaacgaatcactagtgcggccgcctgcaggtcgaccatatgggagagctcccaa 597
<210> 187
<211> 324
<212> DNA
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
<213> Homo sapien
<400> 187
tcgttagggtctctatccacttgcaggtaaaatccaatcctgtgtatatcttatagtctt 60
ccatatgtagtggttcaagagactgcagttccagaaagactagccgagcccatccatgtc 120
ttccacttaaccctgctttgggttacacatcttaacttttctgttcaagtttctctgtgt 180
agtttatagcatgagtattgggawaatgccctgaaacctgacatgagatctgggaaacac 240
aaacttactcaataagaatttctcccatatttttatgatggaaaaatttcacatgcacag 300
aggagtggatagagaccctaacga 324
<210> 188
<211> 178
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (178)
<223> n = A,T,C or G
<400> 188
gcgcggggat tcggggtgat acctcctcat gccaaaatac aacgtntaat ttcacaactt 60
gccttccaat ttacgcattt tcaatttgct ctccccattt gttgagtcac aacaaacacc 120
attgcccaga aacatgtatt acctaacatg cacatactct taaaactact catccctt 178
<210> 189
<211> 367
<212> DNA
<213> Homo sapien
<400> 189
tgacaccttg tccagcatct gacacagtct tggctcttgg aaaatattgg ataaatgaaa 60
atgaatttct ttagcaagtg gtataagctg agaatatacg tatcacatat cctcattcta 120
agacacattc agtgtccctg aaattagaat aggacttaca ataagtgtgt tcactttctc 180
aatagctgtt attcaattga tggtaggcct taaaagtcaa agaaatgaga gggcatgtga 240
aaaaaagctc aacatcactg atcattagaa aacttccatt caaaccccca atgagatacc 300
atctcatacc agtcagaatg gctattatta aaaagtcaaa aaataacaga tgctggacaa 360
ggtgtca 367
<210> 190
<211> 369
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (369)
<223> n = A,T,C or G
<400> 190
gacaccttgtccagcatctgacaacgctaacagcctgaggagatctttatttatttattt 60
agtttttactctggctaggcagatggtggctaaaacattcatttacccatttattcattt 120
aattgttcctgcaaggcctatggatagagtattgtccagcactgctctggaagctaggag 180
catggggatgaacaagataggctacatcctgttcccacagaacttccactttagtctggg 240
aaacagatgatatatacaaatatataaatgaattcaggtagttttaagtacgaaaagaat 300
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
56
aagaaagcag agtcatgatt tanaatgctg gaaacagggg ctattgcttg agatattgaa 360
ggtgcccaa 369
<210> 191
<211> 369
<212> DNA
<213> Homo sapien
<400> 191
tgacaccttgtccagcatctgcacagggaaaagaaactattatcagagtgaacaggcaac 60
ctacagaatgggagaaaatttttgcaatctatccatctgacaaagggctaatatccagaa 120
tctacaaagaacttatacaaatttacaagaaacaaacaaacaaacaactcctcaaaaagt 180
gggtgaaggatgtgaacagacacttctcaaaagaagacatttatggggccaacaaacata 240
tgaaaaaaagctcatcatcactggtcactagataaatgcaaatcaaaaccacaatgagat 300
accatctcattccagttagaatggcaatcattaaaaagtcaggaaacaacagatgctgga 360
caaggtgtc 369
<210> 192
<211> 449
<212> DNA
<213> Homo sapien
<400> 192
tgacgcttggccacttgacacttcatctttgcacagaaaaacttctttacagatttaatt 60
caagactggtctagtgacagtcctccagacattttttcatttgttccatatacgtggaat 120
tttaaaatcatgtttcatcagtttgaaatgatttgggctgctaatcaacacaattggatc 180
gactgttctactaaacaacaggaaaatgtgtatctggcagcctgtggagaaacactaaac 240
attgatttttctttgccttttacggactttgttccagctacatgtaataccaagttctct 300
ttaagaggagaagatgttgatcttcatttgtttctaccagactgccaccctagtaaatat 360
tctttatttatgctggtaaaaaattgccatccaaataagatgattcatgatactggtatt 420
cctgctgagtgtcaagtggccaagcgtca 449
<210> 193
<211> 372
<212> DNA
<213> Homo sapien
<400> 193
tgacgcttggccacttgacaccagggatgtakcagttgaatataatcctgcaattgtaca 60
tattggcaatttcccatcaaacattctagaaagagacaaccaggattgctaggccataaa 120
agctgcaataaataactggtaattgcagtaatcatttcaggccaattcaatccagtttgg 180
ctcagaggtgcctttggctgagagaagaggtgagatataatgtgttttcttgcaacttct 240
tggaagaataactccacaatagtctgaggactagatacaaacctatttgccattaaagca 300
ccagagtctgttaattccagtactgataagtgttggagattagactccagtgtgtcaagt 360
ggccaagcgtca 372
<210> 194
<211> 309
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(309)
<223> n = A,T,C or G
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
57
<400> 194
tgacgcttggccacttgacacttatgtagaatccatcgtgggctgatgcaagccctttat 60
ttaggcttagtgttgtgggcaccttcaatatcacactagagacaaacgccacaagatctg 120
cagaaacattcagttctgancactcgaatggcaggataactttttgtgttgtaatccttc 180
acatatacaaaaacaaactctgcantctcacgttacaaaaaaacgtactgctgtaaaata 240
ttaagaaggggtaaaggataccatctataacaaagtaacttacaactagtgtcaagtggc 300
caagcgtca 309
<210> 195
<211> 312
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(312)
<223> n = A,T,C or G
<400> 195
tgacgcttggccacttgacacccaatctcgcacttcatcctcccagcacctgatgaagta 60
ggactgcaactatccccacttcccagatgaggggaccaangtacacattaggacccggat 120
gggagcacagatttgtccgatcccagactccaagcactcagcgtcactccaggacagcgg 180
ctttcagataaggtcacaaacatgaatggctccgacaaccggagtcagtccgtgctgagt 240
taaggcaatggtgacacggatgcacgtgtnacctgtaatggttcatcgtaagtgtcaagt 300
ggccaagcgtca 312
<210> 196
<211> 288
<212> DNA
<213> Homo sapien
<400> 196
tgtatcgacgtagtggtctcctcagccatgcagaactgtgactcaattaaacctctttcc 60
tttatgaattacccaatctcgggtagtgtctttatagtagtgtgagaatggactaataca 120
agtacattttacttagtaataataataaacaaatatattacatttttgtgtatttactac 180
accatattttttattgttattgtagtgtacaccttctacttattaaaagaaataggcccg 240
aggcgggcagatcacgaggtcaggagatggagaccactacgtcgatac 288
<210> 197
<211> 289
<212> DNA
<213> Homo sapien
<400> 197
ttgggcaccttcaatatcatgacaggtgatgtgataaccaagaaggctactaagtgatta 60
atgggtgggtaatgtatacagagtaggtacactggacagaggggtaattcatagccaagg 120
caggagaagcagaatggcaaaacatttcatcacactactcaggatagcatgcagtttaaa 180
acctataagtagtttatttttggaattttccacttaatattttcagactgcaggtaacta 240
aactgtggaacacaagaacatagataaggggagaccactacgtcgatac 289
<210> 198
<211> 288
<212> DNA
<213> Homo sapien
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
58
<400> 198
gtatcgacgtagtggtctcccaagcagtgggaagaaaacgtgaaccaattaaaatgtatc60
agataccccaaagaaaggcgcttgagtaaagattccaagtgggtcacaatctcagatctt120
aaaattcaggctgtcaaagagatttgctatgaggttgctctcaatgacttcaggcacagt180
cggcaggagattgaagccctggccattgtcaagatgaaggagctttgtgccatgtatggc240
aagaaagaccccaatgagcgggactcctggagaccactacgtcgatac 288
<210> 199
<211> 1027
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(1027)
<223> n = A,T,C or G
<400> 199
gctttttgggaaaaacncaantgggggaaagggggnttnntngcaaggggataaaggggg 60
aancccagggtttccccattcagggaggtgtaaaaagncggccaggggattgtaanagga 120
ttcaataatagggggaatgggcccngaagttgcaaggttccngcccgccatgnccgcggg 180
atttagtgacattacgacgstggtaataaagtgggsccaawaaatatttgtgatgtgatt 240
tttsgaccagtgaacccattgwacaggacctcatttcctytgagatgrtagccataatca 300
gataaaagrttagaagtytttctgcacgttaacagcatcattaaatggagtggcatcacc 360
aatttcaccctttgttagccgataccttccccttgaaggcattcaattaagtgaccaatc 420
gtcatacgagaggggatggcatggggattgatgatgatatcaggggtgataccttcacag 480
gtgaaaggcatatcctcttgtctatactgaataccacaagtacccttttgaccatgtcga 540
ctagcaaatttgtctccaatctgtgtwatccctaacagagcgtacccttattttacaaaa 600
tttatatccttcctgattgagagttaccataacctgatccacaatgcccgtctcgctwgt 660
tctgagaaaagtgctacagtctctcttggtatagcgtctattggtgctctccaattcatc 720
ttcatttttcaggcaaggtgaactgttttgcctataataacmtcatctcctgatacmcga 780
aacccckggarctatcaaaccatcatcatccagcgttcktwatgtymctaaatccctatt 840
gcggccgcctgcaggtcaacatatnggaaaaccccccaccccttnggagcntaccttgaa 900
ttttccatatgtcccntaaattanctngncttancctggccntaacctnttccggtttaa 960
attgtttccgcccccnttccccnccttnnaaccggaaaccttaattttnaaccnggggtt 1020
cctatcc 1027
<210> 200
<211> 207
<212> DNA
<213> Homo sapien
<400> 200
agtgacatta cgacgctggc catcttgaat cctagggcat gaagttgccc caaagttcag 60
cacttggtta agcctgatcc ctctggttta tcacaaagaa taggatggga taaagaaagt 120
ggacacttaa ataagctata aattatatgg tccttgtcta gcaggagaca actgcacagg 180
tatactacca gcgtcgtaat gtcacta 207
<210> 201
<211> 209
<212> DNA
<213> Homo sapien
<400> 201
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
59
tgggcacctt caatatctat taaaagcaca aatactgaag aacacaccaa gactatcaat 60
gaggttacat ctggagtcct cgatatatca ggaaaaaatg aagtgaacat tcacagagtt 120
ttacttcttt gggaactcaa atgctagaaa agaaaagggt gccctctttc tctggcttcc 180
tggtcctatc cagcgtcgta atgtcacta 209
<210> 202
<211> 349
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(349)
<223> n = A,T,C or G
<400> 202
ntacgctgcaacactgtggagccactggtttttattcccggcaggttatccagcaaacag 60
tcactgaacacaccgaagaccgtggtatggtaaccgttcacagtaatcgttccagtcgtc 120
tgcgggaccccgacgagcgtcactgggtacagaccagattcagccggaagagaaagcgcc 180
gcagggagagactcgaactccactccgctggtgagcagccccatgttttcaactcgaagt 240
tcaaacggcattgggttatataccatcagctgaacttcacacacatctccttgaacccac 300
tggaaatctattttcttgttccgctcttctccacagtgttgcagcgtaa 349
<210> 203
<211> 241
<212> DNA
<213> Homo sapier_
<400> 203
tgctcctcttgccttaccaacccaaagcccactgtgaaatatgaagtgaatgacaaaatt 60
cagttttcaacgcaatatagtatagtttatctgattcttttgatctccaggacactttaa 120
acaactgctaccaccaccaccaacctagggatttaggattctccacagaccagaaattat 180
ttctcctttgagtttcaggctcctctgggactcctgttcatcaatgggtggtaaatggct 240
a 241
<210> 204
<211> 248
<212> DNA
<213> Homo sapien
<400> 204
tagccatttaccacccatctgcaaaccswgacmwwcargrcywgwackyaggcgatttga 60
agtactggtaatgctctgatcatgttagttacataagtgtggtcagtttacaaaaattca 120
cagaactaaatactcaatgctatgtgttcatgtctgtgtttatgtgtgtgtaatgtttca 180
attaagtttttttaaaaaaaagagatgatttccaaataagaaagccgtgttggtaaggca 240
agaggagc 248
<210> 205
<211> 505
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(505)
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
<223> n = A,T,C or G
<400> 205
tacgctgcaacactgtggagccattcatacaggtccctaattaaggaacaagtgattatg 60
ctacctttgcacggttagggtaccgcggccgttaaacatgtgtcactgggcaggcggtgc 120
ctctaatactggtgatgctagaggtgatgtttttggtaaacaggcggggtaagatttgcc 180
gagttccttttactttttttaacctttccttatgagcatgcctgtgttgggttgacagtg 240
ggggtaataatgacttgttggttgattgtagatattgggctgttaattgtcagttcagtg 300
ttttaatctgacgcaggcttatgcggaggagaatgttttcatgttacttatactaacatt 360
agttcttctatagggtgatagattggtccaattgggtgtgaggagttcagttatatgttt 420
gggattttttaggtagtgggtgttgancttgaacgctttcttaattggtggctgctttta 480
rgcctactatgggtggtaaatggct 505
<210> 206
<211> 179
<212> DNA
<213> Homo sapien
<400> 206
tagactgact catgtcccct accaaagccc atgtaaggag ctgagttctt aaagactgaa 60
gacagactat tctctggaga aaaataaaat ggaaattgta ctttaaaaaa aaaaaaaatc 120
ggccgggcat ggtagcacac acctgtaatc ccagctacta ggggacatga gtcagtcta 179
<210> 207
<211> 176
<212> DNA
<213> Homo sapien
<400> 207
agactgactc atgtccccta ccccaccttc tgctgtgctg ccgtgttcct aacaggtcac 60
agactggtac tggtcagtgg cctgggggtt ggggacctct attatatggg atacaaattt 120
aggagttgga attgacacga tttagtgact gatgggatat gggtggtaaa tggcta 176
<210> 208
<211> 196
<212> DNA
<213> Homo sapien
<400> 208
agactgactc atgtccccta tttaacaggg tctctagtgc tgtgaaaaaa aaaaatgctg 60
aacattgcat ataacttata ttgtaagaaa tactgtacaa tgactttatt gcatctgggt 120
agctgtaagg catgaaggat gccaagaagt ttaaggaata tgggtggtaa atggctaggg 180
gacatgagtc agtcta 196
<210> 209
<211> 345
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (345)
<223> n = A,T,C or G
<400> 209
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
61
gacgcttggccacttgacaccttttattttttaaggattcttaagtcatttangtnactt 60
tgtaagtttttcctgtgcccccataagaatgatagctttaaaaattatgctggggtagca 120
aagaagatacttctagctttagaatgtgtaggtatagccaggattcttgtgaggaggggt 180
gatttagagcaaatttcttattctccttgcctcatctgtaacatggggataataatagaa 240
ctggcttgacaaggttggaattagtattacatggtaaatacatgtaaaatgtttagaatg 300
gtgccaagtatctaggaagtacttgggcatgggtggtaaatggct 345
<210> 210
<211> 178
<212> DNA
<213> Homo sapien
<400> 210
gacgcttggc cacttgacac tagagtaggg tttggccaac tttttctata aaggaccaga 60
gagtaaatat ttcaggcttt gtgggttgtg cagtctctct tgcaactact cagctctgcc 120
attgtagcat agaaatcagc catagacagg acagaaatga atgggtggta aatggcta 178
<210> 211
<211> 454
<212> DNA
<213> Homo sapien
<400> 211
tgggcaccttcaatatctatccagcgcatctaaattcgcttttttcttgattaaaaattt 60
caccacttgctgtttttgctcatgtataccaagtagcagtggtgtgaggccatgcttgtt 120
ttttgattcgatatcagcaccgtataagagcagtgctttggccattaatttatcttcatt 180
gtagacagcatagtgtagagtggtatctccatactcatctggaatatttggatcagtgcc 240
atgttccagcaacattaacgcacattcatcttcctggcattgtacggcctttgtcagagc 300
tgtcctctttttgttgtcaaggacattaagttgacatcgtctgtccagcacgagttttac 360
tacttctgaattcccattggcagaggccagatgtagagcagtcctcttttgcttgtccct 420
cttgttcacatcagtgtccctgagcataacggaa 454
<210> 212
<211> 337
<212> DNA
<213> Homo sapien
<400> 212
tccgttatgc cacccagaaa acctactgga gttacttatt aacatcaagg ctggaaccta 60
tttgcctcag tcctatctga ttcatgagca catggttatt actgatcgca ttgaaaacat 120
tgatcacctg ggtttcttta tttatcgact gtgtcatgac aaggaaactt acaaactgca 180
acgcagagaa actattaaag gtattcagaa acgtgaagcc agcaattgtt tcgcaattcg 240
gcattttgaa aacaaatttg ccgtggaaac tttaatttgt tcttgaacag tcaagaaaaa 300
cattattgag gaaaattaat atcacagcat aacggaa 337
<210> 213
<211> 715
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(715)
<223> n = A,T,C or G
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
62
<400> 213
tcgggtgatgcctcctcaggcatcttccatccatctcttcaagattagctgtcccaaatg 60
tttttccttctcttctttactgataaatttggactccttcttgacactgatgacagcttt 120
agtatccttcttgtcaccttgcagactttaaacataaaaatactcattggttttaaaagg 180
aaaaaagtatacattagcactattaagcttggccttgaaacattttctatcttttattaa 240
atgtcggttagctgaacagaattcattttacaatgcagagtgagaaaagaagggagctat 300
atgcatttgagaatgcaagcattgtcaaataaacattttaaatgctttcttaaagtgagc 360
acatacagaaatacattaagatattagaaagtgtttttgcttgtgtactactaattaggg 420
aagcaccttgtatagttcctcttctaaaattgaagtagattttaaaaacccatgtaattt 480
aattgagctctcagttcagattttaggagaattttaacagggatttggttttgtctaaat 540
tttgtcaatttntttagttaatctgtataattttataaatgtcaaactgtatttagtccg 600
ttttcatgctgctatgaaagaaatacccangacagggttatttataaanggaaagangtt 660
aatttgactcccagttcacaggcctgaggangnatcncccgaaatccttattgcg 715
<210> 214
<211> 345
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (345)
<223> n = A,T,C or G
<400> 214
ggtaangngcatacntcggtgctccggccgccggagtcgggggattcgggtgatgcctcc 60
tcaggcccacttgggcctgcttttcccaaatggcagctcctctggacatgccattccttc 120
tcccacctgcctgattcttcatatgttgggtgtccctgtttttctggtgctatttcctga 180
ctgctgttcagctgccactgtcctgcaaagcctgcctttttaaatgcctcaccattcctt 240
catttgtttcttaaatatgggaagtgaaagtgccacctgaggccgggcacagtggctcac 300
gcctgtaatcccagcactttgggagcctgaggaggcatcacccga 345
<210> 215
<211> 429
<212> DNA
<213> Homo sapien
<400> 215
ggtgatgcctcctcaggcgaagctcagggaggacagaaacctcccgtggagcagaagggc 60
aaaagctcgcttgatcttgattttcagtacgaatacagaccgtgaaagcggggcctcacg 120
atccttctgaccttttgggttttaagcaggaggtgtcagaaaagttaccacagggataac 180
tggcttgtggcggccaagcgttcatagcgacgtcgctttttgatccttcgatgtcggctc 240
ttcctatcattgtgaagcagaattcaccaagcgttggattgttcacccactaatagggaa 300
cgtgagctgggtttagaccgtcgtgagacaggttagttttaccctactgatgatgtgtkg 360
ttgccatggtaatcctgctcagtacgagaggaaccgcaggttcasacatttggtgtatgt 420
gcttgcctt 429
<210> 216
<211> 593
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (593)
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
