ZA200607348B - Genes associated with canine osteoarthritis and related methods and compositions - Google Patents
Genes associated with canine osteoarthritis and related methods and compositions Download PDFInfo
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Description
GENES ASSOCIATED WITH CANINE OSTEOARTHRITIS AND RELATED
METHODS AND COMPOSITIONS
[0001] This application claims benefit of U.S. Application No. 60/541,346, filed
February 2, 2004, the disclosure of which is hereby incorporated by reference in its entirety.
[0002] This invention relates to the field of degenerative joint diseases, such as osteoarthritis. More particularly, the invention relates to novel compositions, devices and methods based on unique profiles of gene expression associated with osteoarthritis.
[0003] Osteoarthritis (OA), also commonly referred to as degenerative joint disease, is recognized in humans and all veterinary species (Richardson et al., (1997) Vet. Clin. North Am. 27:883-911). OA is a prevalent and debilitating disease in canines and is often associated with hip dysplasia (Martinez, S. (1997) Osteoarthritis, Vet. Clinics of N. Am.: Small Animal Practice 27 (4):735-758.). There is a high degree of similarity between canine and human osteoarthritis, thus making it an excellent animal model for the study of human osteoarthritis. While causative factors remain largely unknown, the disease is characterized by the imbalance of cartilage matrix degradation outweighing cartilage matrix synthesis. Chondrocyte apoptosis and inflammation may also be associated with the disease (Pelletier, J., et al.(2001) Arthritis & Rheumatism 44 (6):1237-1247; Lotz, M. (1999) Osteoarthritis and Cartilage 7: 389-391).
[0004] The disease is typically slow in progression and characterized by degeneration of articular cartilage with a loss of both proteoglycan and collagen and by proliferation of new bone. In addition, an inflammatory response can occur within the synovial membrane. Canine osteoarthritis can arise as a secondary condition resulting, in particular, from hip displasia or from osteochondritis dissecans (Martinez, supra). Acquired conditions involving traumatic events can also lead to osteoarthritis in the dog (Martinez et al., Vet. Clin. North Am. 27:759-7175,
1997). Treatment modalities for osteoarthritis can include the administration of anti- inflammatory drugs as well as the manipulation of dietary fatty acids (Richardson et al., supra).
[0005] Diagnosis of canine osteoarthritis is typically based upon symptomatology.
Dogs having osteoarthritis show a lameness which may have a gradual onset but can flare up acutely after exercise. The lameness is exacerbated by rest but decreases after a few minutes of activity. Cold damp conditions, obesity and prolonged exercise often worsen signs of lameness (Pederson et al, in Textbook of Veterinary Internal Medicine, 5th Ed., Ettinger et al., ed., W.B.
Saunders and Co., Philadelphia, 2000, pp. 1862-1886).
[0006] With the emergence of the genomic sciences, it has become apparent that not only is the regulation of gene expression intimately involved in normal homeostasis, alterations in the differential expression of genes is one aspect in the development of diseases. As a result, the evaluation of gene expression patterns in disease has become increasingly recognized as being crucial to the understanding of disease processes at the molecular level. (Going et al.,
European J. Cancer 35:1895-1904, 1999; Wang et al., Cardiovasc. Res. 35:414-421). A number of approaches have emerged for studying comparative gene expression and the current emphasis has been on high throughput analysis methods. (for review see Carulli et al, J. Cell. Biochem.
Suppl. 30/32:286-296, 1998; Kozian et al., Trends Biotechnol 17-73-78, 1999). Recent methods developed for high throughput analysis of differential gene expression include, for example, EST sequencing (Adams et al., Science 252:1651-1656, 1991; Adams et al., Nature 377:3-16, 1995), microarray hybridization (Schena et al., Science 270:467-470, 1995), and differential display (Liang et al., Science 257:967-970, 1992; Welsh et al., Nucleic Acids Res. 20:4965-4970, 1992).
[0007] Gene expression in osteoarthritis, and particularly in canine osteoarthritis, has not been comprehensively studied. Accordingly, a need exists to identify nucleic acid sequences and their encoded proteins which are differentially expressed in osteoarthritis. This information would be useful to diagnose the osteoarthritic disease state, or pre-disposition to the disease, in a subject, as well as to identify substances useful in the treatment or prevention of osteoarthritis.
[0008] In accordance with an aspect of the present invention, a number of polynucleotides comprising at least a fragment of a gene have been identified as being differentially expressed in osteoarthritic or pre-osteoarthritic subjects, compared to expression in subjects which are not osteoarthritic or pre-osteoarthritic.
[0009] In accordance with an aspect of the present invention, differentially expressed genes, gene fragments, and encoded gene products, as well as the expression patterns associated with the group of genes, are used to advantage in a number of methods for the detection of changes in gene expression associated with osteoarthritis, particularly canine osteoarthritis.