63
<223> n = A,T,C or G
<400>
216
tgacacctatgtccngcatctgttcacagtttccacaaatagccagcctttggccacctc 60
tctgtcctgaggtatacaagtatatcaggaggtgtataccttctcttctcttccccacca 120
aagagaacatgcaggctctggaagctgtcttaggagcctttgggctcagaatttcagagt 180
cttgggtaccttggatgtggtctggaaggagaaacattggctctggataaggagtacagc 240
cggaggagggtcacagagccctcagctcaagcccctgtgccttagtctaaaagcagcttt 300
ggatgaggaagcaggttaagtaacatacgtaagcgtacacaggtagaaagtgctgggagt 360
cagaattgcacagtgtgtaggagtagtacctcaatcaatgagggcaaatcaactgaaaga 420
agaagaccnattaatgaattgcttanggggaaggatcaaggctatcatggagatctttct 480
aggaagattattgtttanaattatgaaaggantagggcagggacagggccagaagtanaa 540
ganaacattgcctatancccttgtcttgcacccagatgctggacaaggtgtca 593
<210> 217
<211> 335
<212> DNA
<213> Homo sapien
<400> 217
tgacaccttgtccagcatctgacgtgaagatgagcagctcagaggaggtgtcctggattt 60
cctggttctgtgggctccgtggcaatgaattcttctgtgaagtggatgaagactacatcc 120
aggacaaatttaatcttactggactcaatgagcaggtccctcactatcgacaagctctag 180
acatgatcttggacctggagcctgatgaagaactggaagacaaccccaaccagagtgacc 240
tgattgagcaggcagccgagatgctttatggattgatccacgcccgctacatccttacca 300
accgtggcatcgcccagatgctggacaaggtgtca 335
<210> 218
<211> 248
<212> DNA
<213> Homo sapien
<400> 218
tacgtactggtcttgaaggtcttaggtagagaaaaaatgtgaatatttaatcaaagacta 60
tgtatgaaatgggactgtaagtacagagggaagggtggcccttatcgccagaagttggta 120
gatgcgtccccgtcatgaaatgttgtgtcactgcccgacatttgccgaattactgaaatt 180
ccgtagaattagtgcaaattctaacgttgttcatctaagattatggttccatgtttctag 240
tactttta 248
<210> 219
<211> 530
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(530)
<223> n = A,T,C or G
<400> 219
tgacgcttgg ccacttgaca caagtagggg ataaggacaa agacccatna ggtggcctgt 60
cagccttttg ttactgttgc ttccctgtca ccacggcccc ctctgtaggg gtgtgctgtg 120
ctctgtggac attggtgcat tttcacacat accattctct ttctgcttca cagcagtcct 180
gaggcgggag cacacaggac taccttgtca gatgangata atgatgtctg gccaactcac 240
cccccaacct tctcactagt tatangaaga gccangccta naaccttcta tcctgncccc 300
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
64
ttgccctatg acctcatccc tgttccatgc cctattctga tttctggtga actttggagc 360
agcctggttt ntcctcctca ctccagcctc tctccatacc atggtanggg ggtgctgttc 420
cacncaaang gtcaggtgtg tctggggaat cctnananct gccnggagtt tccnangcat 480
tcttaaaaac cttcttgcct aatcanatng tgtccagtgg ccaaccntcn 530
<210> 220
<211> 531
<2I2> DNA
<213> Homo sapien
<400> 220
tgacgcttggccacttgacactaaatagcatcttctaaaggcctgattcagagttgtgga 60
aaattctcccagtgtcagggattgtcaggaacagggctgctcctgtgctcactttacctg 120
ctgtgtttctgctggaaaaggagggaagaggaatggctgatttttacctaatgtctccca 180
gtttttcatattcttcttggatcctcttctctgacaactgttcccttttggtcttcttct 240
tcttgctcagagagcaggtctctttaaaactgagaagggagaatgagcaaatgattaaag 300
aaaacacacttctgaggcccagagatcaaatattaggtaaatactaaaccgcttgcctgc 360
tgtggtcacttttctcctctttcacatgctctatccctctatcccccacctattcatatg 420
gcttttatctgccaagttatccggcctctcatcaaccttctcccctagcctactggggga 480
tatccatctgggtctgtctctggtgtattggtgtcaagtggccaagcgtca 531
<210> 221
<211> 530
<212> DNA
<213> Homo sapien
<400> 221
attgacgcttggccacttgacacccgcctgcctgcaatactggggcaagggccttcactg 60
ctttcctgccaccagctgccactgcacacagagatcagaaatgctaccaaccaagactgt 120
tggtcctcagcctctctgaggagaaagagcagaagcctggaagtcagaagagaagctaga 180
tcggctacggccttggcagccagcttccccacctgtggcaataaagtcgtgcatggctta 240
acaatgggggcacctcctgagaaacacattgttaggcaattcggcgtgtgttcatcagag 300
catatttacacaaacctcgatagtgcagcctactatccactattgctcctacgctgcaaa 360
cctgaacagcatgggactgtactgaatactggaagcagctggtgatggtacttatttgtg 420
tatctaaacacagagaaggtacagtaagaatatggtatcataaacttacagggaccgcca 480
tcctatatgcagtctgttgtgaccaaaatgtgtcaagtggccaagcgtca 530
<210> 222
<211> 578
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(578)
<223> n = A,T,C or G
<400> 222
tgtatcgacgtagtggtctccgggctactaggccgttgtgtgctggtagtacctggttca 60
ctgaaaggcgcatctccctccccgcgtcgccctgaagcagggggaggacttcgcccagcc 120
aaggcagttgtatgagttttagctgcggcacttcgagacctctgagcccacctccttcag 180
gagccttccccgattaaggaagccagggtaaggattccttcctcccccagacaccacgaa 240
caaaccaccaccccccctattctggcagcccatatacatcagaacgaaacaaaaataaca 300
aataaacnaaaaccaaaaaaaaaagagaaggggaaatgtatatgtctgtccatcctgttg 360
ctttagcctgtcagctcctanagggcagggaccgtgtcttccgaatggtctgtgcagcgc 420
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
cgactgcggg aagtatcgga ggaggaagca gagtcagcag aagttgaacg gtgggcccgg 480
cggctcttgg gggctggtgt tgtacttcga gaccgctttc gctttttgtc ttagatttac 540
gtttgctctt tggagtggga naccactacn tcnataca 578
<210> 223
<211> 578
<212> DNA
<213> Homo sapien
<400> 223
tgtatcgacgtagtggtctcctcttgcaaaggactggctggtgaatggtttccctgaatt 60
atggacttaccctaaacatatcttatcatcattaccagttgcaaaatattagaatgtgtt 120
gtcactgtttcatttgattcctagaaggttagtcttagatatgttactttaacctgtatg 180
ctgtagtgctttgaatgcattttttgtttgcatttttgtttgcccaacctgtcaattata 240
gctgcttaggtctggactgtcctggataaagctgttaaaatattcaccagtccagccatc 300
ttacaagctaattaagtcaactaaatgcttccttgttttgccagacttgttatgtcaatc 360
ctcaatttctgggttcattttgggtgccctaaatcttagggtgtgactttcttagcatcc 420
tgtaacatccattcccaagcaagcacaacttcacataatactttccagaagttcattgct 480
gaagcctttccttcacccagcggagcaacttgattttctacaacttccctcatcagagcc 540
acaagagtatgggatatggagaccactacgtcgataca 578
<210> 224
<211> 345
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(345)
<223> n = A,T,C or G
<400> 224
tgtatcgacgtantggtctcccaaggtgctgggattgcaggcatgagccaccactcccag 60
gtggatctttttctttatacttacttcattaggtttctgttattcaagaagtgtagtggt 120
aaaagtcttttcaatctacatggttaaataatgatagcctgggaaataaatagaaatttt 180
ttctttcatctttaggttgaataaagaaacagaaaaaatagaacatactgaaaataatct 240
aagttccaaccatagaagaactgcagaagaaatgaagaaagtgatgatgatttagatttt 300
gatattgatttagaagacacaggaggagaccactacgtcgataca 345
<210> 225
<211> 347
<212> DNA
<213> Homo sapien
<400> 225
tgtatcgacgtagtggtctccaaactgaggtatgtgtgccactagcacacaaagccttcc 60
aacagggacgcaggcacaggcagtttaaagggaatctgtttctaaattaatttccacctt 120
ctctaagtattctttcctaaaactgatcaaggtgtgaagcctgtgctctttcccaactcc 180
cetttgacaacagccttcaactaacacaagaaaaggcatgtctgacactcttcctgagtc 240
tgactctgatacgttgttctgatgtctaaagagctccagaacaccaaagggacaattcag 300
aatgctggtgtataacagactccaatggagaccactacgtcgataca 347
<210> 226
<211> 281
<212> DNA
CA 02365909 2001-10-04
WO 00/61753 PCT/LTS00/09312
66
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (281)
<223> n = A,T,C or G
<400> 226
aggngngggantgtatcgacgtagtggtctcccaacagtctgtcattcagtctgcaggtg 60
tcagtgttttggacaatgaggcaccattgtcacttattgactcctcagctctaaatgctg 120
aaattaaatcttgtcatgacaagtctggaattcctgatgaggttttacaaagtattttgg 180
atcaatactccaacaaatcagaaagccagaaagaggatcctttcaatattgcagaaccac 240
gagtggatttacacacctcaggagaccactacgtcgataca 281
<210> 227
<211> 3646
<212> DNA
<213> Homo sapien
<400>
227
gggaaacacttcctcccagccttgtaagggttggagccctctccagtatatgctgcagaa60
tttttctctcggtttctcagaggattatggagtccgccttaaaaaaggcaagctctggac120
actctgcaaagtagaatggccaaagtttggagttgagtggccccttgaagggtcactgaa180
cctcacaattgttcaagctgtgtggcgggttgttactgaaactcccggcctccctgatca240
gtttccctacattgatcaatggctgagtttggtcaggagcaccccttccgtggctccact300
catgcaccattcataattttacctccaaggtcctcctgagccagaccgtgttttcgcctc360
gaccctcagccggttcggctcgccctgtactgcctctctctgaagaagaggagagtctcc420
ctcacccagtcccaccgccttaaaaccagcctactcccttagggtcatcccatgtctcct480
cggctatgtcccctgtaggctcatcacccattgcctcttggttgcaaccgtggtgggagg540
aagtagcccctctactaccactgagagaggcacaagtccctctgggtgatgagtgctcca600
cccccttcctggtttatgtcccttctttctacttctgacttgtataattggaaaacccat660
aatcctcccttctctgaaaagccccaggctttgacctcactgatggagtctgtactctgg720
acacattggcccacctgggatgactgtcaacagctccttttgacccttttcacctctgaa780
gagagggaaagtatccaaagagaggccaaaaagtacaacctcacatcaaccaataggccg840
gaggaggaagctagaggaatagtgattagagacccaattgggacctaattgggacccaaa900
tttctcaagtggagggagaacttttgacgatttccaccggtatctcctcgtgggtattca960
gggagctgctcagaaacctataaacttgtctaaggcgactgaagtcgtccaggggcatga1020
tgagtcaccaggagtgtttttagagcacctccaggaggcttatcagatttacaccccttt1080
tgacctggcagcccccgaaaatagccatgctcttaatttggcatttgtggctcaggcagc1140
cccagatagtaaaaggaaactccaaaaactagagggattttgctggaatgaataccagtc1200
agcttttagagatagcctaaaaggtttttgacagtcaagaggttgaaaaacaaaaacaag1260
cagctcaggcagctgaaaaaagccactgataaagcatcctggagtatcagagtttactgt1320
tagatcagcctcatttgacttcccctcccacatggtgtttaaatccagctacactacttc1380
ctgactcaaactccactattcctgttcatgactgtcaggaactgttggaaactactgaaa1440
ctggccgacctgatcttcaaaatgtgcccctaggaaaggtggatgccaccatgttcacag1500
acagtagcagcttcctcgagaagggactacgaaaggccggtgcagctgttaccatggaga1560
cagatgtgttgtgggctcaggctttaccagcaaacacctcagcacaaaaggctgaattga1620
tcgccctcactcaggctctccgatggggtaaggatattaacgttaacactgacagcaggt'1680
acgcctttgctactgtgcatgtacgtggagccatctaccaggagcgtgggctactcacct1740
cagcaggtggctgtaatccactgtaaaggacatcaaaaggaaaacacggctgttgcccgt1800
ggtaaccagaaagctgattcagcagctcaagatgcagtgtgactttcagtcacgcctcta1860
aacttgctgcccacagtctcctttccacagccagatctgcctgacaatcccgcatactca1920
acagaagaagaaaactggcctcagaactcagagccaataaaaatcaggaaggttggtgga1980
ttcttcctgactctagaatcttcataccccgaactcttgggaaaactttaatcagtcacc2040
tacagtctaccacccatttaggaggagcaaagctacctcagctcctccggagccgtttta2100
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
67
agatcccccatcttcaaagcctaacagatcaagcagctctccggtgcacaacctgcgccc 2160
aggtaaatgccaaaaaaggtcctaaacccagcccaggccaccgtctccaagaaaactcac 2220
caggagaaaagtgggaaattgactttacagaagtaaaaccacaccgggctgggtacaaat 2280
acettctagtactggtagacaccttctctggatggactgaagcatttgctaccaaaaacg 2340
aaactgtcaatatggtagttaagtttttactcaatgaaatcatccctcgacatgggctgc 2400
ctgtttgccatagggtctgataatggaccggccttcgccttgtctatagtttagtcagtc 2460
agtaaggcgttaaacattcaatggaagctccattgtgcctatcgaccccagagctctggg 2520
caagtagaacgcatgaactgcaccctaaaaaacactcttacaaaattaatcttagaaacc 2580
ggtgtaaattgtgtaagtctccttcctttagccctacttagagtaaggtgcaccccttac 2640
tgggctgggttcttaccttttgaaatcatgtatgggagggtgctgcctatcttgcctaag 2700
ctaagagatgcccaattggcaaaaatatcacaaactaatttattacagtacctacagtct 2760
ccccaacaggtacaagatatcatcctgccacttgttcgaggaacccatcccaatccaatt 2820
cctgaacagacagggccctgccattcattcccgccaggtgacctgttgtttgttaaaaag 2880
ttccagagagaaggactccctcctgcttggaagagacctcacaccgtcatcacgatgcca 2940
acggctctgaaggtggatggcattcctgcgtggattcatcactcccgcatcaaaaaggcc 3000
aacagagcccaactagaaacatgggtccccagggctgggtcaggccccttaaaactgcac 3060
ctaagttgggtgaagccattagattaattctttttcttaattttgtaaaacaatgcatag 3120
cttctgtcaaacttatgtatcttaagactcaatataacccccttgttataactgaggaat 3180
caatgatttgattcccccaaaaacacaagtggggaatgtagtgtccaacctggtttttac 3240
taaccctgtttttagactctccctttcctttaatcactcagcttgtttccacctgaattg 3300
actctcccttagctaagagcgccagatggactccatcttggctctttcactggcagccgc 3360
ttcctcaaggacttaacttgtgcaagctgactcccagcacatccaagaatgcaattaact 3420
gataagatactgtggcaagctatatccgcagttcccaggaattcgtccaattgatcacag 3480
cccctctacccttcagcaaccaccaccctgatcagtcagcagccatcagcaccgaggcaa 3540
ggccctccaccagcaaaaagattctgactcactgaagacttggatgatcattagtatttt 3600
tagcagtaaagtttttttttctttttctttctttttttctcgtgcc 3646
<210> 228
<211> 419
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(419)
<223> n = A,T,C or G
<400> 228
taagagggtacaagatctaagcacagccgtcaatgcagaacacagaacgtagcctggtaa 60
gtgtgttaagagtgggaatttttggagtacagagtaaggcacctaaccctagctggggtt 120
tggtgacggtcccagatggcttacagaagaaagtgtcctgagatgagtttttaagaatga 180
ataaggatagacacaagtgaggactgacttggcagtggtgaatggtgggtggcaaaaaac 240
ttcgcatgtatggaaactgcacgtacaggaatgaagaatgagactgtgtggtgtttaatg 300
agctgcaaatactaattttatcctgaaagttttgaagagttaactaaaaagtatttttta 360
gtaaggaaataaccctacatttcagggttattgtttgtttanatattgaaggtgcccaa 419
<210> 229
<211> 148
<212> DNA
<213> Homo sapien
<400> 229
aagagggtac ctgtatgtag ccatggtggc aatgagagac tgattactac ctgctggaga 60
ttgtttaagt gagttaatat attaaggata aagggagcca ggttttttga ctgttggaga 120
aggaaattac agatattgaa ggtcccaa 148
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
68
<210> 230
<211> 257
<212> DNA
<213> Homo sapien
<400> 230
taagagggtacmaaaaaaaaaaaatagaacgaatgagtaagacctactatttgatagtac 60
aacagggtgactatagtcaatgataacttaattatacatttaacatagagtgtaattgga 120
ttgtttgtaactcgaaggataaatgcttgagaggatggataccccattctccatgatgta 180
cttatttcacattacatgcctgtatcaaagcatctcatataccctataaatatgtacacc 240
tactatgtaccctctta 257
<210> 231
<211> 260
<212> DNA
<213> Homo sapien
<400> 231
taagagggta cgggtatttg ctgatgggat ttttttttct ttctttttct ttggaaaaca 60
aaatgaaagc cagaacaaaa ttattgaaca aaagacaggg actaaatctg gagaaatgaa 120
gtcccctcac ctgactgcca tttcattcta tctgaccttc cagtctaggt taggagaata 180
gggggtggag gggattaatc tgatacaggt atatttaaag caactctgca tgtgtgccag 240
aagtccatgg taccctctta 260
<210> 232
<211> 596
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(596)
<223> n = A,T,C or G
<400> 232
tgctcctcttgccttaccaaccacaaattagaaccataatgagatgtcacctcatacctg 60
gtgggattaacattatttaaaaaatcagaagtattgacaaggatgtgaagaaattagaac 120
atctgtgcactgttggtgggaatgtaaaaaaggtgtggccactatgggtaacagcatgaa 180
ggttcctcaaaaaaaattttttttaatctactctatgatcgatcttgaggttgtttatgc 240
aaaagaactgaaatcaggattttgaggaaatattcacattcccacatccatttctgcttt 300
attcataatactcaagagatggaaacaacctaaatgtccatcccgggatgaatggataaa 360
cacagtgtggtatatgcatacaatggaatattatttagtctttaaaaagaaaaattctat 420
catatactacaacttanatnaaccttgaggacacaatgctnagtgaaataagccacggaa 480
ggacgaatactgcattattcccttatatgaagtatctaaagtggtcaaactcttanagca 540
naaagtaaaaatgggtggttgccanacagttggttaggcnagaaganaancctant 596
<210> 233
<211> 96
<212> DNA
<213> Homo sapien
<400> 233
tcttctgaag acctttcgcg actcttaagc tcgtggttgg taaggcaaga ggagcgttgg 60
taaggcaaga ggagcgttgg taaggcaaga ggagca 96
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
69
<210> 234
<211> 313
<212> DNA
<213> Homo sapien
<400> 234
tgtaagtcga gcagtgtgat gataaaactt gaatggatca atagttgctt cttatggatg 60
agcaaagaaa gtagtttctt gtgatggaat ctgctcctgg caaaaatgct gtgaacgttg 120
ttgaaaagac aacaaagagt ttagagtagt acataaattt agaatagtac ataaacttag 180
aatagtacat aaacttagta cataaataat gcacgaagca ggggcagggc ttgagagaat 240
tgacttcaat ttggaaagag tatctactgt aggttagatg ctctcaaaca gcatcacact 300
gctcgactta caa 313
<210> 235
<211> 550
<212> DNA
<213> Homo sapien
<400>
235
aacgaggacagatccttaaaaagaatgttgagtgaaaaaagtagaaaataagataatctc 60
caaagtccagtagcattatttaaacatttttaaaaaatacactgataaaaattttgtaca 120
tttcccaaaaatacatatggaagcacagcagcatgaatgcctatgggrttgaggataggg 180
gttgggagtagggatggggataaagggggaaaataaaaccagagaggagtcttacacatt 240
tcatgaaccaaggagtataattatttcaactatttgtaccwgaagtccagaaagagtgga 300
ggcagaagggggagaagagggcgaagaaacgtttttgggagaggggtcccasaagagaga 360
ttttcgcgatgtggcgctacatacgtttttccaggatgccttaagctctgcaccctattt 420.