Additional aspects of the invention relate to methods for the identification of agents useful in treating and/or preventing osteoarthritis.
[0010] In accordance with additional aspects of the present invention, compositions, devices and test kits are provided to facilitate the practice of methods provided according to certain embodiments of the invention.
[0011] Other features and advantages of the present invention will be understood by reference to the detailed description and the examples that follow.
[0012] Figure 1 shows representative gels used in differential display analysis of canine osteoarthritis. A. Differential display of osteoarthritic vs. normal transcripts loaded in duplicate prior to band excision (D=osteoarthritic (Diseased), N=Normal). B. The same gel after band excision.
[0013] Figure 2 shows quantitative PCR analysis (QPCR) for selected OA-associated transcripts in canine cartilage. RNA expression is shown in arbitrary units. (OA AVG = average expression for osteoarthritic cartilage; C AVG = average expression in normal control).
TABLE 1: Correlation of Gene ID Numbers with Sequence ID Numbers.
SEQID | | GeneID |SEQID | | GeneID |SEQID | [GeneID |SEQID 1028c | L [ |768a [2 | [alc |3 | [1548 “i357a 5 | [desc |6 | [38a 7 | J2127c [8 530b 9 | osc [10 | |i7esa [ii | [166a [12 7978 [13 | [1720a [14 | [ies7c [15 [ [523% [16 |] 2172c | 17 | 58a [18 | [244 |lo []70d [20 14724 |21 | |452a [22 | |i48lc [23 | [1040 1930a [25 | | 739% [26 | [lela [27 | [14a [28 17272 | 29 | [12200 [30 | [33% [31 | |1ll46a 1738 [33 | |810a _ [34 | [1093 [35 | [2147a 1678s [37 | |S6a _ |38 | [isd [39 | |12% 19240 | 41 | |s57b [42 | |I2s4a [43 | [1292 [2231c [45 | [490c__ 146 | [907a [47 . | [460d 713a___ [49 | |1372a [50 | [48a © }ST | [1098 1785a | 53 | [1624p [54 | |1aeid [55 =] [553b 2170a 57 | [1257 | s8 | [1s06d [59 | ]193% 160 2007261 | [13a [ez | |i288a |63 [ |1940% 452c 65 | |1054a [66 | |1a04c 67 | [8a 168 46a 69 | |1985a |70 | [326 |711 [[85ic [72 16758 | 73 | |574a [74 | [215% 175 | 12108b 45ab 77 | 121738 [78 | [l66a |79 | [58la [80 16952 [81 | [1414p [82 | [sib [83 | liad 46la [85 | |i6isb [86 | [3ioh [87 [ [207a [88 18016 [89 | |23a [90 | {179a [or | [170s [92 1955 [93 | |2088a [94 | 2243p [95 | 1440a [O06 (2351c [97 | [1415p {98 | |2074b [99 [ [2250
(11472 | 105 | [2266b | 108 ssa [105 | [206 [uo | {ag nu | [20a [ID rT I VE IN ISVS I BC VCR 777 NI EV CI
Sova 1Ti7 | [odsa Jus [lead [uo | [24a [130 osha T12l | [184 [1p | [oseb los | lla 1124
Hee Tis | [47a [126 | [737 [127 | [2166s [128 oe [12s | [20s0d [130 | [isos [13L | [73a 1132 lor [135 | [1650s [13 | [ie20a [135 | [1951a ]136 355 [137 | [i394 [138 | 27a [139 | [340 1140 ] Seg [141 | [76a 142 | [1a 143 [11475 [144
Sasac [145 | [1540s [146 | |isoib [147 | T21s6c [148 035d [149 | [19192 [150 | [edsa | 151 | Jizdla J152 73a 155 | [1442s [156 | 55a [155 | 1690 1156
Sigsa [157 | 1979a [158 | [i747a [150 | [S07a [160
S50 [161 | |39%a [162 | 1309p [163 | [1d62a [6s ose [165 | [13138 [166 | [1436 [167 | |1s3b [168
TT7o0a [169 | [96la [170 | [493 [i711 | [1463 [172 7a [175 | [1454d [17a | [143d | 175 | |766b 1176
Tab [177 | [1423 [178 | [850a [179 | [148a 1180 606s [181 | [1396b [182 | |214la [183 | [1503c | i84 |] 63a | 185 | |1682a [186 | [215% [187 | [2241a 1188 22655 [189 | [1438a [190 | [2050p | io1 | |i646a [192 d6sb [193 | [990a [104 | |i4ssb [105 | 14522 [196
Ci2joa [197 | |2142a [198 | |o45a [109 | [1367a 1200 3198b | 201 | | 1136a [202 | [11388 [203 | [10082 [204 (5s2a [205 | |2374a 206 | |i532a [207 | |aiisa [208 “1366s [209 | [1262p [210 | [iadlc [211 | [21a [212
C1246a | 213 | [1253 [214 | [22248 215 | [10154 [216
S252 217 | [154s [218 | [718 [210 | [1b [220 |] 3633 220 | [370s [222 | |1551a [223 | [376a [204 8a2c 1205 | [380a [226 | [372a [227 | [2148s [228 1800s | 229 | |109%0a [230 | [60a |231 | [96 1232 2015¢ | 233 | [128a _ |23¢ | Jez [235 | [1174d [236 oa7a 1237 | [194 [238 | [619% [230 | [202%b [240 1468c | 241 | [1620a [242 | [174a [243 | [2085 [244 1461a | 245 | [7646 [246 | [731a |247 | ['1051a [248 613a___ | 249 | [531a [250 | |147la [251 | ['138la [252 adc | 253 | [1892a |254 | |76b [255 | [366a [256 004 [257 | [1958 [258 | [409 [250 | [2120a [260 638b [261 | [3204 [262 | |1853a [263 | [2047a [264 |] 1746s | 265 | |108la | 266 | [2002c [267 | [785b [268 (10926 [260 | [1788 [270 | [isiib [271 | [18izb 1272
C1885c [273 | [1610a [274 | |2344a |275 | [1477a 1276 360s | 277 | [568a [278 | [1109a [279 | [128% |280
T1276a | 281 | |1728a [28> | [1023p [283 | [2020p [284 556b 285 | |i711a [286 | [49a [287 | [1271a [288 (1497c [289 | [9676 [290 | [1329a [291 | |d6ab [292 [14502 [203 | |188o [204 | [78a [205 | [631b [296 [1244b | 207 | [758 | 298 | | 1807a [299 | [276a [300 [2042 [301 | [543a [302 | [1764s [303 | [71a [304 [35c___ 305 | [140ic [306 | {3c [307 | [494s [308 1616a__ [300 | |1070b [310 | [1928 [311 | |'597c [312 [1505c | 313 | |194le | 314 | [742a [315 | |'1299c [316 (1960a | 317 | |1101a | 318 | |s6za _ [319 | |2223%a [320 2099a [321 | |342a [322 | [13476 [323 | [738 [324 (1744a [325 | |1918a | 326 | |1060a [327 | |1224b [328 [861c | 329 | [2033a [330 | [134% [331 | [7i5a [332 (1621a 333 | |379%a [334 _ | [570 [335 | [1i504d [336 _4.
eT [om [ew [Jose [wo [use [30]
PS YW I 7S ETM ZW V5 J 0 7 TO 7” ie Daas | [oaoss [346 | i7a (sar | [ois 1348)
A ese [sso | [oma [3st | [woh [55 [355 [oa [ssa | [isasp [3s | Jama 13% eT | [4c [sm | iavsa 3 | [10a 1360
Heer [me [36 | [oot [ses | [1st [364
Sos [36s | [iowa [366 | [Ura [ser | [1400s 1568 re Teo | [usta [30 | [105m [smi | [oda |570 eos [3s | [oass [34 | [ona 355 | [10d 1576 esta [37 | ietze [3% | |ateic [a | [dew [380
Ste asi | [isos [382 | [som [38 | [21008 [38d ose Tass | [133 [386 | [13174 [ss | [iis [388]
ST. 38s [T1708 (3% | [sec [391 | [1371a [32 |]
Si [393 | [isis [394 | [esta [3s | [21a [36 oso 35 [Toe [38 | [otf [30 | [oc [400
Sosa dol lseld [4 | [ed [40s | [soi [404 es Taos | [78 [406 | [74c [407 | [73 [408 aos [em [410 | [era [mr | lea [42 ess an [Tea [44 [Tee [aes | [59a [416
Ta [ssa [4s | [52a [ao | [sole [0 [aa [a [42 [38a [a3 | [3c [ma
ECTS SN UN CN TR I TV A I 7S 7 ee Tao | [25a [4 | [2 [a | [20a a3 ioe 435 [lie [ae | [ib [#35 | [ioc [a6 log [43m | [0% [43% | [104s [439 | [10a [440 (la [ML | [T0s [a2 Ti2th [as | [imc [as oie [ads | [12a [ade | |i2ea |aar | [1306 [ass ois [44 | [132 [#50 | [isd [asi | [isa [452 36 45 | [dare [4s | [las [ass | [ideb [4s6 la 457 | [150s [dss | [152% [aso | [iso [460 iss del | [159 [46 | [dete [463 | [ies [des oie [des | [165s [de | [173 lae1 | [17a des
Te des | rr [ro [trop [ari | [isa [412 ge [43 | [185s [47d | [ses [ars | [iste [476 “iss 477 | [oop [478 | [19]a [470 | [15a [480 loca [4s | liom Jam | [io [ass | [lose [dea 070 [4s | [1072s [ase | [dos 487 | [10a [dss dass | [irra [ao [ism [aor | [ia [42 ods [493 | [usta [doa | [198 _ [a5 | [ood [496 aoa 407 [201 [49s | [20a [499 | [203 [500