ttctcatcactaatattagattaaaccctttgaagacagcgtctgtggtttctctacttc 480
agctttccctccgtgtcttgcacacagtagctgttttacaagggttgaactgactgaagt 540
gagattattc 550
<210> 236
<211> 325
<212> DNA
<213> Homo sapien
<400> 236
tagactgact catgtcccct accagagtag ctagaattaa tagcacaagc ctctacaccc 60
aggaactcac tattgaatac ataaatggaa tttattcagc cttaaaaagt ttggaaggaa 120
attctgacat atgctaaaac atggatgaac cttgaagact ttatgataag taaaagaagc 180
cagtcataaa aggaaaaata ttgcatgatt ccacttatat gaggtaccta gagtagtcaa 240
tttcatagaa acacaaaata gaatggtgtt tgccagggct tttgaggaaa agggaatgac 300
aagttagggg acatgagtca gtcta 325
<210> 237
<211> 373
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (373)
<223> n = A,T,C or G
<400> 237
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
tagactgactcatgtcccctatctactcaacatttccacttgaagtctgataggcatctc 60
agacttatcttgtcccaaagcaaactctttatttcttttcatcctagtctttatttcttg 120
tgctgtcttacccatctcaaaagagtgccaaaatccaccaagttgctgaaacagaaatct 180
aagaaatatccttgattcttctttttcccatctacttcacttctaattcattagtaaata 240
atctgtttcagaaaaccaaacacctcatgttctcactcataagggggagttgaacaatga 300
gaacacacagacacagggaggggaacatcacacaccacggcccgtcagggagtangggac 360
atgagtcagtcta 373
<210> 238
<211> 492
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (492)
<223> n = A,T,C or G
<400> 238
tagactgactcatgtcccctataatgctcccaggcatcagaaagcatctcaaactggagc 60
tgacaccatggcagaggtttcaggtaagtcacaaaaggggtcctaaagaatttgccctca 120
atatcagagtgattagaagaagtggacagagctacccaagttaaacatatgcgagataaa 180
aaaaatatggcacttgtgaacacacactacaggaggaaaataaggaacataatagcatat 240.
tgtgctattatgatgatgaagaacctctctanaagaaaacataaccaaagaaacaaagaa 300
aattcctgcnaatgtttaatgctatagaagaaattaacaaaaacatatattcaatgaatt 360
cagaaaagttagcaggtcanaagaaaacaaatcaaagacc.agaataatcccattttagat 420
tgtcgagtaaactanaacagaaagaataccactggaaattgaattcctacgtangggaca 480
tgantcantcto 492
<210> 239
<211> 482
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(482)
<223> n = A,T,C or G
<400> 239
tggaaagtatttaatgatgggcaacttgctgtttacttcctacatatcccatcatcttct 60
gtatttttttaaataacttttttttggatttttaaagtaaccttattctgagaggtaaca 120
tggattacatacttctaagccattaggagactctatgttaaaccaaaaggaaatgttact 180
agatcttcatttgatcaataggatgtgataatcatcatctttctgctctaatggaaaagt 240
actanaaacatggaaccataatcttagatgaacaacgttagaatttgcactaattctacg 300
gaatttcagtaattcggcaaatgtcgggcagtgacacaacatttcatgacggggacgcat 360
ctaccaacttctggcgataagggccacccttccctctgtacttacagtcccatttcatac 420
acagtctttgattaaatattcacattttttctctacctaaagaccttcaagaccagtacg 480
to 482
<210> 240
<211> 519
<212> DNA
<213> Homo sapien
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
71
<220>
<221> misc_feature
<222> (1) . . (519)
<223> n = A,T,C or G
<400> 240
tgtatcgacgtagtggtctccccatgtgatagtctgaaatatagcctcatgggatgagag 60
gctgtgccccagcccgacacccgtaaagggtctgtgctgaggtggattagtaaaagagga 120
aagccttgcagttgagatagaggaagggcactgtctcctgcctgcccctgggaactgaat 180
gtctcggtataaaacccgattgtacatttgttcaattctgagataggagaaaaaccaccc 240
tatggcgggaggcgagacatgttggcagcaatgctgccttgttatgctttactccacaga 300
tgtttgggcggagggaaacataaatctggcctacgtgcacatccaggcatagtacctccc 360
tttgaacttaattatgacacagattcctttgctcacatgtttttttgctgaccttctcct 420
tattatcaccctgctctcctaccgcattccttgtgctgagataatgaaaataatatcaat 480
aaaaacttganggaactcggagaccactacgtcgataca 519
<210> 241
<211> 771
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (771)
<223> n = A,T,C or G
<400> 241
tgtatcgacgtagtggtctccactcccgccttgacggggctgctatctgccttccaggcc 60
actgtcacggctcccgggtagaagtcacttatgagacacaccagtgtggccttgttggct 120
tgaagctcctcagaggagggtgggaacagagtgaccgagggggcagccttgggctgacct 180
aggacggtcagcttggtccctccgccaaacacgagagtgctgctgcttgtatatgagctg 240
cagtaataatcagcctcgtcctcagcctggagcccagagatggtcagggaggccgtgttg 300
ccanacttggagccagagaagcgattagaaacccctgagggccgattaccgacctcataa 360
atcatgaatttgggggctttgcctgggtgctgttggtaccangagacattattataacca 420
ccaacgtcactgctggttccantgcagggaaaatggttgatcnaactgtccaagaaaacc 480
actacgtccataccaatccactaattgccngccgcctgcaggttcaaccatattggggaa 540
naactccccnccgccgtttgggattgncatnaacctttgaaattttttcctattanttgt 600
ccccctaaaataaaccnttgggcnttaatccattgggtccatancttntttncccggttt 660
ttaaaanttgtttatcccgccncccnatttcccccccaactttccaaaacccgaaaccnt 720
tnaaatttnttnaaaccctggggggttcccnnaattnnanttnaanctncc 771
<210> 242
<211> 167
<212> DNA
<213> Homo sapien
<400> 242
tgggcacctt caatatcggg ctcatcgata acatcacgct gctgatgctg ctgttgctgg 60
tcctctctag gaacctctgg attttcaaat tctttgagga attcatccaa attatctgcc 120
tctcctcctt tcctcctttt tctaaggtct tctggtacaa gcggtca 167
<210> 243
<211> 338
<212> DNA
<213> Homo sapien
CA 02365909 2001-10-04
WO 00/61753 PCT/LTS00/09312
72
<400> 243
ttgggcaccttcaatatctactgatctaaatagtgtggtttgaggcctcttgttcctggc 60
taaaaatccttggcaagagtcaatctccactttacaatagaggtaaaaatcttacaatgg 120
atattcttgacaaagctagcatagagacagcaattttacacaaggtatttttcacctgtt 180
taataacagtggttttcctacacccatagggtgccaccaagggaggagtgcacagttgca 240
gaaacaaattaagatactgaagacaacactacttaccatttcccgtatagctaaccacca 300
gttcaactgtacatgtatgttcttatgggcaatcaaga 338
<210> 244
<211> 346
<212> DNA
<213> Homo sapien
<400> 244 ,
tttttggctc ccatacagca cactctcatg ggaaatgtct gttctaaggt caacccataa 60
tgcaaaaatc atcaatatac ttgaagatcc ccgtgtaagg tacaatgtat ttaatattat 120
cactgataca attgatccaa taccagtttt agtctggcat tgaatcaaat cactgttttt 180
gttgtataaa aagagaaata tttagcttat atttaagtac catattgtaa gaaaaaagat 240
gcttatcttt acatgctaaa atcatgatct gtacattggt gcagtgaata ttactgtaaa 300
agggaagaag gaatgaagac gagctaagga tattgaaggt gcccaa 346
<210> 245
<211> 521
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (521)
<223> n = A,T,C or G
<400> 245
accaatcccacacggatactgagggacaagtatatcatcccatttcatccctacagcagc 60
aacttcatgaggcaggagttattagtcccattttacagaagaggaaactgagacttaggg 120
agatcaagtaatttgcccaggtcgcacaattagtgatagagccagggcttgaagcgacgt 180
ctgtcttaagccaatgacccctgcagattattagagcaactgttctccacaacagtgtaa 240
gcctcttgctanaagctcaggtccacaagggcagagatttttgtctgttttgctcattgc 300
tccttccccattgcttagagcagggtctgccacgaancaggttctcaatgcatagttatt 360
aaatgtatataagagcaaacatatgttacagagaactttctgtatgcttgtcacttacat 420
gaatcacctgtganatgggtatgcttgttccccantgttgcagatnaagatattgaangt 480
gcccaaatcactanttgcgggcgcctgcangtccancatat 521
<210> 246
<211> 482
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(482)
<223> n = A,T,C or G
<400> 246
tggaaccaat ccaaataccc atcaatgata gactggataa agaaaatttg gcacatgttc 60
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
73
accatgaaatactatgcagccataaaaaaggatgagttcatatcctttgcagggacatgg 120
atgaagctggagaccatcattctcagcaaactaacaagggaacagaaaaccaaacactgc 180
atgttctcactcttaagtgggagctgaacaatgagaacacatggacacagggaggggaac 240
atcacacagtggggcctgctggtgggtaggggtctaggggagggatagcattaggagaaa 300
tacctaatgtagatgacgggttgatgggtgcagcaaaccaccatgacacgtgtataccta 360
tgtaacaaacctgcatgttctgcacatgtaccccagaacttaaagtgttaataaaaaaat 420
taagaaaaaagttaagtatgtcatagatacataaaatattgtanatattgaaggtgccca 480
as 482
<210> 247
<211> 474
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(474)
<223> n = A,T,C or G
<400> 247
ttcgatacaggcacagagtaagcagaaaaatggctgtggtttaaccaagtgagtacagtt 60
aagtgagagaggggcagagaagacaagggcatatgcagggggtgattataacaggtggtt 120
gtgctgggaagtgagggtactcggggatgaggaacagtgaaaaagtggcaaaaagtggta 180
agatcagtgaattgtacttctccagaatttgatttctggnggagtcaaataactatccag 240
tttggggtatcatanggcaacagttgaggtataggaggtagaagtcncagtgggataatt 300
gaggttatgaanggtttggtactgactggtactgacaangtctgggttatgaccatggga 360
atgaatgactgtanaagcgtanaggatgaaactattccacganaaaggggtccnaaaact 420
aaaaannnaagnnnnnggggaatattatttatgtggatattgaangtgcccaaa 474
<210> 248
<211> 355
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(355)
<223> n = A,T,C or G
<400> 248
ttcgatacag gcaaacatga actgcaggag ggtggtgacg atcatgatgt tgccgatggt 60
ccggatggnc acgaagacgc actggancac gtgcttacgt ccttttgctc tgttgatggc 120
cctgagggga cgcaggaccc ttatgaccct cagaatcttc acaacgggag atggcactgg 180
attgantccc antgacacca gagacacccc aaccaccagn atatcantat attgatgtag 240
ttcctgtaga nggccccctt gtggaggaaa gctccatnag ttggtcatct tcaacaggat 300
ctcaacagtt tccgatggct gtgatgggca tagtcatant taaccntgtn tcgaa 355
<210> 249
<211> 434
<212> DNA
<213> Homo sapien
<400> 249
ttggattggt cctccaggag aacaagggga aaaaggtgac egagggctcc ctggaactca 60
aggatctcca ggagcaaaag gggatggggg aattcctggt cctgctggtc ccttaggtcc 120
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
74
acctggtcctccaggcttaccaggtcctcaaggcccaaagggtaacaaaggctctactgg 180
acccgctggccagaaaggtgacagtggtcttccagggcctcctgggcctccaggtccacc 240
tggtgaagtcattcagcctttaccaatcttgtcctccaaaaaaacgagaagacatactga 300
aggcatgcaagcagatgcagatgataatattcttgattactcggatggaatggaagaaat 360
atttggttccctcaattccctgaaacaagacatcgagcatatgaaatttccaatgggtac 420
tcagaccaatccaa 434
<210> 250
<211> 430
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(430)
<223> n = A,T,C or G
<400> 250
tggattggtcacatggcagagacaggattccaaggcagtgagaggaggatacaatgcttc 60
tcactagttattattatttattttatttttgagatgaagtctcgctttgtctcccaggct 120
ggagagcggtggtgcgatcttggctctctgcaacccccgcctcaagcaattctcctgtct 180
tagcctcgcgggtagatggaattacaggcgcccaccgccatgcccaactaatttttttgt 240
gtcttcagtagagacagggtttcgccatgttgggcaggctggtcttgaactcctgacctc 300
nagtgatctgccctcctcggcctcacaaagtgctggaattacaggcatgggctgctgcac 360
ccagtcaacttctcactagt.tatggccttatcattttcaccacattctattggcccaaaa 420
aaaaaaaaan 430
<210> 251
<211> 329
<212> DNA
<213> Homo sapien
<400> 251
tggtactccaccatyatggggtcaaccgccatcctcgccctcctcctggctgttctccaa 60
ggagtctgtgccgaggtgcagctgrtgcagtctggagcagaggtgaaaaagtccggggag 120
tctctgaagatctcctgtaagggttctggatacacctttaagatctactggatcgcctgg 180
gtgcgccagttgcccgggaaaggcctggagtggatggggctcatctttcctgatgactct 240
gataccagatacagcccgtccttccaaggccaggtcaccatctcagtcgataagtccatc 300
agcaccgcctatctgcagtggagtaccaa 329
<210> 252
<211> 536
<212> DNA
<213> Homo sapien
<400> 252
tggtactccactcagcccaaccttaattaagaattaagagggaacctattactattctcc 60
caggctcctctgctctaaccaggcttctgggacagtattagaaaaggatgtctcaacaag 120
tatgtagatcetgtactggcctaagaagttaaactgagaatagcataaatcagaccaaac 180
ttaatggtcgttgagacttgtgtcctggagcagctgggataggaaaacttttgggcagca 240
agaggaagaactgcctggaagggggcatcatgttaaaaattacaaggggaacccacacca 300
ggcccccttcccagctctcagcctagagtattagcatttctcagctagagactcacaact 360
tccttgcttagaatgtgccaccggggggagtccctgtgggtgatgaggctctcaagagtg 420
agagtggcatcctatcttctgtgtgcccacaggagcctggcccgagacttagcaggtgaa 480
gtttctggtccaggctttgcccttgactcactatgtgacctctggtggagtaccaa 536
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
<210> 253
<211> 507
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(507)
<223> n = A,T,C or G
<400> 253
ntgttgcgatcccagtaactcgggaagctgaggcgggaggatcacctgagctcaggaggt 60
tgaggccgcagtgagccgggaccacgccactacactccagcctggggcatagagtgagac 120
cctccaagacagaaaagaaaagaaaggaagggaaagggaaagggaaaaggaaaaggaaaa 180
ggaaaaggaaaaggaaaagacaagacaaaacaagacttgaatttggatctcctgacttca 240
~
attttatgttctttctacaccacaattcctctgcttactaagatgataatttagaaaccc 300
ctcgttccattctttacagcaagctggaagtttggtcaagtaattacaataatagtaaca 360
aatttgaatattatatgccaggtgtttttcattcctgctctcacttaattctcaccactc 420
tgatataaatacaattgctgccgggtgtggtggctcatgcctgtaatcccggcactttgg 480
gagaccgaggtgggcggatsgcaacaa 507
<210> 254
<211> 222
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(222)
<223> n = A,T,C or G
<400> 254
ttggattggt cactgtgagg aagccaaatc ggatccgaga gtctttttct aaaggccagt 60
actggccaca ctttctcctg ccgccttcct caaagctgaa gacacacaga gcaaggcgct 120
tctgttttac tccccaatgg taactccaaa ccatagatgg ttagctnccc tgctcatctt 180
tccacatccc tgctattcag tatagtccgt ggaccaatcc as 222
<210> 255
<211> 463
<212> DNA
<213> Homo sapien
<400> 255
tgttgcgatccataaatgctgaaatggaaataaacaacatgatgagggaggattaagttg 60
gggagggagcacattaaggtggccatgaagtttgttggaagaagtgacttttgaacaagg 120
ccttggtgttaagagctgatgagagtgtcccagacagaggggccactggtacaatagacg 180
agatgggagagggcttggaaggtgtgcgaaataggaaggagtttgttctggtatgagtct 240
agtgaacacagaggcgagaggccctggtgggtgcagctggagagttatgcagaataacat 300
taggccctgtgggggactgtagactgtcagcaataatccacagtttggattttattctaa 360
gagtgatgggaagccgtggaaagggggttaagcaaggagtgaaattatcagatttacagt 420
gataaaaataaattggtctggctactggggaaaaaaaaaaaaa 463
<210> 256
<211> 262
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
76
<212> DNA
<213> Homo sapien
<400> 256
ttggattggtcaacctgctcaactctacytttcctccttcttcctaaaaaattaatgaat 60
ccaatacattaatgccaaaacccttgggttttatcaatatttctgttaaaaagtattatc 120
cagaactggacataatactacataataatacataacaaccccttcatctggatgcaaaca 180
tctattaatatagcttaagatcactttcactttacagaagcaacatcctgttgatgttat 240
tttgatgtttggaccaatccas 262
<210> 257
<211> 461
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (461)
<223> n = A,T,C or G
<400> 257
gnggnnnnnnnnncaattcgactcngttcccntggtanccggtcgacatggccgcgggat 60
taccgcttgtnnctgggggtgtatgggggactatgaccgcttgtagctgggggtgtatgg 120
gggactatgaccgcttgtagmtggkggtgtatgggggactatgaccgcttgtcgggtggt 180
.