Sosa [Sol | [208 [30 | [209 [503 | [20a [S04
Site [505 | [ota [06 | [215s [507 | [ala [S08
Si [509 | [218 [si0__ | [21% [sii | [20d [512 ab [513 | [oman [sid [22a [515 | [24a [516
SaaS [loa [sis | [22a [519 | [00a [50
EEC I WN I ST 7 A NN 7 7S MX ES sta [sis | [osm [6 [2% sm | [aie [58 3a [529 | [23 [50 | [240s [sl [oats 53 [ia [53 | [em [ssa [24s [535 | [ose [536 47a [531 | [ods [538 | [24% [S30 | [250s _ [340 51a [sal | [2520 [582 | [25% [sas | [5a [sa 355 [sas | [sta [sd6 | [2st [se | [o60c [548 26lc [549 | [2600 [550 [263 [ss | |oeea sn 67a [sss | ze [554 | [Ziv [sss | [oma [55 ab [S57 | [21s [558 | [27a [550 | [ove [560 2800 | sel | [98a [52 | [28 [se | [asap |s64 sh [ses | [sea [566 | [289 [567 | [20la [ses om 565 | [oan 1570 | [205 |571 | [296s [572 _5-
PCT/US2005/003375 (299 [553 | [301 [574 | [302a [575 | [4% S76 [4982 [577 | (497a [578 | [49%6c |579 | [495a [580 |] 491a__ | 581 | [39a [582 | {351b [583 | |34da |S84 343 | 585 | |338a [586 | [337c [587 | |33%a 588 [3552 | 580 | 334s | 590 | [3280 [sor | 13250 ]s92 [324 [593 | [312a [594 | [31lc _ [505 | |309 [59 308c | 597 | [3070 [598 | |306b [509 | [303a ]600 |] [3006 [601 | [163% _ [602 | [5736 [603 | [56lb [604 |]
S60b [605s | |559c _|e06 | [554c [607 | |s51b [608 5492 [609 | |542a [610 | [540m |6lL | [53% 1612 [5382 [613 | [537c [614 | [53a [61s | [535 [616 } [5346 617 | [5330 | 618 | [527a [619 | |526a [620 521b |e21 | [520s |622 | [519 [623 | [517c [624 |] [Si6c | 625 | [sia [626 | {514s [627 | [513 [628 [5026 [620 | |5090 [630 | [508a [631 | |505b }632 [504a [633 | |503a | 634 | |502a |635 | [50b [636 (500a [637 | |3asb [638 | |362b |639 | |364a [640 [367a [641 | |369a 642 | |37la [643 | [374a [644 (3770 | 645 | |378a 1646 | |38la [647 | [386b [648 [389c [649 | [39a [650 | [301a [e€51 | [393 [652 3976 [653 | |455c | 654 | |456c [655 | [457c [656 [4586 [657 | [450a [658 | [4626 [659 | [466b [660 [4742 | 661 | [4782 [662 | [480a [663 | [483a [664 4842 [665 | |485f [666 | |486a | 667 | [487a | 668 (4882 1669 | [s545a [670 | |s48c [671 | [558a [672 [571a [673 | [572b [674 | [578 [675 | [579 [676 1 582c 1677 | |s84b [678 | [s87b [679 | [590a ]680 505a [681 | |684a 1682 [| |685a | 683 | [686b [684 (687a | 685 | |688a |686 | |69la |687 | [692a [688 [695a [e689 [| 169% [690 | [697a [691 | [698 |692 (6992 [693 | [700a [694 [| [701a [695 | [702a | 696 [7046 [697 | [706b 1698 | [708s [699 | 1709a [700 [7t0a 701 | 1712a [702 | [714a [703 | [716b [704 {7176 705 | [719a 706 | [720s [707 | [722b [708 (7232 [709 | [724s [710 | {7252 [711 | [7272 [712 728b 1713 | |730b }714 | [732a [715 | [733a [716 (734a [717 | [740b [718 | 1741b 719 | [743a [720 (7442 [721 | [7452 [722 | [748 }723 | 174% _ [724 [752 [725 | ]753b 1726 | [754d [727 | |757a [728 750b 1729 [| 1761a }730 | [7622 [731 | [763d [732 1 765a [733 | [770b 1734 [ [773 |735 | 774a [736 [7752 [737 | 1780s [738 | [78a ]739 | [783a [740 (7842 [741 | [786a |742 [ |787b 1743 | [788a [744 17892 [745 | [791b [746 | [792a [747 | [797a |748 17982 [749 | [799a 1750 | 969a [751 | [968a |752 (966a [753 | [964a [754 | {963c 1755 | [959a 1756 (957c [757 | [956d [758 | [953 [759 | [952a [760 1946a | 761 | [944d [762 | [943% |763 | |942b [764 1939a [765 | [938b [766 | [9356 ]767 | 934b [768 19312 769 | 1930a [770 | [928a [771 | [927a [772 (926s [773 | [9252 [774 | [923 [775 | [o2lc [776 jo1b 1777 [ 1918s [778 | Jot6c [779 | [915a [780 [O14a [781 | [913a |782 | fo12p [783 | [olla [784 [910c 785 | [909a |786 | |906a ]787 | [905a _ [788 (9042 [780 [| [902a [790 | [900a [791 | [899a [792 1 806b_ [793 | [8o4b ]794 | [893a [795 | [&9la [796 [8852 [797 | [883c [798 | [843a [799 | [8alb [800 1839a sor [| [838 |s802 | [837c [803 | [83a | 804 [834b [805 | [833a [806 | [832a [807 | [31a __ [808
Tem [Jeo [80 | (edb [eu | [sma 81D
Hats [sis [sa [se | [eva [eis | [Sika 1816 ie Ter | Jess [sis | [sia [sio | [808 }830
Hess Te [ez [sm | [ies [ms [Lio jwd ea 8s [lesb [826 | leona [g2 | ]160SH J ®8 sano | [52a [830 | |1so4a [m3 | |ismb 1832 50a [831 | [1519 [3a | [isisa [85 | [isla 836 52a Iss7 | [sos [sss | [sora [so | [149% [840 asa [8a | [14s [sap | [186d [eas | |1482a [sad lagon [845 | [147s [46 | [aoa [sar | [lde6b [848 } docs [849 | [soc [850 | [14a [81 | | 1418 [852 lao [853 | | 1407a [854 | |1406a 85 | [dos 1856 399s [857 | | 1397b [ess | |isesc [eso | [364d [860 32s [sel | | 1324a [862 | |1321a [83 | [1316s 864 3166 [865 | | 1312a [866 | |10la [867 | | 1289 1868
Tossa [80 | [1277a__ [870 | [1z3b |e | | |872
Cogob [83 | | 1267a _|s7a | [1266a |&r5 | [163 1876
Taste [877 | [1105s _[®78 | [liohe go | |uiosb [880 ilozo [ssl | [1ls9a sg» | [iiss [ees | |7i8Se [884
Tisda [885 | [1183a_ [886 | [1i82a [87 | [1178s [883 © [isa [sso | [i172a__ [800 | [ti7ta [or ['11i70e [892 J
Tiles [893 | [ileeb [soa | [1i32a [895 | [11266 [896
Tii7a [897 | [iio [sos | [toa |899 | [4103 [900 . [Gia [oor | [toasc _[ooz | [ioosc [903 | Told [oo4 loc [905 | [1239 [906 | [1240s |907 | [i243 [508 i368 [909 | [1370s [910 | [1383 [oii | [408 O12 alsb oi | [420a Joa | [assy [o15 | [863 1916
Sac |o17 | [867d _ lots | [870e [ow | |€74c [920
Teele [921 | [940a 1922 | [oala [923 | [058 [024
To75a [925 | |980b [926 | [98la [927 | [967a [928 oo3 [020 | [9%a [030 | |loi2a [931 | li0i3a 932 [loiga [033 | [1019a [034 | |1020a |935 | 110232 [936 | :
T026b [937 | [10094 [038 | [103la [935 | ]1034a [040 (1036s [od | [10s [od | [trie [943 | [1252s [044 2552 [945 | |126dc [046 | |1274c o47 | [1275c [948 270 [045 | |io8lc [050 | [1286a [951 | 11287c [O52 12004 [053 | [1310a [954 | [idea [955 | |1426a [956 (1427s [057 | [1428a [oss | [1430s 950 | [1431a [960 14324 [961 | [1435 [962 | |1436b [963 | | 1437c [064 (7444b | 065 | | 1445p [966 | [1446s [967 | |1447a [968 (14482 [069 | [1451a [oj0 | [iasse [oj | [154 [o72 (i529. [o73 | [16lla [974 | [163% Jo75 | [i64lb 1976
TTi52d [077 | [1158 ov | [1isob oro [ [1163 1980
Ci420c [O81 | |i77mb |o82 | |i85%a [083 | [186la [O84 [1886s [O85 | | i889 |o86 | |1o00b [9087 [ [1005a [988 [2110s [989 | [2120a J000 | Jota7o |oo1 | [2143 [om 2205, [093 | [2234 [004 | |oo37b [995 | 12238 1996 [32306 | oo7 | [2248a [098 | |oo67a [999 | [436c 11000 [4d6f [1001 | [54a [1002 | [sost [1003 | ]520b 11004 [salb [1005 | [547c | 1006 | [S63 [1007 | [S64a [1008 [S65a | 1000 | |566a | 3010 | [5756 joi | [58% }1012 [Sota [1013 | [609 [1014 | [610s [1015 | [6lla [1016 (612 [1017 | [64a [1018 | J617a [1019 | ]620a ]1020
T6222 [1021 | [623 [1022 | |e24b 1023 | [625a | 1024 |] (626a [1025 | |629a [1026 | |630a [1027 | [63a | 1028 33a [1009 | [63a [1030 | [es7e [1031 | [edob }1032