cggataaaccgacgcaagggacgtgatcgaagctgcgttcccgctctttcgcatcggtag 240
ggatcatggacagcaatatccgcattcgyctgaaggcgttcgaccatcgcgtgctcgatc 300
aggcgaccggcgacatcgccgacaccgcacgccgtaccggcgcgctcatcegcggtccga 360
tcccgcttcccacgcgcatcgagaagttcacggtcaaccgtggcccgcacgtcgacaaga 420
agtcgcgcgagcagttcgaggtgcgtacctacaagcggtca 461
<210> 258
<211> 332
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(332)
<223> n = A,T,C or G
<400> 258
tgaccgcttgtagctgggggtgtatgggggactacgaccgcttgtagctgggggtgtatg 60
ggggactatgaccgcttgtagctgggggtgtatgggggactatgaccgcttgtagctggg 120
ggtgtatgggggactaggaccgcttgtagctgggggtgtatgggggactatgaccgcttg 180
tagctgggggtgtatgggggactacgaccgcttgtagctgggggtgtatgggggactatg 240
accgcttgtanctgggggtgtatgggggactatgaccgcttgtgctgcctgggggatggg 300
aggagagttgtggttggggaaaaaaaaaaaas 332
<210> 259
<211> 291
<212> DNA
<213> Homo sapien
<220>
<221> misc feature
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
77
<222> (1)...(291)
<223> n = A,T,C or G
<400>
259
taccgcttgtgaccgcttgtgaccgcttgtgaccgcttgtgaccgcttgtgaccgcttgt 60
gaccgcttgtgaccgcttgtgaccgcttgtgaccgcttgtgaccgcttgtgaccgcttgt 120
gaccgcttgtgaccgcttgtnacngggggtgtctgggggactatganngantgtnactgg 180
gggtgtctgggggnctatganngantgtnacngggggtgtctgggggactatganngact 240
gtgcnncctgggggatcngaggagantngnggntagngatggttngggana 291
<210> 260
<211> 238
<212> DNA
<213> Homo sapien
<400> 260
taagagggta ctggttaaaa tacaggaaat ctggggtaat gaggcagaga accaggatac 60
tttgaggtca gggatgaaaa ctagaatttt tttctttttt tttgcctgag aaacttgctg 120
ctctgaagag gcccatgtat taattgcttt gatcttcctt ttcttacagc cctttcaagg 180
gcagagccct ccttatcctg aaggaatctt atccttagct atagtatgta ccctctta 238
<210> 261
<211> 746
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(746)
<223> n = A,T,C or G
<400> 261
ttgggcaccttcaatatcaatagctaacatttattgagtgtttatcgtatcataaaacac 60
tgttctaagcctttaaacgtactaattcatttaatgctcataatcactttagaaggtggg 120
tactagtattagtctcatttacagatgcaacatgcaggcacagagaggttaattaacttg 180
cccaaggtaacacagctaagaaatagaaaaaatattgaatctggaaagttgggcttctgg 240
gtaacccacagagtcttcaatgagcctggggcctcactcagtttgcttttacaaagcgaa 300
tgagtaacatcacttaattcagtgagtaggccaaatggaggtcagctacgagtttctgct 360
gttcttgcagtggactgacagatgtttacaacgtctggccatcagtwaatggactgatta 420
tcattgggawgtgggtgggctgaatgttggccagtgaagtttattcawgccatattttta 480
tgtttaggatgacttttggctggtcctagggcaagctctgtctgscacggaacacagaat 540
wacacagggaccccctcaatttctggtgtggctagaaccatgaaccactggttgggggaa 600
caagcggtcaaaacctaagtgcggccggctggcagggtccacccatatggggaaaactcc 660
cnacgcgtttggaatgcctnagctngaattattctaanagttgtccncntaaaattagcc 720
tgggcgttaatcangggtcnnaagcc 746
<210> 262
<211> 588
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(588)
<223> n = A,T,C or G
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
78
<400> 262
tgaccgcttgtcatctcacatggggtcctgcacgcttttgcctttgtaggaaacctgaca 60
tttgtctgtttcttctttctcttttccttcccatatcctcctaatttacgtttgacttgt 120
ttgctgaggaggcaggagctagagactgctgtgagctcataggggtgggaagtttatcct 180
tcaagtcccgcccactcatcactgcttctcaccttcccctgaccaggcttacaagtgggt 240
tcttgcctgctttccctttggacccaacaagcccctgtaatgagtgtgcatgactctgac 300
agctgtggactcagggtccttggctacagctgccatgtaaaatatctcatccagttctcg 360
caaattgttaaaataaccacatttcttagattccagtacccaaatcatgtctttacgaac 420
tgctcctcacacccagaagtggcacaataattcttggggaattattacttttttttttct 480
ctctnttnncgnnngnnnnggnnngnccaggaattaccacnttggaagacctggccngaa 540
tttattatanaggggagccgattntttttcctaacacaaagcgggtca 588
<210> 263
<211> 730
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(730)
<223> n = A,T,C or G
<400> 263
tttttttttttttggcctgagcaactgaaattatgaaatttccatatactcaaaagagta 60
agactgcaaaaagattaaatgtaaaagttgtcttgtatacagtaatgtttaagataccta 120
ttanatttataaatggaaaattagggcatttggatatacaagttgaaaattcaggagtga 180
ggttgggctggctgggtatatactgaaaactgtcagtacacagatgacatctaaaaccac 240
aaatctggttttattttagcagtgatatgtgtcactcccacaaaagccttcccaattggc 300
ctcagcatacacaacaagtcacctccccacagccctctacacataaacaaattccttagt 360
ttagttcaggaggaaatgcgcccttttccttccgctctaggtgaccgcaaggcccagttc 420
tcgtcaccaagatgttaagggaagtctgccaaagaggcatctgaaaggaaataaggggaa 480
tgggagtgaccacaaaggaaagccaagganaaactttggagaccgtttctaganccctgg 540
catttcacaacaaaactcnggaacaaaccttgtctcatcaatcatttaagcccttcgttt 600
ggannagactttctgaactgggcgctgaacataancctcattgaatgtcttcacagtctc 660
ccagctgaaggcacaccttgggccagaaggggaatcttccaggtcctcaanacagggctc 720
gccctttgnc 730
<210> 264
<211> 715
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(715)
<223> n = A,T,C or G
<400> 264
tttttttttttttggccagtatgatagtctctaccactatattgaagctcttaggtcatt 60
tacacttaatgtggttatagatgctgttgagcttacttctaccaccttgctatttctccc 120
gtctcttttttgttccttttctcttcttttcctcccttattttataattgaattttttag 180
gattctattttatatagatttatcagctataacactttgtattcttttgttttgtggttc 240
ttctgtcatttcaatgtgcatcttaaactcatcacaatctattttcaaataatatcatat 300
aaccttacatataatgtaagaatctaccaccatatatttccatttctcccttccatccta 360
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
79
tgtntgtcatattttttcctttatatatgttttaaagacataatagtatatgggaggttt 420
ttgcttaaaatgtgatcaatattccttcaangaaacgtaaaaattcaaaataaatntctg 480
tttattctcaaatnnacctaatatttcctaccatntctnatacntttcaagaatctgaag 540
gcattggttttttccggcttaagaacctcctctaaagcactctaagcagaattaagtctt 600
ctgggagaggaattctcccaagcttgggccttnanntgtactccntnanggttaaanttt 660
ggccgggaaatagaaattccaagttaacaggntantttttntttttnttntcncc 715
<210> 265
<211> 152
<212> DNA
<213> Homo sapien
<400> 265
tttttttttt tttcccaaca caaagcacca ttatctttcc tcacaatttt caacatagtt 60
tgattcccat gaagaggtta tgatttctaa agaaaacatg gctactatac tatcaatcag 120
ggttaaatct tttttttttg agacggagtt to 152
<210> 266
<211> 193
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(193)
<223> n = A,T,C or G
<400> 266
taaactccgtccccttctta atcaatatgg aggctaccca ctccacatta ccttcttttc60
aagggactgtttccgtaact gttgtgggta ttcacgacca ggcttctaaa cctcttaaaa120
ctccccaattctggtgccaa cttggacaac atgctttttt tttttttttt tttttttttn180
gagacggagttta 193
<210> 267
<211> 460
<212> DNA
<213> Homo sapien
<400> 267
tgttgcgatcccttaagcatgggtgctattaaaaaaatggtggagaagaaaatacctgga60
atttacgtcttatctttagagattgggaagaccctgatggaggacgtggagaacagcttc120
ttcttgaatgtcaattcccaagtaacaacagtgtgtcaggcacttgctaaggatcctaaa180
ttgcagcaaggctacaatgctatgggattctcccagggaggccaatttctgagggcagtg240
gctcagagatgcccttcacctcccatgatcaatctgatctcggttgggggacaacatcaa300
ggtgtttttggactccctcgatgcccaggagagagctctcacatctgtgacttcatccga360
aaaacactgaatgctggggcgtactccaaagttgttcaggaacgcctcgtgcaagccgaa420
tactggcatgacccataaaaggaggatgtggatcgcaaca 460
<210> 268
<211> 533
<212> DNA
<213> Homo sapien
<220>
<221> misc feature
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
<222> (1)...(533)
<223 > n = A, T, C or G
<400> 268
tgttgcgatccgttgatagaatagcgacgtggtaatgagtgcatggcacgcctccgactt 60
accttcgcccgtggggaccccgagtacgtctacggcgtcgtcacttagagtaccctctgg 120
acgcccgggcgcgttcgatttaccggaagcgcgagctgcagtgggcttgcgcccccggcc 180
aaattctttggggggtttaaggccgcggggaatttgaggtatctctatcagtatgtagcc 240
aagttggaacagtcgccattcccgaaatcgctttctttgaatccgcaccgcctccagcat 300
tgcctcattcatcaacctgaaggcacgcataagtgacggttgtgtcttcagcagctccac 360
tccataactagcgcgctcgacctcgtcttcgtacgcgccaggtccgtgcgtgcgaattcc 420
caactccggtgagttgcgcatttcaagttncgaaactgttcgcctccacnatttggcatg 480
ttcacgcatgacacggaataaactcgtccagtaccgggaatgggatcgcaaca 533
<210> 269
<211> 50
<212> DNA
<213> Homo sapien
<400> 269
tttttttttt ttcgcctgaa ttagctacag atcctcctca caagcggtca 50
<210> 270
<211> 519
<212> DNA
<213> Homo sapien
<400> 270
tgttgcgatccaaataacccaccagcttcttgcacacttcgcagaagccaccgtcctttg 60
gctgagtcacgtgaacggtcagtgcaagcagccgcgtgccagagcagaggtgcagcatgc 1.20
tgcacaccagctcagggctgacctcctccagcaggatggacaggatggagctgccgtacg 180
tgtccaccacctcctggcactcttccgacagggacttcggcagcttcgagcacattttgt 240
caaaagcgtcgagtatttctttctcagtcttgttgttgtcaatcagcttggtcacctcct 300
tcaccaggaattcacacacctcacagtaaacatcagactttgctgggacctcgtgcttct 360
taatgggctccaccagttccagggcagggatgacattcttggaggccactttggcgggga 420
ccagagtctgcatgggcatctctttcacctcatcacagaacccaaccagcgcacagatct 480
ccttgggttgcatgtgcatcatcatctgggatcgcaaca 519
<210> 271
<211> 457
<212> DNA
<213> Homo sapien
<400>
271
ttttttttttttcgggcggcgaccggacgtgcactcctccagtagcggctgcacgtcgtg 60
ccaatggcccgctatgaggaggtgagcgtgtccggcttcgaggagttccaccgggccgtg 120
gaacagcacaatggcaagaccattttcgcctactttacgggttctaaggacgccgggggg 180
aaaagctggtgccccgactgcgtgcaggctgaaccagtcgtacgagaggggctgaagcac 240
attagtgaaggatgtgtgttcatctactgccaagtaggagaagagccttattggaaagat 300
ccaaataatgacttcagaaaaaacttgaaagtaacagcagtgcctacactacttaagtat 360
ggaacacctcaaaaactggtagaatctgagtgtcttcaggccaacctggtggaaatgttg 420
ttctctgaagattaagattttaggatggcaatcaaga 457
<210> 272
<211> 102
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
81
<212> DNA
<213> Homo sapien
<400> 272
tttttttttt ttgggcaaca acctgaatac cttttcaagg ctctggcttg ggctcaagcc 60
cgcaggggaa atgcaactgg ccaggtcaca gggcaatcaa ga 102
<210> 273
<211> 455
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(455)
<223> n = A,T,C or G
<400> 273
tttttttttt ttggcaatcaacaggtttaagtcttcggccgaagttaatctcgtgttttt 60
ggcaatcaac aggtttaagtcttcggccgaagttaatctcgtgtttttggcaatcaacag 120
gtttaagtct tcggccgaagttaatctcgtgtttttggcaatcaacaggtttaagtcttc 180
ggccgaagtt aatctcgtgtttttggcaatcaacaggtttaagtcttcggccgaagttaa 240
tctcgtgttt ttggcaatcaacaggtttaagtcttcggccgaagttaatctcgtgttttt 300
ggcaatcaag aggtttaagtcttcggccgaagttaatctcgtgtttttggcaatcaacag 360
gtttaagtct tcggccgaanttaatctcgtgtttttggcaatcaacaggtttaantcttc 420
ggccgaagtt aatctcgtgtttttggcaatcaana 455
<210> 274
<211> 461
<212> DNA
<213> Homo sapien
<400>
274
ttttttttttttggccaatacccttgatgaacatcaatgtgaaaatcctcggtaaaatac 60
tggcaaaccaaatccagcagcacatcaaaaagcttatccaccatgatcaagtgggcttca 120
tccctgggatgcaaggctggttcaacataagaaaatcaataaatgtaatccatcacataa 180
acagaaccaaagacaaaaaccacatgattatctcaatagatgcagaaaaggccttggaca 240
aattcaacagcccttcatgctaaacactcttaataaactagatattgatggaatgtatct 300
caaaataataagagctatttatgacaaacccacagccaatatcatactgaatgggcaaag 360
actggaagcattccctttgaaaactggcacaagacaaggatgccctctctcaccgctcct 420
attcaacatagtattggaagttctggccagggcaatcaaga 461
<210> 275
<211> 729
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (729)
<223> n = A,T,C or G
<400> 275
tttttttttt ttggccaaca ccaagtcttc cacgtgggag gttttattat gttttacaac
catgaaaaca taggaaggtg gctgttacag caaacatttc agatagacga atcggccaag 120
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
82
ctccccaaaccccaccttcacagcctcttccacacgtctcccanagattgttgtccttca 180
cttgcaaattcanggatgttggaagtngacatttnnagtngcnggaaccccatcagtgaa 240
ncantaagcagaantacgatgactttgananacanctgatgaagaacacnctacnganaa 300
ccctttctntcgtgttangatctcnngtccntcactaatgcggccccctgcnggtccacc 360
atttgggagaactccccccncgttggatccccccttgagtntcccattctngtcccccan 420
accngncttgngngncantncnncctcncaccntgtttccctgnngtnaaaatnngtttt 480
nccgccncccnaattcccacccnaatcacagcgaanccngaaggccttcnnaagtgttta 540
angcccngnggtttcctcntntanttgcagcctaccctcccncttnnnnttncgngttgg 600
tcgcgccctggncncgcctngttcctctttnnggnnacaacctngntcnnnggcncntcn 660
nnnctnttcctnnnactagctngcctntccncnccgnggnncanngcacattncncnnac 720
tntgtnncc 729
<210> 276
<211> 339
<212> DNA
<213> Homo sapien
<400> 276
tgacctgacatgtagtagatacttaataaatatttgtggaatgaatggatgaagtggagt 60
tacagagaaaaatagaaaagtacaaattgttgtcagtgttttgaaggaaaattatgatct 120
ttcccaaagttctgacttcattctaagacagggttagtatctccatacataattttactt 180
gcttttgaaaatcaaatgagataatctatttagattgataatttatttagactggctata 240
aactattaagtgctagcaaatatacattttaatctcattttccacctcttgtgatatagc 300
tatgtaggtgttgactttaatggatgtcaggtcaatccc 339
<210> 277
<211> 664
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (664)
<223> n = A,T,C or G
<400> 277
tgacctgacatccataacaaaatctttctccattatattcttctaggggaatttcttgaa 60
aagcatccaaaggaaacaaatgatggtaagaccgtgccaagtggggagcagacaccaaag 120
taagaccacagattttacattcaacaggtagctcacagtactttgcccgacactgtgggc 180
agaaatagcctcctaatgtaagccctggctcagtattgccatccaaatgcgccatgctga 240
aagagggttttgcatcctggtcagatnaagaagcaatggtgtgctgaggaaatcccatac 300
gaataagtgagcattcagaacttgagctagcaggaggaggactaagatgatgtgtgagca 360
actctttgtaatggctttcatctaaaataacatggtacgtgccaccagtttcacgagcaa 420
gtacagtgcaaacgcgaacttctgcagacaatccaataacagatactctaattttagctg 480
cctttagggtcttgattaaatcataaatattagatggatcgcaagttgtaaggntgctaa 540
aagatgattagtacttctcgacttgtatgtccaggcatgttgttttaaantctgccttag 600
nccctgcttaggggaatttttaaagaagatggctctccatgttcanggtcaatcacnaat 660
tgcc 664
<210> 278
<211> 452
<212> DNA
<213> Homo sapien
<220>
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
83
<221> misc_feature
<222> (1). .(452)
<223> n = A,T,C or G
<400> 278
tgacctgacattgaggaagagcacacacctctgaaattccttaggttcagaagggcattt 60
gacacagagtgggcctctgataattcatgaaatgcattctgaagtcatccagaatggagg 120
ctgcaatctgctgtgctttgggggttgcctcactgtgctcctggatatcacacaaaagct 180
gcaatccttcttcttcaactaacattttgcagtatttgctgggatttttactgcagacat 240
gatacatagcccatagtgcccagagctgaacctctggttgagagaagttgccaaggagcg 300
ggaaaaatgtcttgaaagatctataggtcaccaatgctgtcatcttacaacttgaacttg 360
gccaattctgtatggttgcatgcagatcttggagaagagtacgcctctggaagtcacggg 420
atatccaaanctgtctgtcagatgtcaggtca 452
<210> 279
<211> 274
<212> DNA
<213> Homo sapien
<400> 279
ttttttttttttcggcaaggcaaatttacttctgcaaaagggtgctgcttgcacttttgg 60
ccactgcgagagcacaccaaacaaagtagggaaggggtttttatccctaacgcggttatt 120
ccctggttctgtgtcgtgtccccattggctggagtcagactgcacaatctacactgaccc 180
aactggctactgtttaaaattgaatatgaataattaggtaggaagggggaggctgtttgt 240
tacggtacaagacgtgtttgggcatgtcaggtca 274
<210> 280
<211> 272
<212> DNA
<213> Homo sapien
<400>
280
tacctgacatggagaaataacttgtagtattttgcgtgcaatggaatact atatgagggt60
gaaaatgaatgaactagcaatgcgtgtatcaacatgaataaatccccaaa acataataat120
gttgaatggaaaaggtgagtttcagaaggatatatatgccctctaaatcc atttatgtaa180
acctttaaaaaactacattatttatggtcataagtccatccagaaaatat ttaaaaacct240
acatgggattgataactactgatgtcaggtca 272
<210> 281
<211> 431
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1) . . (431)
<223> n = A,T,C or G
<400> 281
ttttttttttttggccaatagcatgatttaaacattggaaaaagtcaaatgagcaatgcg 60
aatttttatgttctcttgaataatcaaaagagtaggcaacattggttcctcattcttgaa 120
tagcattaatcagaaaatattgcatagcctctagcctccttagagtaggtgtgctctctc 180
aaatatatcatagtcccacagtttatttcatgtatattttctgcctgaatcacatagaca 240
tttgaatttgcaacgcctgatgtaaatatataaattcttaccaatcagaaacatagcaag 300
aaattcagggacttggtcatyatcagggtatgacagcanatccctgtaraaacactgata 360
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
84
cacactcaca cacgtatgca acgtggagat gtcgcyttww kkktwywcwm rmrycrwcgn 420
aatcacttan n 431
<210> 282
<211> 98
<212> DNA
<213> Homo sapien
<400> 282
attcgattcg atgcttgagc ccaggagttc aagactgcag tgagccactg cacttcaggc 60
tggacaacag agcgagtccc tgtgccaaaa aaaaaaaa 98
<210> 283
<211> 764
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(764)
<223> n = A,T,C or G
<400> 283
ttttttttttttcgcaagcacgtgcactttattgaatgacactgtagacaggtgtgtggg 60
tataaactgctgtatctaggggcaggaccaagggggcaggggcaacagccccagcgtgca 120
gggccascattgcacagtggastgcaaaggttgcaggctatgggcggctactavtaaccc 180
cgtttttcctgtattatctgtaacataatatggtagactgtcacagagccgaatwccart 240
hacasgatgaatccaawggtcaygaggatgcccasaatcagggcccasatsttcaggcac 300
ttggcggtgggggcatasgcctgkgccccggtcacgtcsccaaccwtctycctgtcccta 360
cmcttgawtccncnccttnnnntnccntnatntgcccgcccncctcctngngtcaaccng 420
natctgcactanctccctcnccccttntggantctcntccttcaantaannttatccttn 480
acncccccctcncctttcccctnccncccntnatcccngnnccnctatcantcntnccct 540
cnctntnctncnnatcgttccncctnntaactacnctttnnacnanncctcactnatncc 600
ngnnanttctttccttccctcccnacgcnntgcgtgcgcccgtctngcctnnnctncgna 660
cccnnactttatttacctttncaccctagcnctctacttnacccanccnctcctacctcc 720
nggnccacccnnccctnatcnctnnctctntcnnctcnttcccc 764
<210> 284
<211> 157
<212> DNA
<213> Homo sapien
<400> 284
caagtgtagg cacagtgatg aaagcctgga gcaaacacaa tctgtgggta attaacgttt 60
atttctcccc ttccaggaac gtcttgcatg gatgatcaaa gatcagctcc tggtcaacat 120
aaataagcta gtttaagata cgttccccta cacttga 157
<210> 285
<211> 150
<212> DNA
<213> Homo sapien
<400> 285
attcgattgt actcagacaa caatatgcta agtggaagaa gtcagtcaca aaagaccaca 60
tactgtatga cttcatttac attaagtgtc cagaataggc aaatccgtag agacagaaag 120
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
tagatgagca gctgcctagg tctgagtaca 150
<210> 286
<211> 219
<212> DNA
<213> Homo sapien
<400> 286
attcgatttt tttttttttg gccatgatga aattcttact ccctcagatt ttttgtctgg 60
ataaatgcaa gtctcaccac cagatgtgaa attacagtaa actttgaagg aatctcctga 120
gcaaccttgg ttaggatcaa tccaatattc accatctggg aagtcaggat ggctgagttg 180
caggtcttta caagttcggg ctggattggt ctgagtaca 219
<210> 287
<211> 196
<212> DNA
<213> Homo sapien
<400> 287
attcgattct tgaggctacc aggagctagg agaagaggca tggaacaaat tttccctcat 60
atccatactc agaaggaacc aaccctgctg acaccttaat ttcagcttct ggcctctaga 120
actgtgagag agtacatttc tcttggttta agccaagaga atctgtcttt tggtacttta 180
tatcatagcc tcaaga 196
<210> 288
<211> 199
<212> DNA
<213> Homo sapien
<400> 288
attcgatttc agtccagtcc cagaacccac attgtcaatt actactctgt araagattca 60
tttgttgaaa ttcattgagt aaaacattta tgatccctta atatatgcca attaccatgc 120
taggtactga agattcaagt gaccgagatg ctagcccttg ggttcaagtg atccctctcc 180
cagagtgcac tggactgaa 199
<210> 289
<211> 182
<212> DNA
<213> Homo sapien
<400> 289
attcgattct tgaggctaca aacctgtaca gtatgttact ctactgaata ctgtaggcaa 60
tagtaataca gaagcaagta tctgtatatg taaacattaa aaaggtacag tgaaacttca 120
gtattataat cttagggacc accattatat atgtggtcca tcattggcca aaaaaaaaaa 180
as 182
<210> 290
<211> 1646
<212> DNA
<213> Homo sapien
<400> 290
ggcacgagga gaaatgtaat tccatatttt atttgaaact tattccatat tttaattgga 60
tattgagtga ttgggttatc aaacacccac aaactttaat tttgttaaat ttatatggct 120
ttgaaataga agtataagtt gctaccattt tttgataaca ttgaaagata gtattttacc 180
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
86
atctttaatcatcttggaaaatacaagtcctgtgaacaaccactctttcacctagcagca 240
tgaggccaaaagtaaaggctttaaattataacatatgggattcttagtagtatgtttttt 300
tcttgaaactcagtggctctatctaaccttactatctcctcactctttctctaagactaa 360
actctaggctcttaaaaatctgcccacaccaatcttagaagctctgaaaagaatttgtct 420
ttaaatatcttttaatagtaacatgtattttatggaccaaattgacattttcgactattt 480
tttccaaaaaagtcaggtgaatttcagcacactgagttgggaatttcttatcccagaaga 540
ccaaccaatttcatatttatttaagattgattccatactccgttttcaaggagaatccct 600
gcagtctccttaaaggtagaacaaatactttctatttttttttcaccattgtgggattgg 660
actttaagaggtgactctaaaaaaacagagaacaaatatgtctcagttgtattaagcacg 720
gacccatattatcatattcacttaaaaaaatgatttcctgtgcaccttttggcaacttct 780
cttttcaatgtagggaaaaacttagtcaccctgaaaacccacaaaataaataaaacttgt 840
agatgtgggcagaaggtttgggggtggacattgtatgtgtttaaattaaaccctgtatca 900
ctgagaagctgttgtatgggtcagagaaaatgaatgcttagaagctgttcacatcttcaa 960
gagcagaagcaaaccacatgtctcagctatattattatttattttttatgcataaagtga 1020
atcatttcttctgtattaatttccaaagggttttaccctctatttaaatgctttgaaaaa 1080
cagtgcattgacaatgggttgatatttttctttaaaagaaaaatataattatgaaagcca 1140
agataatctgaagcctgttttattttaaaactttttatgttctgtggttgatgttgtttg 1200
tttgtttgtttctattttgttggttttttactttgttttttgttttgttttgttttgttt 1260
kgcatactacatgcagttctttaaccaatgtctgtttggctaatgtaattaaagttgtta 1320
atttatatgagtgcatttcaactatgtcaatggtttcttaatatttattgtgtagaagta 1380
ctggtaatttttttatttacaatatgtttaaagagataacagtttgatatgttttcatgt 1440
gtttatagcagaagttatttatttctatggcattccagcggatattttggtgtttgcgag 1500
gcatgcagtcaatattttgtacagttagtggacagtattcagcaacgcctgatagcttct 1560
ttggccttatgttaaataaaaagacctgtttgggatgtattttttatttttaaaaaaaaa 1620
aaaaaaaaaaaaaaaaaaaaaaaaaa 1646
<210> 291
<211> 1851
<212> DNA
<213> Homo sapien
<400> 291
tcatcaccattgccagcagcggcaccgttagtcaggttttctgggaatcccacatgagta60
cttccgtgttcttcattcttcttcaatagccataaatcttctagctctggctggctgttt120
tcacttcctttaagcctttgtgactcttcctctgatgtcagctttaagtcttgttctgga180
ttgctgttttcagaagagatttttaacatctgtttttctttgtagtcagaaagtaactgg240
caaattacatgatgatgactagaaacagcatactctctggccgtctttccagatcttgag300
aagatacatcaacattttgctcaagtagagggctgactatacttgctgatccacaacata360
cagcaagtatgagagcagttcttccatatctatccagcgcatttaaattcgcttttttct420
tgattaaaaatttcaccacttgctgtttttgctcatgtataccaagtagcagtggtgtga480
ggccatgcttgttttttgattcgatatcagcaccgtataagagcagtgctttggccatta540
atttatcttcattgtagacagcatagtgtagagtggtatttccatactcatctggaatat600
ttggatcagtgccatgttccagcaacattaacgcacattcatcttcctggcattgtacgg660
cctttgtcagagctgtcctctttttgttgtcaaggacattaagttgacatcgtctgtcca720
gcacgagttttactacttctgaattcccattggcagaggccagatgtagagcagtcctct780
tttgcttgtccctcttgttcacatccgtgtccctgagcatgacgatgagatcctttctgg840
ggactttaccccaccaggcagctctgtggagcttgtccagatcttctccatggacgtggt900
acctgggatccatgaaggcgctgtcatcgtagtctccccaagcgaccacgttgctcttgc960
cgctcccctgcagcaggggaagcagtggcagcaccacttgcacctcttgctcccaagcgt1020
cttcacagaggagtcgttgtggtctccagaagtgcccacgttgctcttgccgctccccct1080
gtccatccagggaggaagaaatgcaggaaatgaaagatgcatgcacgatggtatactcct1140
cagccatcaaacttctggacagcaggtcacttccagcaaggtggagaaagctgtccaccc1200
acagaggatgagatccagaaaccacaatatccattcacaaacaaacacttttcagccaga1260
cacaggtactgaaatcatgtcatctgcggcaacatggtggaacctacccaatcacacatc1320
aagagatgaagacactgcagtatatctgcacaacgtaatactcttcatccataacaaaat1380
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
87
aatataattttcctctggagccatatggatgaactatgaaggaagaactccccgaagaag1440
ccagtcgcagagaagccacactgaagctctgtcctcagccatcagcgccacggacaggar1500
tgtgtttcttccccagtgatgcagcctcaagttatcccgaagctgccgcagcacacggtg1560
gctcctgagaaacaccccagctcttccggtctaacacaggcaagtcaataaatgtgataa1620
tcacataaacagaattaaaagcaaagtcacataagcatctcaacagacacagaaaaggca1680
tttgacaaaatccagcatccttgtatttattgttgcagttctcagaggaaatgcttctaa1740
cttttccccatttagtattatgttggctgtgggcttgtcataggtggtttttattacttt1800
aaggtatgtcccttctatgcctgttttgctgagggttttaattctcgtgcc 1851
<210> 292
<211> 1851
<212> DNA
<213> Homo sapien
<400> 292
tcatcaccattgccagcagcggcaccgttagtcaggttttctgggaatcccacatgagta60
cttccgtgttcttcattcttcttcaatagccataaatcttctagctctgg~ctggctgttt120
tcacttcctttaagcctttgtgactcttcctctgatgtcagctttaagtcttgttctgga180
ttgctgttttcagaagagatttttaacatctgtttttctttgtagtcagaaagtaactgg240
caaattacatgatgatgactagaaacagcatactctctggccgtctttccagatcttgag300
aagatacatcaacattttgctcaagtagagggctgactatacttgctgatccacaacata360
cagcaagtatgagagcagttcttccatatctatccagcgcatttaaattcgcttttttct420
tgattaaaaatttcaccacttgctgtttttgctcatgtataccaagtagcagtggtgtga480
ggccatgcttgttttttgattcgatatcagcaccgtataagagcagtgctttggccatta540
at.ttatcttcattgtagacagcatagtgtagagtggtatttccatactcatctggaatat600
ttggatcagtgccatgttccagcaacattaacgcacattcatcttcctggcattgtacgg660
cctttgtcagagctgtcctctttttgttgtcaaggacattaagttgacatcgtctgtcca720
gcacgagttttactacttctgaattcccattggcagaggccagatgtagagcagtcctct780
tttgcttgtccctcttgttcacatccgtgtccctgagcatgacgatgagatcctttctgg840
ggactttaccccaccaggcagctctgtggagcttgtccagatcttctccatggacgtggt900
acctgggatccatgaaggcgctgtcatcgtagtctccccaagcgaccacgttgctcttgc960
cgctcccctgcagcaggggaagcagtggcagcaccacttgcacctcttgctcccaagcgt1020
cttcacagaggagtcgttgtggtctccagaagtgcccacgttgctcttgccgctccccct1080
gtccatccagggaggaagaaatgcaggaaatgaaagatgcatgcacgatggtatactcct1140
cagccatcaaacttctggacagcaggtcacttccagcaaggtggagaaagctgtccaccc1200
acagaggatgagatccagaaaccacaatatccattcacaaacaaacacttttcagccaga1260
cacaggtactgaaatcatgtcatctgcggcaacatggtggaacctacccaatcacacatc1320
aagagatgaagacactgcagtatatctgcacaacgtaatactcttcatccataacaaaat1380
aatataattttcctctggagccatatggatgaactatgaaggaagaactccccgaagaag1440
ccagtcgcagagaagccacactgaagctctgtcctcagccatcagcgccacggacaggar1500
tgtgtttcttccccagtgatgcagcctcaagttatcccgaagctgccgcagcacacggtg1560
gctcctgagaaacaccccagctcttccggtctaacacaggcaagtcaataaatgtgataa1620
tcacataaacagaattaaaagcaaagtcacataagcatctcaacagacacagaaaaggca1680
tttgacaaaatccagcatccttgtatttattgttgcagttctcagaggaaatgcttctaa1740
cttttccccatttagtattatgttggctgtgggcttgtcataggtggtttttattacttt1800
aaggtatgtcccttctatgcctgttttgctgagggttttaattctcgtgcc 1851
<210> 293
<211> 668
<212> DNA
<213> Homo sapien
<400> 293
cttgagcttc caaataygga agactggccc ttacacasgt caatgttaaa atgaatgcat 60
ttcagtattt tgaagataaa attrgtagat ctataccttg ttttttgatt cgatatcagc 120
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
88
accrtataagagcagtgctttggccattaatttatctttcattrtagacagcrtagtgya 180
gagtggtatttccatactcatctggaatatttggatcagtgccatgttccagcaacatta 240
acgcacattcatcttcctggcattgtacggcctgtcagtattagacccaaaaacaaatta 300
catatcttaggaattcaaaataacattccacagctttcaccaactagttatatttaaagg 360
agaaaactcatttttatgccatgtattgaaatcaaacccacctcatgctgatatagttgg 420
ctactgcatacctttatcagagctgtcctctttttgttgtcaaggacattaagttgacat 480
cgtctgtccagcaggagttttactacttctgaattcccattggcagaggccagatgtaga 540
gcagtcctatgagagtgagaagactttttaggaaattgtagtgcactagctacagccata 600
gcaatgattcatgtaactgcaaacactgaatagcctgctattactctgccttcaaaaaaa 660