T6ala [1033 _ | |642a [034 | [85a [7035 | [®46a [1036 [847a [1057 | [82a _ [1038 | Jo48a [1030 | [1242a 11040 |] [1634s 11041 | |2i38a [1042 | [2233a [1043 [ [615a | 1044 ios [Jams [10% | [ea [iow | [esc [0d os ios | [1050 [1050 | [1106 [os | [128s 11052 ies [1055 | [ews [1056 | [1e13b [oss | [1694 [1056
How [1057 | [irom [tose | [174 [1050 | |U77a [1060
Tie Ter | [17a [1062 | [10a [063 | viola [1064 i065 | | T724a [1066 | [ima | t067 | [1130s [1068
Tata T1065 | [17a [1070 | [vasa |d07i | [150s [i072 sts T1075 | [istes _[J074 | [1g80a [tors | [lesa [1076 a7. [07 | [18os» [1078 | [io03a [079 | [1o12a |1080 “Iota [lost | [1921a [1082 | [i067a _|l085 | 1968 | i084 ora oss | [19792 [1086 | [108la [087 | [1982s [088 “loses [1089 | | 1987a [1090 | |1o8sa [1091 | [1990s [1092 |] “Too T1093 | | 1994s [1094 | [20736 [1095 | 12075 [1096 rec ToT | [2078 [1098 | |2086a [1095 | [209% [1100 |]
S093 [i101 | [2094s [1102 | [20674 [1103 | [21000 [1104 oss [1105 | [21052 [1106 | [2106s [1107 | [2016 1108 ios T1100 | [21266 [1110 | [2128s [11 | [21328 [1112
S135 Tus | [2136b [ua | [2usc [11s | [21408 [1116 50a IIT | [2154s [111s | [2158 [1119 | [2160s [1120
Diem Tizi| [2l67a [122 | [270s [1123 | [217lc [1124
Sivas [1135 | [2178 [1126 | |2issb [1127 | 388 _ [1128 35. [i> | [856c [1130 | [D216a [131 | [170sa [113 “Tosa [1133 [17346 [i134 | [1781a [1135 | [178% [1136 “Tea [137 | [170m [113 | [19% [1139 | [1794 [1140 “i795 [1141 | [1796a [1142 | |1817a [1143 | [sorb [1144 lov [1145 | [2095s [1146 | [2144s [147 | [2id6a [1148 38d [114 | [600s [1130 | [878 [us | [ola [U5
Soo [1155 | [1025s [ise | [1037c | iss | [1030c [1156 “lodob [1157 | [1058 | 1138 | | 1059a [1150 | [i06la [1160 fo6za[1i6l | [1063 | ilez | [1064s [1163 | [l06sa | ii6¢ logon [116s | [1071b | 1l66 | [10728 [167 | [10738 [1168
Sota Tes | [i2zp [70 | [1130s [171 | [13a [1172
T3513 | [1b [17a | [1i76a [175 | [18a [1176 sob [1177 | [1204s [1178 | [1208a [179 | [12156 [1180 oa [181 | [122p [is | |1236a [1183 | [12400 [1184 1257 [1185 | [1308 [1186 | |13l4a [1187 | [13558 [1188 i361a [1185 | | 13630 [1100 | | 1386a__ [1191 | [138% [1192 “1390s [1193 | [1391a [19a | [1417a_ [1195 | [1sloa [i196
Tisseb [1197 | [1537c [110s | [isdeb | 1199 | [sarc [1200 “is52a [1200 | [155k [1202 | [1556s | 1205 | |1ss8c [1204
Sota [1205 | [15924 [1206 | [1504s [1207 | [15956 [1208 “Ts06b [1200 | [15972 [1210 | [1508s [doi | [1s0a [1212
Sleooa [1213 | [1601s [1214 | [1602s [1215 | |l603a [1216 leo [1217 | [1617s [1218 | [i626c [1219 | [i62sa [1220 este 12i | [ie 2 | [1657 1223 | [1esla [1224
Siegza [1235 | [lees [1226 | [1665 [1227 | [le7ib | 1228 lg72a [1229 | [esse [12300 | [169th [i231 | [17isa [1232 i735 [1233 | [1810s [1234 | |issec [1235 | | 1860a [1236 1g7ab [1257 | [issio [1238 | [1901 [1239 | [1013 | 1240
To0ab [1241 | [230 [1242 | [1035 | f2a3 | [1124 [1244
T2045 | [319 [1246 | [lalla i247 | [dota [1288 “15880 [1249 | [lease | 1250 | [667s [1251 | [178 [1252 450s [1255 | [1076c [1254 | [10774 [i255 | [1085 [1256 los7c [1257 | [1093 [1258 | [1094p [1259 | [1l02a | 1260
Tio6a [1261 | [108s [12 | [1112 | 1263 | |1llea | 1264
T133sb [i265 | [13sec [1266 | [1338s [1267 | [133% [1268 341a [1260 | [1449 [1270 | [1457 [1271 | [1458s [1072 49a [aziz | iassh [174 | [148% | 125 | 149% 1276 “isola T1277 | [1509 |iz78 | [1525s [1215 | [153 | 1380
{5346 [128i | [15358 [iss | [isso | ips3 | [183ab [1284