aaaaaaaa 668
<210> 294
<211> 1512
<212> DNA
<213> Homo sapien
<400> 294
gggtcgcccagggggsgcgtgggctttcctcgggtgggtgtgggttttccctgggtgggg60
tgggctgggctrgaatcccctgctggggttggcaggttttggctgggattgacttttytc120
ttcaaacagattggaaacccggagttacctgctagttggtgaaactggttggtagacgcg180
atctgttggctactactggcttctcctggctgttaaaagcagatggtggttgaggttgat240
tccatgccggctgcttcttctgtgaagaagccatttggtctcaggagcaagatgggcaag300
tggtgctgccgttgcttcccctgctgcagggagagcggcaagagcaacgtgggcacttct360
ggagaccacgacgactctgctatgaagacactcaggagcaagatgggcaagtggtgccgc420
cactgcttcccctgctgcagggggagtggcaagagcaacgtgggcgcttctggagaccac480
gacgaytctgctatgaagacactcaggaacaagatgggcaagtggtgctgccactgcttc540
ccctgctgcagggggagcrgcaagagcaaggtgggcgcttggggagactacgatgacagt600
gccttcatggagcccaggtaccacgtccgtggagaagatctggacaagctccacagagct660
gcctggtggggtaaagtccccagaaaggatctcatcgtcatgctcagggacactgacgtg720
aacaagaaggacaagcaaaagaggactgctctacatctggcctctgccaatgggaattca780
gaagtagtaaaactcstgctggacagacgatgtcaacttaatgtccttgacaacaaaaag840
aggacagctctgayaaaggccgtacaatgccaggaagatgaatgtgcgttaatgttgctg900
gaacatggcactgatccaaatattccagatgagtatggaaataccactctrcactaygct960
rtctayaatgaagataaattaatggccaaagcactgctcttatayggtgctgatatcgaa1020
tcaaaaaacaaggtatagatctactaattttatcttcaaaatactgaaatgcattcattt1080
taacattgacgtgtgtaagggccagtcttccgtatttggaagctcaagcataacttgaat1140
gaaaatattttgaaatgacctaattatctmagactttattttaaatattgttattttcaa1200
agaagcattagagggtacagttttttttttttaaatgcacttctggtaaatacttttgtt1260
gaaaacactgaatttgtaaaaggtaatacttactatttttcaatttttccctcctaggat1320
ttttttcccctaatgaatgtaagatggcaaaatttgccctgaaataggttttacatgaaa1380
actccaagaaaagttaaacatgtttcagtgaatagagatcctgctcctttggcaagttcc1440
taaaaaacagtaatagatacgaggtgatgcgcctgtcagtggcaaggtttaagatatttc1500
tgatctcgtgcc 1512
<210> 295
<211> 1853
<212> DNA
<213> Homo sapien
<400> 295
gggtcgcccagggggsgcgtgggctttcctcgggtgggtgtgggttttccctgggtgggg60
tgggctgggctrgaatcccctgctggggttggcaggttttggctgggattgacttttytc120
ttcaaacagattggaaacccggagttacctgctagttggtgaaactggttggtagacgcg180
atctgttggctactactggcttctcctggctgttaaaagcagatggtggttgaggttgat240
tccatgccggctgcttcttctgtgaagaagccatttggtctcaggagcaagatgggcaag300
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
89
tggtgctgccgttgcttcccctgctgcagggagagcggcaagagcaacgtgggcacttct 360
ggagaccacgacgactctgctatgaagacactcaggagcaagatgggcaagtggtgccgc 420
cactgcttcccctgctgcagggggagtggcaagagcaacgtgggcgcttctggagaccac 480
gacgaytctgctatgaagacactcaggaacaagatgggcaagtggtgctgccactgcttc
540ccctgctgca
gggggagcrg
caagagcaag
gtgggcgctt
ggggagacta
cgatgacagy
600
gccttcatggakcccaggtaccacgtccrtggagaagatctggacaagctccacagagct 660
gcctggtggggtaaagtccccagaaaggatctcatcgtcatgctcagggacackgaygtg 720
aacaagarggacaagcaaaagaggactgctctacatctggcctctgccaatgggaattca 780
gaagtagtaaaactcstgctggacagacgatgtcaacttaatgtccttgacaacaaaaag 840
aggacagctctgayaaaggccgtacaatgccaggaagatgaatgtgcgttaatgttgctg 900
gaacatggcactgatccaaatattccagatgagtatggaaataccactctrcactaygct 960
rtctayaatgaagataaattaatggccaaagcactgctcttatayggtgctgatatcgaa 1020
tcaaaaaacaagcatggcctcacaccactgytacttggtrtacatgagcaaaaacagcaa 1080
gtsgtgaaatttttaatyaagaaaaaagcgaatttaaaatgcrctggatagatatggaag 1140
ractgctctcatacttgctgtatgttgtggatcagcaagtatagtcagccytctacttga 1200
gcaaaatrttgatgtatcttctcaagatctggaaagacggccagagagtatgctgtttct 1260
agtcatcatcatgtaatttgccagttactttctgactacaaagaaaaacagatgttaaaa 1320
~
atctcttctgaaaacagcaatccagaacaagacttaaagctgacatcagaggaagagtca 1380
caaaggcttaaaggaagtgaaaacagccagccagaggcatggaaacttttaaatttaaac 1440
ttttggtttaatgttttttttttttgccttaataatattagatagtcccaaatgaaatwa 1500
cctatgagactaggctttgagaatcaatagattctttttttaagaatcttttggctagga 1560
gcggtgtctcacgcctgtaattccagcaccttgagaggctgaggtgggcagatcacgaga 1620
tcaggagatcgagaccatcctggctaacacggtgaaaccccatctctactaaaaatacaa 1680
aaacttagctgggtgtggtggcgggtgcctgtagtcccagctactcaggargctgaggca 1740
ggagaatggcatgaacccgggaggtggaggttgcagtgagccgagatccgccactacact 1800
ccagcctgggtgacagagcaagactctgtctcaaaaaaaaaaaaaaaaaaaaa 1853
<210> 296
<211> 2184
<212> DNA
<213> Homo sapien
<400>
296
ggcacgagaattaaaaccctcagcaaaacaggcatagaagggacataccttaaagtaata60
aaaaccacctatgacaagcccacagccaacataatactaaatggggaaaagttagaagca120
tttcctctgagaactgcaacaataaatacaaggatgctggattttgtcaaatgccttttc180
tgtgtctgttgagatgcttatgtgactttgcttttaattctgtttatgtgattatcacat240
ttattgacttgcctgtgttagaccggaagagctggggtgtttctcaggagccaccgtgtg300
ctgcggcagcttcgggataacttgaggctgcatcactggggaagaaacacaytcctgtcc360
gtggcgctgatggctgaggacagagcttcagtgtggcttctctgcgactggcttcttcgg420
ggagttcttccttcatagttcatccatatggctccagaggaaaattatattattttgtta480
tggatgaagagtattacgttgtgcagatatactgcagtgtcttcatctcttgatgtgtga540
ttgggtaggttccaccatgttgccgcagatgacatgatttcagtacctgtgtctggctga600
aaagtgtttgtttgtgaatggatattgtggtttctggatctcatcctctgtgggtggaca660
gctttctccaccttgctggaagtgacctgctgtccagaagtttgatggctgaggagtata720
ccatcgtgcatgcatctttcatttcctgcatttcttcctccctggatggacagggggagc780
ggcaagagcaacgtgggcacttctggagaccacaacgactcctctgtgaagacgcttggg840
agcaagaggtgcaagtggtgctgccactgcttcccctgctgcaggggagcggcaagagca900
acgtggtcgcttggggagactacgatgacagcgccttcatggatcccaggtaccacgtcc960
atggagaagatctggacaagctccacagagctgcctggtggggtaaagtccccagaaagg1020
atctcatcgtcatgctcagggacacggatgtgaacaagagggacaagcaaaagaggactg1080
ctctacatctggcctctgccaatgggaattcagaagtagtaaaactcgtgctggacagac1140
gatgtcaacttaatgtccttgacaacaaaaagaggacagctctgacaaaggccgtacaat1200
gccaggaagatgaatgtgcgttaatgttgctggaacatggcactgatccaaatattccag1260
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
atgagtatggaaataccactctacactatgctgtctacaatgaagataaattaatggcca1320
aagcactgctcttatacggtgctgatatcgaatcaaaaaacaagcatggcetcacaccac1380
tgctacttggtatacatgagcaaaaacagcaagtggtgaaatttttaatcaagaaaaaag1440
cgaatttaaatgcgctggatagatatggaagaactgctctcatacttgctgtatgttgtg1500
gatcagcaagtatagtcagccctctacttgagcaaaatgttgatgtatcttctcaagatc1560
tggaaagacggccagagagtatgctgtttctagtcatcatcatgtaatttgccagttact1620
ttctgactacaaagaaaaacagatgttaaaaatctcttctgaaaacagcaatccagaaca1680
agacttaaagctgacatcagaggaagagtcacaaaggcttaaaggaagtgaaaacagcca1740
gccagaggcatggaaacttttaaatttaaacttttggtttaatgttttttttttttgcct1800
taataatattagatagtcccaaatgaaatwacctatgagactaggctttgagaatcaata1860
gattctttttttaagaatcttttggctaggagcggtgtctcacgcctgtaattccagcac1920
cttgagaggctgaggtgggcagatcacgagatcaggagatcgagaccatcctggctaaca1980
cggtgaaaccccatctctactaaaaatacaaaaacttagctgggtgtggtggcgggtgcc2040
tgtagtcccagctactcaggargctgaggcaggagaatggcatgaacccgggaggtggag2100
gttgcagtgagccgagatccgccactacactccagcctgggtgacagagcaagactctgt2160
ctcaaaaaaaaaaaaaaaaaaaaa 2184
<210> 297
<211> 1855
<212> DNA
<213> Homo sapien
<220>
<221> misc_feature
<222> (1). .(1855)
<223> n = A,T,C or G
<400> 297
tgcacgcatcggccagtgtctgtgccacgtacactgacgccccctgagatgtgcacgccg 60
cacgcgcacgttgcacgcgcggcagcggcttggctggcttgtaacggcttgcacgcgcac 12C
gccgcccccgcataaccgtcagactggcctgtaacggcttgcaggcgcacgccgcacgcg 180
cgtaacggcttggctgccctgtaacggcttgcacgtgcatgctgcacgcgcgttaacggc 240
ttggctggcatgtagccgcttggcttggctttgcattytttgctkggctkggcgttgkty 300
tcttggattgacgcttcctccttggatkgacgtttcctccttggatkgacgtttcytyty 360
tcgcgttcctttgctggacttgaccttttytctgctgggtttggcattcctttggggtgg 420
gctgggtgttttctccgggggggktkgcccttcctggggtgggcgtgggkcgcccccagg 480
gggcgtgggctttccccgggtgggtgtgggttttcctggggtggggtgggctgtgctggg 540
atccccctgctggggttggcagggattgacttttttcttcaaacagattggaaacccgga 600
gtaacntgctagttggtgaaactggttggtagacgcgatctgctggtactactgtttctc 660
ctggctgttaaaagcagatggtggctgaggttgattcaatgccggctgcttcttctgtga 720
agaagccatttggtctcaggagcaagatgggcaagtggtgcgccactgcttcccctgctg 780
cagggggagcggcaagagcaacgtgggcacttctggagaccacaacgactcctctgtgaa 840
gacgcttgggagcaagaggtgcaagtggtgctgcccactgcttcccctgctgcaggggag 900
cggcaagagcaacgtggkcgcttggggagactacgatgacagcgccttcatggakcccag 960
gtaccacgtccrtggagaagatctggacaagctccacagagctgcctggtggggtaaagt 1020
ccccagaaaggatctcatcgtcatgctcagggacactgaygtgaacaagarggacaagca 1080
aaagaggactgctctacatctggcctctgccaatgggaattcagaagtagtaaaactcgt 1140
gctggacagacgatgtcaacttaatgtccttgacaacaaaaagaggacagctctgacaaa 1200
ggccgtacaatgccaggaagatgaatgtgcgttaatgttgctggaacatggcactgatcc 1260
aaatattccagatgagtatggaaataccactctacactatgctgtctacaatgaagataa 1320
attaatggccaaagcactgctcttatacggtgctgatatcgaatcaaaaaacaaggtata 1380
gatctactaattttatcttcaaaatactgaaatgcattcattttaacattgacgtgtgta 1440
agggccagtcttccgtatttggaagctcaagcataacttgaatgaaaatattttgaaatg 1500
acctaattatctaagactttattttaaatattgttattttcaaagaagcattagagggta 1560
cagttttttttttttaaatgcacttctggtaaatacttttgttgaaaacactgaatttgt 1620
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
91
aaaaggtaat acttactatt tttcaatttt tccctcctag gatttttttc ccctaatgaa 1680
tgtaagatgg caaaatttgc cctgaaatag gttttacatg aaaactccaa gaaaagttaa 1740
acatgtttca gtgaatagag atcctgctcc tttggcaagt tcctaaaaaa cagtaataga 1800
tacgaggtga tgcgcctgtc agtggcaagg tttaagatat ttctgatctc gtgcc 1855
<210> 298
<211> 1059
<212> DNA
<213> Homo sapien
<400>
298
gcaacgtgggcacttctggagaccacaacgactcctctgtgaagacgcttgggagcaaga 60
ggtgcaagtggtgctgcccactgcttcccctgctgcaggggagcggcaagagcaacgtgg 120
gcgcttgrggagactmcgatgacagygccttcatggagcccaggtaccacgtccgtggag 180
aagatctggacaagctccacagagctgccctggtggggtaaagtccccagaaaggatctc 240
atcgtcatgctcagggacactgaygtgaacaagarggacaagcaaaagaggactgctcta 300
catctggcctctgccaatgggaattcagaagtagtaaaactcstgctgga~cagacgatgt 360
caacttaatgtccttgacaacaaaaagaggacagctctgayaaaggccgtacaatgccag 420
gaagatgaatgtgcgttaatgttgctggaacatggcactgatccaaatattccagatgag 480
tatggaaataccactctrcactaygctrtctayaatgaagataaattaatggccaaagca 540
ctgctcttatayggtgctgatatcgaatcaaaaaacaaggtatagatctactaattttat 600
cttcaaaatactgaaatgcattcattttaacattgacgtgtgtaagggccagtcttccgt 660
atttggaagctcaagcataacttgaatgaaaatattttgaaatgacctaattatctaaga 720
ctttattttaaatattgttattttcaaagaagcattagagggtacagtttttttttttta 780
aatgcacttctggtaaatacttttgttgaaaacactgaatttgtaaaaggtaatacttac 840
tatttttcaatttttccctcctaggatttttttcccctaatgaatgtaagatggcaaaat 900
ttgccctgaaataggttttacatgaaaactccaagaaaagttaaacatgtttcagtgaat 960
agagatcctgctcctttggcaagttcctaaaaaacagtaatagatacgaggtgatgcgcc 1020
tgtcagtggcaaggtt.taagatatttctgatctcgtgcc 1059
<210> 299
<211> 329
<212> PRT
<213> Homo sapien
<400> 299
Met Asp Ile Val Val Ser Gly Ser His Pro Leu Trp Val Asp Ser Phe
1 5 10 15
Leu His Leu Ala Gly Ser Asp Leu Leu Ser Arg Ser Leu Met Ala Glu
20 25 30
Glu Tyr Thr Ile Val His Ala Ser Phe Ile Ser Cys Ile Ser Ser Ser
35 40 45
Leu Asp Gly Gln Gly Glu Arg Gln Glu Gln Arg Gly His Phe Trp Arg
50 55 60
Pro Gln Arg Leu Leu Cys Glu Asp Ala Trp Glu Gln Glu Val Gln Val
65 70 75 80
Val Leu Pro Leu Leu Pro Leu Leu Gln Gly Ser Gly Lys Ser Asn Val
85 90 95
Val Ala Trp Gly Asp Tyr Asp Asp Ser Ala Phe Met Asp Pro Arg Tyr
100 105 110
His Val His Gly Glu Asp Leu Asp Lys Leu His Arg Ala Ala Trp Trp
115 120 125
Gly Lys Val Pro Arg Lys Asp Leu Ile Val Met Leu Arg Asp Thr Asp
130 135 140
Val Asn Lys Arg Asp Lys Gln Lys Arg Thr Ala Leu His Leu Ala Ser
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
92
145 150 155 160
Ala Asn Gly Asn Ser Glu Val Val Lys Leu Val Leu Asp Arg Arg Cys
165 170 175
Gln Leu Asn Val Leu Asp Asn Lys Lys Arg Thr Ala Leu Thr Lys Ala
180 185 190
Val Gln Cys Gln Glu Asp Glu Cys Ala Leu Met Leu Leu Glu His Gly
195 200 205
Thr Asp Pro Asn Ile Pro Asp Glu Tyr Gly Asn Thr Thr Leu His Tyr
210 215 220
Ala Val Tyr Asn Glu Asp Lys Leu Met Ala Lys Ala Leu Leu Leu Tyr
225 230 235 240
Gly Ala Asp Ile Glu Ser Lys Asn Lys His Gly Leu Thr Pro Leu Leu
245 250 255
Leu Gly Ile His Glu Gln Lys Gln Gln Val Val Lys Phe Leu Ile Lys
260 265 270
Lys Lys Ala Asn Leu Asn Ala Leu Asp Arg Tyr Gly Arg Thr Ala Leu
275 280 285
Ile Leu Ala Val Cys Cys Gly Ser Ala Ser Ile Val Ser Pro Leu Leu
290 295 300
Glu Gln Asn Val Asp Val Ser Ser Gln Asp Leu Glu Arg Arg Pro Glu
305 310 315 320
Ser Met Leu Phe Leu Val Ile Ile Met
325
<210> 300
<211> 148
<212> PRT
<213> Homo sapien
<220>
<221> VARIANT
<222> (1)...(148)
<223> Xaa = Any Amino Acid
<400> 300
Met Thr Xaa Pro Ser Trp Ser Pro Gly Thr Thr Ser Val Glu Lys Ile
1 5 10 15
Trp Thr Ser Ser Thr Glu Leu Pro Trp Trp Gly Lys Val Pro Arg Lys
20 25 30
Asp Leu Ile Val Met Leu Arg Asp Thr Asp Val Asn Lys Xaa Asp Lys
35 40 45
Gln Lys Arg Thr Ala Leu His Leu Ala Ser Ala Asn Gly Asn Ser Glu
50 55 60