To27a | 1285 | [1920c [1286 | [1037c | iog7 | | 10426 [1288 |] 104dn | 1280 | | 1o46b [1200 | [1o47a | lpo1 | J 1948b | 1292 050s [1203 | [1952a | 1294 | [1056a | 1295 | [1958 11296 2003a__ | 1207 | [2021a | 1208 | |2002a [1299 | 120236 | 1300
So24a | 1301 | [2020a [1302 | |203%b [1308 | |2053%a 1304 305601305 | |2065a | 1306 | |2070a 11307 | |1334a | 1308 lassa [1309 | [2066b | 1310 | [17376 [i311 | [174la [1312 17796 [1313 | | 1891s [1314 | [totlb [1315 | [1922s | 1316
T067a___ | 1317 | [1091b [1318 | [10058 | 1319 | [1i05a [1320
T3ib [i321 | [11696 [1322 | |uio6b [1323 | [1213d ]1324
Ti222a | 1325 | |1220c | 1326 | [1327a [i327 [ T1346b [1328
Ti358b [1320 | |1384a [1350 | [14eb [1331 | 11500b ]1332 [i6o3b [1333 | [1752a [1334 | [1802a [1335 [ T1871a [1336 (852b [1337 | |233lc [1338 | [1687a [1339 | [16604 [1340 l654c_ | 1341 | [1808a [1342 | |1425a [1343 | ]1410b 1344 i378b | 1345 | [1376s | 1346 | |0osa | i347 [ [98% ]1348 2358a | 1340 | [2084c [1350 | |1250a [1351 | 10026 [1352 583¢ | 1353 | |2220a [1354 | |100ia | 1355 | J1002b 11356 (10032 | 1357 | | 10042 | 1358 | {10058 | 1359 | ]1006b [1360 [1007a [1361 | [10422 [1362 | |1044c | 1363 | ]1045a [1364 [1099c [1365 | [1120s [1366 | |1i2sa | 1367 | [1212b | 1368 (12256 [1369 | |[1226d [1370 | [1304s [1371 | |132c [1372 [1515c [1373 | |1527a | 1374 | [i580 [1375 | [1530c [1376 1541 [1377 | |1561a [1378 | |1690a [1379 | |1692a [1380 [G736b | 1381 | | 1763b | 1382 | |i766a [1383 | |1777a | 1384 [1883b | 1385 | | 1888c [1386 | |1898a | 1387 | |2043b |1388 [20454 | 1389 | |2130b [1300 | [213%a [1391 | [213% [1392 / [2140b___ | 1393 | |2165a | 1394 | [2199a [1395 | ]2210a [1396 [2254s | 1397 | [2264b [1398 | |2268a [1399 | |265a | 1400 [365b | 1401 | |492a [1400 | [550a [1403 | [635a [1404 [7266 | 1405 | [750b [1406 | [7726 | 1407 | [7762 | 1408 777a___ [1409 | [793a [1410 [ [soob [1411 | |sotb [1412 [803b | 1413 | [804a 1414 | ]806b [1415 | }827b [1416 (855c [1417 | [877e [1418 | [880e [1419 | [032b [1420 [0330 | 1421 | [984a | 1422 | Jo86a [1423 | 1988p | 1424 [0892 | 1425 | [997a [1426 | [1016b [1427 | [1027a [1428 1030a___ | 1420 | [1038p [1430 | J1052b [1431 | 11053 1432 1088c | 1433 | [10804 [1434 | |1097c [1435 | [1145a | 1436 1165d__ [1437 | [1260c | 1438 | |1315c [1439 | [1348p [14401352b___ | 1441 | [1360b | 1442 | |1387b [1443 | 1403a, | 1444 [1413b__ | 1445 | |1416a | 1446 | [1419a [1447 | ]1d42dr 1448 14432 [1449 | [1450s | 1450 | 11483 [1451 | |1562a [1452 15642 | 1453 | [1565c _ [1454 | [1567a | 1455 | |1568a | 1456 [1560b | 1457 | [1570a [1458 | [1572a | 1450 | [1573a [1460 [1574b | 1461 | [1575a [1462 | [1576a [1463 [| [1577a [1464 [15782 [1465 | | 1570a | 1466 | [1580b [1467 | [1581a [1468 15832 | 1460 | |1584a [1470 | |1585b [1471 | 11586a [1472 [16284 [1473 | [1630p [1474 | [1666d [1475 | |1669d [1476 (16704 |1477 | [1755a [1478 | 117500 |1479 | ]1760c | 1480 [1775a__ [1481 [[1778c [1482 | [1780a [1483 | [18092 | 1484 1846d | 1485 | [18490 | 1486 | [1852s [1487 | |1863c | 1488 [1864b [1489 | |i865c [1490 | [1879a [1491 | [1894a [1492 1906a | 1493 | [196le [1494 | |1966a | 1495 | |1980b [1496 1901d [1497 | [2008a [1498 [| ]2013a [1499 | 12014f [1500 2034a [1501 | [2036b [1502 | [2041d [1503 | [2042h |1504 [2043p | 1505 | [2044a [1506 | [20454 [1507 | }2046a | 1508 [20482 [1509 | [210lc [1510 | [21076 [1511 | [212dar 1512 [2235a {1513 | [2240s [1514 | [2251d [1515 [ [2271a [1516