Val Val Lys Leu Xaa Leu Asp Arg Arg Cys Gln Leu Asn Val Leu Asp
65 70 75 80
Asn Lys Lys Arg Thr Ala Leu Xaa Lys Ala Val Gln Cys Gln Glu Asp
85 90 95
Glu Cys Ala Leu Met Leu Leu Glu His Gly Thr Asp Pro Asn Ile Pro
100 105 110
Asp Glu Tyr Gly Asn Thr Thr Leu His Tyr Ala Xaa Tyr Asn Glu Asp
115 120 125
Lys Leu Met Ala Lys Ala Leu Leu Leu Tyr Gly Ala Asp Ile Glu Ser
130 135 140
Lys Asn Lys Val
145
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
93
<210> 301
<211> 1155
<212> DNA
<213> Homo sapien
<400> 301
atggtggttgaggttgattccatgccggctgcctcttctgtgaagaagccatttggtctc 60
aggagcaagatgggcaagtggtgctgccgttgcttcccctgctgcagggagagcggcaag 120
agcaacgtgggcacttctggagaccacgacgactctgctatgaagacactcaggagcaag 180
atgggcaagtggtgccgccactgcttcccctgctgcagggggagtggcaagagcaacgtg 240
ggcgcttctggagaccacgacgactctgctatgaagacactcaggaacaagatgggcaag 300
tggtgctgccactgcttcccctgctgcagggggagcggcaagagcaaggtgggcgcttgg 360
ggagactacgatgacagtgccttcatggagcccaggtaccacgtccgtggagaagatctg 420
gacaagctccacagagctgcctggtggggtaaagtccccagaaaggatctcatcgtcatg 480
ctcagggacactgacgtgaacaagaaggacaagcaaaagaggactgctctacatctggcc 540
tctgccaatgggaattcagaagtagtaaaactcctgctggacagacgatgtcaacttaat 600
gtccttgacaacaaaaagaggacagctctgataaaggccgtacaatgccaggaagatgaa 660
tgtgcgttaatgttgctggaacatggcactgatccaaatattccagatgagtatggaaat 720
accactctgcactacgctatctataatgaagataaattaatggccaaagcactgctctta 780
tatggtgctgatatcgaatcaaaaaacaagcatggcctcacaccactgttacttggtgta 840
catgagcaaaaacagcaagtcgtgaaatttttaatcaagaaaaaagcgaatttaaatgca 900
ctggatagatatggaaggactgctctcatacttgctgtatgttgtggatcagcaagtata 960
gtcagccttctacttgagcaaaatattgatgtatcttctcaagatctatctggacagacg 1020
gccagagagtatgctgtttctagtcatcatcatgtaatttgccagttactttctgactac 1080
aaagaaaaacagatgctaaaaatctcttctgaaaacagcaatccagaaaatgtctcaaga 1140
accagaaataaataa 1155
<210> 302
<211> 2000
<212> DNA
<213> Homo sapien
<400>
302
atggtggttgaggttgattccatgccggctgcctcttctgtgaagaagccatttggtctc60
aggagcaagatgggcaagtggtgctgccgttgcttcccctgctgcagggagagcggcaag120
agcaacgtgggcacttctggagaccacgacgactctgctatgaagacactcaggagcaag180
atgggcaagtggtgccgccactgcttcccctgctgcagggggagtggcaagagcaacgtg240
ggcgcttctggagaccacgacgactctgctatgaagacactcaggaacaagatgggcaag300
tggtgctgccactgcttcccctgctgcagggggagcggcaagagcaaggtgggcgcttgg360
ggagactacgatgacagtgccttcatggagcccaggtaccacgtccgtggagaagatctg420
gacaagctccacagagctgcctggtggggtaaagtccccagaaaggatctcatcgtcatg480
ctcagggacactgacgtgaacaagaaggacaagcaaaagaggactgctctacatctggcc540
tctgccaatgggaattcagaagtagtaaaactcctgctggacagacgatgtcaacttaat600
gtccttgacaacaaaaagaggacagctctgataaaggccgtacaatgccaggaagatgaa660
tgtgcgttaatgttgctggaacatggcactgatccaaatattccagatgagtatggaaat720
accactctgcactacgctatctataatgaagataaattaatggccaaagcactgctctta780
tatggtgctgatatcgaatcaaaaaacaagcatggcctcacaccactgttacttggtgta840
catgagcaaaaacagcaagtcgtgaaatttttaatcaagaaaaaagcgaatttaaatgca900
ctggatagatatggaaggactgctctcatacttgctgtatgttgtggatcagcaagtata960
gtcagccttctacttgagcaaaatattgatgtatcttctcaagatctatctggacagacg1020
gccagagagtatgctgtttctagtcatcatcatgtaatttgccagttactttctgactac1080
aaagaaaaacagatgctaaaaatctcttctgaaaacagcaatccagaacaagacttaaag1140
ctgacatcagaggaagagtcacaaaggttcaaaggcagtgaaaatagccagccagagaaa1200
atgtctcaagaaccagaaataaataaggatggtgatagagaggttgaagaagaaatgaag1260
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
94
aagcatgaaagtaataatgtgggattactagaaaacctgactaatggtgtcactgctggc 1320
aatggtgataatggattaattcctcaaaggaagagcagaacacctgaaaatcagcaattt 1380
cctgacaacgaaagtgaagagtatcacagaatttgcgaattagtttctgactacaaagaa 1440
aaacagatgccaaaatactcttctgaaaacagcaacccagaacaagacttaaagctgaca 1500
tcagaggaagagtcacaaaggcttgagggcagtgaaaatggccagccagagctagaaaat 1560
tttatggctatcgaagaaatgaagaagcacggaagtactcatgtcggattcccagaaaac 1620
ctgactaatggtgccactgctggcaatggtgatgatggattaattcctccaaggaagagc 1680
agaacacctgaaagccagcaatttcctgacactgagaatgaagagtatcacagtgacgaa 1740
caaaatgatactcagaagcaattttgtgaagaacagaacactggaatattacacgatgag 1800
attctgattcatgaagaaaagcagatagaagtggttgaaaaaatgaattctgagctttct 1860
cttagttgtaagaaagaaaaagacatcttgcatgaaaatagtacgttgcgggaagaaatt 1920
gccatgctaagactggagctagacacaatgaaacatcagagccagctaaaaaaaaaaaaa 1980
aaaaaaaaaaaaaaaaaaaa 2000
<210> 303
<211> 2040
<212> DNA
<213> Homo sapien
<400> 303
atggtggttgaggttgattccatgccggctgcctcttctgtgaagaagccatttggtctc60
aggagcaagatgggcaagtggtgctgccgttgcttcccctgctgcagggagagcggcaag120
agcaacgtgggcacttctggagaccacgacgactctgctatgaagacactcaggagcaag180
atgggcaagtggtgccgccactgcttcccctgctgcagggggagtggcaagagcaacgtg240
ggcgcttctggagaccacgacgactctgctatgaagacactcaggaacaagatgggcaag300
tggtgctgccactgcttcccctgctgcagggggagcggcaagagcaaggtgggcgcttgg360
ggagactacgatgacagtgccttcatggagcccaggtaccacgtccgtggagaagatctg42.0
gacaagctccacagagctgcctggt.ggggtaaagtccccagaaaggatctcatcgtcatg480
ctcagggacactgacgtgaacaagaaggacaagcaaaagaggactgctctacatctggcc540
tctgccaatgggaattcagaagtagtaaaactcctgctggacagacgatgtcaacttaat500
gtccttgacaacaaaaagaggacagctctgataaaggccgtacaatgccaggaagatgaa660
tgtgcgttaatgttgctggaacatggcactgatccaaatattccagatgagtatggaaat720
accactctgcactacgctatctataatgaagataaattaatggccaaagcactgctctta780
tatggtgctgatatcgaatcaaaaaacaagcatggcctcacaccactgttacttggtgta840
catgagcaaaaacagcaagtcgtgaaatttttaatcaagaaaaaagcgaatttaaatgca900
ctggatagatatggaaggactgctctcatacttgctgtatgttgtggatcagcaagtata960
gtcagccttctacttgagcaaaatattgatgtatcttctcaagatctatctggacagacg1020
gccagagagtatgctgtttctagtcatcatcatgtaatttgccagttactttctgactac1080
aaagaaaaacagatgctaaaaatctcttctgaaaacagcaatccagaacaagacttaaag1140
ctgacatcagaggaagagtcacaaaggttcaaaggcagtgaaaatagccagccagagaaa1200
atgtctcaagaaccagaaataaataaggatggtgatagagaggttgaagaagaaatgaag1260
aagcatgaaagtaataatgtgggattactagaaaacctgactaatggtgtcactgctggc1320
aatggtgataatggattaattcctcaaaggaagagcagaacacctgaaaatcagcaattt1380
cctgacaacgaaagtgaagagtatcacagaatttgcgaattagtttctgactacaaagaa1440
aaacagatgccaaaatactcttctgaaaacagcaacccagaacaagacttaaagctgaca1500
tcagaggaagagtcacaaaggcttgagggcagtgaaaatggccagccagagaaaagatct1560
caagaaccagaaataaataaggatggtgatagagagctagaaaattttatggctatcgaa1620
gaaatgaagaagcacggaagtactcatgtcggattcccagaaaacctgactaatggtgcc1680
actgctggcaatggtgatgatggattaattcctccaaggaagagcagaacacctgaaagc1740
cagcaatttcctgacactgagaatgaagagtatcacagtgacgaacaaaatgatactcag1800
aagcaattttgtgaagaacagaacactggaatattacacgatgagattctgattcatgaa1860
gaaaagcagatagaagtggttgaaaaaatgaattctgagctttctcttagttgtaagaaa1920
gaaaaagacatcttgcatgaaaatagtacgttgcgggaagaaattgccatgctaagactg1980
gagctagacacaatgaaacatcagagccagctaaaaaaaaaaaaaaaaaaaaaaaaaaaa2040
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
<210> 304
<211> 384
<212> PRT
<213> Homo sapien
<400> 304
Met Val Val Glu Va1 Asp Ser Met Pro Ala Ala Ser Ser Val Lys Lys
1 5 10 15
Pro Phe Gly Leu Arg Ser Lys Met Gly Lys Trp Cys Cys Arg Cys Phe
20 25 30
Pro Cys Cys Arg Glu Ser Gly Lys Ser Asn Val Gly Thr Ser Gly Asp
35 40 45
His Asp Asp Ser Ala Met Lys Thr Leu Arg Ser Lys Met Gly Lys Trp
50 55 60
Cys Arg His Cys Phe Pro Cys Cys Arg Gly Ser Gly Lys Ser Asn Val
65 70 75 80
Gly Ala Ser Gly Asp His Asp Asp Ser Ala Met Lys Thr Leu Arg Asn
85 90 95
Lys Met Gly Lys Trp Cys Cys His Cys Phe Pro Cys Cys Arg Gly Ser
100 105 110
Gly Lys Ser Lys Val Gly Ala Trp Gly Asp Tyr Asp Asp Ser Ala Phe
115 120 125
Met Glu Pro Arg Tyr His Val Arg Gly Glu Asp Leu Asp Lys Leu His
130 135 140
Arg Ala Ala Trp Trp Gly Lys Val Pro Arg Lys Asp Leu Ile Val Met
145 150 155 160
Leu Arg Asp Thr Asp Val Asn Lys Lys Asp Lys Gln Lys Arg Thr Ala
165 170 175
Leu His Leu Ala Ser Ala Asn Gly Asn Ser Glu Val Val Lys Leu Leu
180 185 190
Leu Asp Arg Arg Cys Gln Leu Asn Val Leu Asp Asn Lys Lys Arg Thr
195 200 205
Ala Leu Ile Lys Ala Val Gln Cys Gln Glu Asp Glu Cys Ala Leu Met
210 215 220
Leu Leu Glu His Gly Thr Asp Pro Asn Ile Pro Asp Glu Tyr Gly Asn
225 230 235 240
Thr Thr Leu His Tyr Ala Ile Tyr Asn Glu Asp Lys Leu Met Ala Lys
245 250 255
Ala Leu Leu Leu Tyr Gly Ala Asp Ile Glu Ser Lys Asn Lys His Gly
260 265 270
Leu Thr Pro Leu Leu Leu Gly Val His Glu Gln Lys Gln Gln Val Val
275 280 285
Lys Phe Leu Ile Lys Lys Lys Ala Asn Leu Asn Ala Leu Asp Arg Tyr
290 295 300
Gly Arg Thr Ala Leu Ile Leu Ala Val Cys Cys Gly Ser Ala Ser Ile
305 310 315 320
Val Ser Leu Leu Leu Glu Gln Asn Ile Asp Val Ser Ser Gln Asp Leu
325 330 335
Ser Gly Gln Thr Ala Arg Glu Tyr Ala Val Ser Ser His His His Val
340 345 350
Ile Cys Gln Leu Leu Ser Asp Tyr Lys Glu Lys Gln Met Leu Lys Ile
355 360 365
Ser Ser Glu Asn Ser Asn Pro Glu Asn Val Ser Arg Thr Arg Asn Lys
370 375 380
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
96
<210> 305
<211> 656
<212> PRT
<213> Homo sapien
<400> 305
Met Val Val Glu Val Asp Ser Met Pro Ala Ala Ser Ser Val Lys Lys
1 5 10 15
Pro Phe Gly Leu Arg Ser Lys Met Gly Lys Trp Cys Cys Arg Cys Phe
20 25 30
Pro Cys Cys Arg Glu Ser Gly Lys Ser Asn Val Gly Thr Ser Gly Asp
35 40 45
His Asp Asp Ser Ala Met Lys Thr Leu Arg Ser Lys Met Gly Lys Trp
50 55 60
Cys Arg His Cys Phe Pro Cys Cys Arg Gly Ser Gly Lys Ser Asn Val
65 70 75 80
Gly Ala Ser Gly Asp His Asp Asp Ser Ala Met Lys Thr Leu Arg Asn
85 90 95
Lys Met Gly Lys Trp Cys Cys His Cys Phe Pro Cys Cys Arg Gly Ser
100 ' 105 . 110
Gly Lys Ser Lys Val Gly Ala Trp Gly Asp Tyr Asp Asp Ser Ala Phe
115 120 125
Met Glu Pro Arg Tyr His Val Arg Gly Glu Asp Leu Asp Lys Leu His
130 135 140
Arg Ala Ala Trp Trp Gly Lys Val Pro Arg Lys Asp heu Ile Val Met
145 150 155 160
Leu Arg Asp Thr Asp Val Asn Lys Lys Asp Lys Gln Lys Arg Thr Ala
165 170 175
Leu His Leu Ala Ser Ala Asn Gly Asn Ser G1u Val Val Lys Leu Leu
180 185 190
Leu Asp Arg Arg Cys Gln Leu Asn Val Leu Asp Asn Lys Lys Arg Thr
195 200 205
Ala Leu Ile Lys Ala Val Gln Cys Gln Glu Asp Glu Cys Ala Leu Met
210 215 220
Leu Leu Glu His Gly Thr Asp Pro Asn Ile Pro Asp Glu Tyr Gly Asn
225 230 235 240
Thr Thr Leu His Tyr Ala Ile Tyr Asn Glu Asp Lys Leu Met Ala Lys
245 250 255
Ala Leu Leu Leu Tyr Gly Ala Asp Ile Glu Ser Lys Asn Lys His Gly
260 265 270
Leu Thr Pro Leu Leu Leu Gly Val His Glu Gln Lys Gln Gln Val Val
275 280 285
Lys Phe Leu Ile Lys Lys Lys Ala Asn Leu Asn Ala Leu Asp Arg Tyr
290 295 300
Gly Arg Thr Ala Leu Ile Leu Ala Val Cys Cys Gly Ser Ala Ser Ile
305 310 315 320
Val Ser Leu Leu Leu Glu Gln Asn Ile Asp Val Ser Ser Gln Asp Leu
325 330 335
Ser Gly Gln Thr Ala Arg Glu Tyr Ala Val Ser Ser His His His Val
340 345 350
Ile Cys Gln Leu Leu Ser Asp Tyr Lys Glu Lys Gln Met Leu Lys Ile
355 360 365
Ser Ser Glu Asn Ser Asn Pro Glu Gln Asp Leu Lys Leu Thr Ser Glu
370 375 380
Glu Glu Ser Gln Arg Phe Lys Gly Ser Glu Asn Ser Gln Pro Glu Lys
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
97
385 390 395 400
Met Ser Gln Glu Pro Glu Ile Asn Lys Asp Gly Asp Arg Glu Val Glu
405 410 415
Glu Glu Met Lys Lys His Glu Ser Asn Asn Val Gly Leu Leu Glu Asn
420 425 430
Leu Thr Asn Gly Val Thr Ala Gly Asn Gly Asp Asn Gly Leu Ile Pro
435 440 445
Gln Arg Lys Ser Arg Thr Pro Glu Asn Gln Gln Phe Pro Asp Asn Glu
450 455 460
Ser Glu Glu Tyr His Arg Ile Cys Glu Leu Val Ser Asp Tyr Lys Glu
465 470 475 480
Lys Gln Met Pro Lys Tyr Ser Ser Glu Asn Ser Asn Pro Glu Gln Asp
485 490 495
Leu Lys Leu Thr Ser Glu Glu Glu Ser Gln Arg Leu Glu Gly Ser Glu
500 505 510
Asn Gly Gln Pro Glu Leu Glu Asn Phe Met Ala Ile Glu Glu Met Lys
515 520 525
Lys His Gly Ser Thr His Val Gly Phe Pro Glu Asn Leu Thr Asn Gly
530 535 540
Ala Thr Ala Gly Asn Gly Asp Asp Gly Leu Ile Pro Pro Arg Lys Ser
545 550 555 560
Arg Thr Pro Glu Ser Gln Gln Phe Pro Asp Thr Glu Asn Glu Glu Tyr
565 570 575
His Ser Asp Glu Gln Asn Asp Thr Gln Lys Gln Phe Cys Glu Glu Gln
580 585 590
Asn Thr Gly Ile Leu His Asp Glu Ile Leu Il.e His Glu Glu Lys Gln '
595 600 6D5
Ile Glu Val Val Glu Lys Met Asn Ser Glu Leu Ser Leu Ser Cys Lys
610 615 52U
Lys Glu Lys Asp Ile Leu His Glu Asn Ser Thr Leu Arg Glu Glu Ile
625 630 635 640
Ala Met Leu Arg Leu Glu Leu Asp Thr Met Lys His Gln Ser Gln Leu
645 650 655
<210> 306
<211> 671
<212> PRT
<213> Homo sapien
<400> 306
Met Val Val Glu Val Asp Ser Met Pro Ala Ala Ser Ser Val Lys Lys
1 5 10 15
Pro Phe Gly Leu Arg Ser Lys Met Gly Lys Trp Cys Cys Arg Cys Phe
20 25 30
Pro Cys Cys Arg Glu Ser Gly Lys Ser Asn Val Gly Thr Ser Gly Asp
35 40 45
His Asp Asp Ser Ala Met Lys Thr Leu Arg Ser Lys Met Gly Lys Trp
50 55 60
Cys Arg His Cys Phe Pro Cys Cys Arg Gly Ser Gly Lys Ser Asn Val
65 70 75 80
Gly Ala Ser Gly Asp His Asp Asp Ser Ala Met Lys Thr Leu Arg Asn
85 90 95
Lys Met Gly Lys Trp Cys Cys His Cys Phe Pro Cys Cys Arg Gly Ser
100 105 110
Gly Lys Ser Lys Val Gly Ala Trp Gly Asp Tyr Asp Asp Ser Ala Phe
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
98
115 120 125
Met Glu Pro Arg Tyr His Val Arg Gly Glu Asp Leu Asp Lys Leu His
130 135 140
Arg Ala Ala Trp Trp Gly Lys Val Pro Arg Lys Asp Leu Ile Val Met
145 150 155 160
Leu Arg Asp Thr Asp Val Asn Lys Lys Asp Lys Gln Lys Arg Thr Ala
165 170 175
Leu His Leu Ala Ser Ala Asn Gly Asn Ser Glu Val Val Lys Leu Leu
180 185 190
Leu Asp Arg Arg Cys Gln Leu Asn Val Leu Asp Asn Lys Lys Arg Thr
195 200 205
Ala Leu Ile Lys Ala Val Gln Cys Gln Glu Asp Glu Cys Ala Leu Met
210 215 220
Leu Leu Glu His Gly Thr Asp Pro Asn Ile Pro Asp Glu Tyr Gly Asn
225 230 235 240
Thr Thr Leu His Tyr Ala Ile Tyr Asn Glu Asp Lys Leu Met Ala Lys
245 250 255
Ala Leu Leu Leu Tyr Gly Ala Asp Ile Glu Ser Lys Asn Lys His Gly
260 265 270
Leu Thr Pro Leu Leu Leu Gly Val His Glu Gln Lys Gln Gln Val Val
275 280 285
Lys Phe Leu Ile Lys Lys Lys Ala Asn Leu Asn Ala Leu Asp Arg Tyr
290 295 300
Gly Arg Thr Ala Leu Ile Leu Ala Val Cys Cys Gly Ser Ala Ser Ile
305 310 315 320
Val Ser Leu Leu Leu Glu Gln Asn Ile Asp Val Ser Ser Gln Asp Leu
325 330 335
Ser Gly Gln Thr Ala Arg Glu Tyr Ala Val Ser Ser His His His Val
340 345 350
Ile Cys Gln Leu Leu Ser Asp Tyr Lys Glu Lys Gln Met Leu Lys Ile
355 360 365
Ser Ser Glu Asn Ser Asn Pro Glu Gln Asp Leu Lys Leu Thr Ser Glu
370 375 380
Glu Glu Ser Gln Arg Phe Lys Gly Ser Glu Asn Ser Gln Pro Glu Lys
385 390 395 400
Met Ser Gln Glu Pro Glu Ile Asn Lys Asp Gly Asp Arg Glu Val Glu
405 410 415
Glu Glu Met Lys Lys His Glu Ser Asn Asn Val Gly Leu Leu Glu Asn
420 425 430
Leu Thr Asn Gly Val Thr Ala Gly Asn Gly Asp Asn Gly Leu Ile Pro
435 440 445
Gln Arg Lys Ser Arg Thr Pro Glu Asn Gln Gln Phe Pro Asp Asn Glu
450 455 460
Ser Glu Glu Tyr His Arg Ile Cys Glu Leu Val Ser Asp Tyr Lys Glu
465 470 475 480
Lys Gln Met Pro Lys Tyr Ser Ser Glu Asn Ser Asn Pro Glu Gln Asp
485 490 495
Leu Lys Leu Thr Ser Glu Glu Glu Ser Gln Arg Leu Glu Gly Ser Glu
500 505 510
Asn Gly Gln Pro Glu Lys Arg Ser Gln Glu Pro Glu Ile Asn Lys Asp
515 520 525
Gly Asp Arg Glu Leu Glu Asn Phe Met Ala Ile Glu Glu Met Lys Lys
530 535 540
His Gly Ser Thr His Val Gly Phe Pro Glu Asn Leu Thr Asn Gly Ala
545 550 555 560
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
99
Thr Ala Gly Asn Gly Asp Asp Gly Leu Ile Pro Pro Arg Lys Ser Arg
565 570 575
Thr Pro Glu Ser Gln Gln Phe Pro Asp Thr Glu Asn Glu Glu Tyr His
580 585 590
Ser Asp Glu Gln Asn Asp Thr Gln Lys Gln Phe Cys Glu Glu Gln Asn
595 600 605
Thr Gly Ile Leu His Asp Glu Ile Leu Ile His Glu Glu Lys Gln Ile
610 615 620
Glu Val Val Glu Lys Met Asn Ser Glu Leu Ser Leu Ser Cys Lys Lys
625 630 635 640
Glu Lys Asp Ile Leu His Glu Asn Ser Thr Leu Arg Glu Glu Ile Ala
645 650 655
Met Leu Arg Leu Glu Leu Asp Thr Met Lys His Gln Ser Gln Leu
660 665 670
<210> 307
<211> 800
<212> DNA
<213> Homo sapien
<400>
307
atkagcttccgcttctgacaacactagagatccctcccctccctcagggtatggccctcc 60
acttcatttttggtacataacatctttataggacaggggtaaaatcccaatactaacagg 120
agaatgcttaggactctaacaggtttttgagaatgtgttggtaagggccactcaatccaa 180
tttttcttggtcctccttgtggtctaggaggacaggcaagggtgcagattttcaagaatg 240
catcagtaagggccactaaatccgaccttcctcgttcctccttgtggtctgggaggaaaa 3C0
ctagtgtttctgttgctgtgtcagtgagcacaactattccgatcagcagggtccagggac 360
cactgcaggttcttgggcagggggagaaacaaaacaaaccaaaaccatgggcrgttttgt 420
ctttcagatgggaaacactcaggcatcaacaggctcacctttgaaatgcatcctaagcca 480
atgggacaaatttgacccacaaaccctggaaaaagaggtggctcattttttttgcactat 540
ggcttggccccaacattctctctctgatggggaaaaatggccacctgagggaagtacaga 600
ttacaatactatcctgcagcttgaccttttctgtaagagggaaggcaaatggagtgaaat 660
accttatgtccaagctttcttttcattgaaggagaatacactatgcaaagcttgaaattt 720
acatcccacaggaggacctctcagcttacccccatatcctagcctccctatagctcccct 780
tcctattagtgataagcctc 800
<210> 308
<211> 102
<212> PRT
<213> Homo sapien
<220>
<221> VARIANT
<222> (1)...(102)
<223> Xaa = Any Amino Acid
<400> 308
Met Gly Xaa Phe Val Phe Gln Met Gly Asn Thr Gln Ala Ser Thr Gly
1 5 10 15
Ser Pro Leu Lys Cys Ile Leu Ser Gln Trp Asp Lys Phe Asp Pro Gln
20 25 30
Thr Leu Glu Lys Glu Val Ala His Phe Phe Cys Thr Met Ala Trp Pro
35 40 45
Gln His Ser Leu Ser Asp Gly Glu Lys Trp Pro Pro Glu Gly Ser Thr
50 55 60
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
100
Asp Tyr Asn Thr Ile Leu Gln Leu Asp Leu Phe Cys Lys Arg Glu Gly
65 70 75 80
Lys Trp Ser Glu Ile Pro Tyr Val Gln Ala Phe Phe Ser Leu Lys Glu
85 90 95
Asn Thr Leu Cys Lys Ala
100
<210> 309
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in the lab
<400> 309
Leu Met Ala Glu Glu Tyr Thr Ile Val
1 5
<210> 310
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in ~he lab
<400> 310
Lys Leu Met Ala Lys Ala Leu Leu Leu
1 5
<210> 311
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in the lab
<400> 311
Gly Leu Thr Pro Leu Leu Leu Gly Ile
1 5
<210> 312
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Made in the lab
<400> 312
Lys Leu Val Leu Asp Arg Arg Cys Gln Leu
1 5 10
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
101
<210> 313
<211> 1852
<212> DNA
<213> Homo Sapiens
<400> 313
ggcacgagaa ttaaaaccct cagcaaaaca ggcatagaag ggacatacct taaagtaata 60
aaaaccacct atgacaagcc cacagccaac ataatactaa atggggaaaa gttagaagca 120
tttcctctga gaactgcaac aataaataca aggatgctgg attttgtcaa atgccttttc 180
tgtgtctgtt gagatgctta tgtgactttg cttttaattc tgtttatgtg attatcacat 240
ttattgactt gcctgtgtta gaccggaaga gctggggtgt ttctcaggag ccaccgtgtg 300
ctgcggcagc ttcgggataa cttgaggctg catcactggg gaagaaacac aytcctgtcc 360
gtggcgctga tggctgagga cagagcttca gtgtggcttc tctgcgactg gcttcttcgg 420
ggagttcttc cttcatagtt catccatatg gctccagagg aaaattatat tattttgtta 480
tggatgaaga gtattacgtt gtgcagatat actgcagtgt cttcatctct tgatgtgtga 540
ttgggtaggt tccaccatgt tgccgcagat gacatgattt cagtacctgt gtctggctga 600
aaagtgtttg tttgtgaatg gatattgtgg tttctggatc tcatcctctg ~gggtggaca 660
gctttctcca ccttgctgga agtgacctgc tgtccagaag tttgatggct gaggagtata 720
ccatcgtgca tgcatctttc atttcctgca tttcttcctc cctggatgga cagggggagc 780
ggcaagagca acgtgggcac ttctggagac cacaacgact cctctgtgaa gacgcttggg 840
agcaagaggt gcaagtggtg ctgccactgc ttcccctgct gcagggggag cggcaagagc 900
aacgtggtcg cttggggaga ctacgatgac agcgccttca tggatcccag gtaccacgtc 960
catggagaag atctggacaa gctccacaga gctgcctggt ggggtaaagt ccccagaaag 1020
gatctcatcg tcatgctcag ggacacggat gtgaacaaga gggacaagca aaagaggact 1080
gctctacatc tggcctctgc caatgggaat tcagaagtag taaaactcgt gctggacaga 1140
cgatgtcaac ttaatgtcct tgacaacaaa aagaggacag ctctgacaaa ggccgtacaa 1200
tgccaggaag atgaatgtgc gttaatgttg ctggaacatg gcactgatcc aaatattcca 1260
gatgagtatg gaaataccac tctacactat gctgtctaca atgaagataa attaatggcc 1320
aaagcactgc tcttatacgg tgctgatatc gaatcaaaaa acaagcatgg cctcacacca 1380
ctgct.acttg gtatacatga gcaaaaacag caagtggtga aatttttaat caagaaaaaa 1440
gcgaatttaa atgcgctgga tagatatgga agaactgctc tcatacttgc tgtatgttgt 1500
ggatcagcaa gtatagtcag ccctctactt gagcaaaatg ttgatgtatc ttctcaagat 1560
ctggaaagac ggccagagag tatgctgttt ctagtcatca tcatgtaatt tgccagttac 1620
tttctgacta caaagaaaaa cagatgttaa aaatctcttc tgaaaacagc aatccagaac 1680
aagacttaaa gctgacatca gaggaagagt cacaaaggct taaaggaagt gaaaacagcc 1740
agccagagct agaagattta tggctattga agaagaatga agaacacgga agtactcatg 1800
tgggattccc agaaaacctg actaacggtg ccgctgctgg caatggtgat ga 1852
<210> 314
<211> 879
<212> DNA
<213> Homo Sapiens
<400> 314
atgcatcttt catttcctgc atttcttcct ccctggatgg acagggggag cggcaagagc 60
aacgtgggca cttctggaga ccacaacgac tcctctgtga agacgcttgg gagcaagagg 120
tgcaagtggt gctgccactg cttcccctgc tgcaggggga gcggcaagag caacgtggtc 180
gcttggggag actacgatga cagcgccttc atggatccca ggtaccacgt ccatggagaa 240
gatctggaca agctccacag agctgcctgg tggggtaaag tccccagaaa ggatctcatc 300
gtcatgctca gggacacgga tgtgaacaag agggacaagc aaaagaggac tgctctacat 360
ctggcctctg ccaatgggaa ttcagaagta gtaaaactcg tgctggacag acgatgtcaa 420
cttaatgtcc ttgacaacaa aaagaggaca gctctgacaa aggccgtaca atgccaggaa 480
gatgaatgtg cgttaatgtt gctggaacat ggcactgatc caaatattcc agatgagtat 540
ggaaatacca ctctacacta tgctgtctac aatgaagata aattaatggc caaagcactg 600
ctcttatacg gtgctgatat cgaatcaaaa aacaagcatg gcctcacacc actgctactt 660
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
102
ggtatacatg agcaaaaaca gcaagtggtg aaatttttaa tcaagaaaaa agcgaattta 720
aatgcgctgg atagatatgg aagaactgct ctcatacttg ctgtatgttg tggatcagca 780
agtatagtca gccctctact tgagcaaaat gttgatgtat cttctcaaga tctggaaaga 840
cggccagaga gtatgctgtt tctagtcatc atcatgtaa 879
<210> 315
<211> 293
<212> PRT
<213> Homo sapiens
<400> 315
Met His Leu Ser Phe Pro Ala Phe Leu Pro Pro Trp Met Asp Arg Gly
10 15
Ser Gly Lys Ser Asn Val Gly Thr Ser Gly Asp His Asn Asp Ser Ser
20 25 30
Val Lys Thr Leu Gly Ser Lys Arg Cys Lys Trp Cys Cys His Cys Phe
35 40 45
Pro Cys Cys Arg Gly Ser Gly Lys Ser Asn Val Val Ala Trp Gly Asp
50 55 60
Tyr Asp Asp Ser Ala Phe Met Asp Pro Arg Tyr His Val His Gly Glu
65 70 75 80
Asp Leu Asp Lys Leu His Arg Ala Ala Trp Trp Gly Lys 'Jal Pro Arg
85 90 95
Lys Asp Leu Ile Val Met Leu Arg Asp Thr Asp Val Asn Lys Arg Asp
100 105 110
Lys Gln Lys Arg Thr Ala Leu His Leu Ala Ser Ala Asn Gly Asn Ser
115 120 125
Glu Val Val Lys Leu Val Leu Asp Arg Arg Cys Gln Leu Asn Val Leu
130 135 140
Asp Asn Lys Lys Arg Thr Ala Leu Thr Lys Ala Val Gln Cys Gln Glu
145 150 155 160
Asp Glu Cys Ala Leu Met Leu Leu Glu His Gly Thr Asp Pro Asn Ile
165 170 175
Pro Asp Glu Tyr Gly Asn Thr Thr Leu His Tyr Ala Val Tyr Asn Glu
180 185 190
Asp Lys Leu Met Ala Lys Ala Leu Leu Leu Tyr Gly Ala Asp Ile Glu
195 200 205
Ser Lys Asn Lys His Gly Leu Thr Pro Leu Leu Leu Gly Ile His Glu
210 215 220
Gln Lys Gln Gln Val Val Lys Phe Leu Ile Lys Lys Lys Ala Asn Leu
225 230 235 240
CA 02365909 2001-10-04
WO 00/61753 PCT/US00/09312
103
Asn Ala Leu Asp Arg Tyr Gly Arg Thr Ala Leu Ile Leu Ala Val Cys
245 250 255
Cys Gly Ser Ala Ser Ile Val Ser Pro Leu Leu Glu Gln Asn Val Asp
260 265 270
Val Ser Ser Gln Asp Leu Glu Arg Arg Pro Glu Ser Met Leu Phe Leu
275 280 285
Val Ile Ile Met
290
<210> 316
<211> 584
<212> DNA
<213> Homo Sapiens
<400> 316
agttgggcca aattcccctc cccctacagc ttgaagggga cataaccaat agcctggggt 60
ttttttgtgg tcctttggag atttctttgc ttattttctt ctgggtgggg gtgattagag 120
gaggcttatc actaatagga aggggagcta tagggaggct aggatatggg ggtaagctga 180
gaggtcctcc tgtgggatgt aaatttcaag ctttgcatag tgtattctcc ttcaatgaaa 240
agaaagcttg gacataaggt atttcactcc atttgccttc cctcttacag aaaaggtcaa 300
gctgcaggat agtattgtaa tctgtacttc cctcaggtgg ccatttttcc ccatcagaga 360
gagaatgttg gggccaagcc atagtgcaga aaaaaaaatg agccacctct ttttccaggg 420
tttgtgggtc aaatttgtcc cattggctta ggatgcattt caaaggtgag cctgttgatg 480
cctgagtgtt tcccatctga aagacaaaac tgcccatggt tttggtttgt tttgtttctc 540
cccctgccca agaactatca aactcctgag ccaacaacta aaaa 584
<210> 317
<211> 829
<212> DNA
<213> Homo Sapiens
<400> 317
attagcttcc gcttctgaca acactagaga tccctcccct ccctcagggt atggccctcc 60
acttcatttt tggtacataa catctttata ggacaggggt aaaatcccaa tactaacagg 120
agaatgctta ggactctaac aggtttttga gaatgtgttg gtaagggcca ctcaatccaa 180
tttttcttgg tcctccttgt ggtctaggag gacaggcaag ggtgcagatt ttcaagaatg 240
catcagtaag ggccactaaa tccgaccttc ctcgttcctc cttgtggtct gggaggaaaa 300
ctagtgtttc tgttgctgtg tcagtgagca caactattcc gatcagcagg gtccagggac 360
cactgcaggt tcttgggcag ggggagaaac aaaacaaacc aaaaccatgg gcagttttgt 420
ctttcagatg ggaaacactc aggcatcaac aggctcacct ttgaaatgca tcctaagcca 480
atgggacaaa tttgacccac aaaccctgga aaaagaggtg gctcattttt tttgcactat 540
ggcttggccc caacattctc tctctgatgg ggaaaaatgg ccacctgagg gaagtacaga 600
ttacaatact atcctgcagc ttgacctttt ctgtaagagg gaaggcaaat ggagtgaaat 660
accttatgtc caagctttct tttcattgaa ggagaataca ctatgcaaag cttgaaattt 720
acatcccaca ggaggacctc tcagcttacc cccatatcct agcctcccta tagctcccct 780
tcctattagt gataagcctc ctctaatcac ccccacccag aagaaaata 829
tgcaagtggt gctgccactg cttcccctgc tgcaggggga g