Tai [15 [2556 [1518 | [oasep [isto | [237La | 1520 (2373a___| 1521 | [32a [1522 [805s | 1525 | |924a [1504 esa [1525 | [898s [1526 | [oc _ [lso7 | [865 1528 ooo [1520 | [40ear [1530 | [321s [sal | [320s 11532
Stoo [1535 | [ala [1534 | [315 _ [is35 | [31a 11536 [3132 | 1537 2249s i538 | [2isop | 1is30 | [21346 [1540
S135 | 1sar | [isiib | isax | [Issa [is43 | [139%
T38ob | 1545 | [1377b | 1546 | |13s6a | is47 | | 1353 oats [1580 | [1635a [1550 | [isso | 1ssL | |1365a [1552 (500b | 1553 | [48b | 1554 | |4d0a 1555 | [4132 [1556 1557 | |iszeor lisse || | |]
[0014] The following definitions are provided to facilitate an understanding of the present invention: :
[0015] "Nucleic acid" or a "nucleic acid molecule" as used herein refers to any DNA or
RNA molecule, either single or double stranded and, if single stranded, the molecule of its complementary sequence in either linear or circular form. In discussing nucleic acid molecules, a sequence or structure of a particular nucleic acid molecule may be described herein according to "the normal convention of providing the sequence in the 5' to 3' direction. With reference to nucleic acids according to aspects of the invention, the term "isolated nucleic acid" is sometimes used. This term, when applied to DNA, refers to a DNA molecule that is separated from sequences with which it is immediately contiguous in the naturally occurring genome of the organism in which it originated. For example, an "isolated nucleic acid" may comprise a DNA molecule inserted into a vector, such as a plasmid or virus vector, or integrated into the genomic
DNA of a prokaryotic or eukaryotic cell or host organism.
[0016] When applied to RNA, the term "isolated nucleic acid" refers primarily to an
RNA molecule encoded by an isolated DNA molecule as defined above. Alternatively, the term may refer to an RNA molecule that has been sufficiently separated from other nucleic acids with which it would be associated in its natural state (i.e., in cells or tissues). An isolated nucleic acid (either DNA or RNA) may further represent a molecule produced directly by biological or synthetic means and separated from other components present.during its production.
[0017] The terms "percent similarity", “percent identity" and "percent homology" when referring to a particular sequence are used as set forth in the University of Wisconsin GCG software program.
[0018] A "polynucleotide," "polynucleotide molecule" or "polynucleotide sequence” refers to a chain of nucleotides. It may refer to a DNA or RNA molecule, either single or double stranded and, if single stranded, the molecule of its complementary sequence in either linear or circular form. Preferably, the chain has from about 50 to 10,000 nucleotides, more preferably from about 150 to 3,500 nucleotides. In some instances, the sequences will be fully complementary (no mismatches) when aligned. In other instances, there may be up to about a 30% mismatch in the sequences.
[0019] The term "oli gonucleotide," as used herein refers to sequences, primers and probes of the present invention, and is defined as a nucleic acid molecule comprised of two or more ribo or deoxyribonucleotides, preferably more than three. The exact size of the oligonucleotide will depend on various factors and on the particular application and use of the oligonucleotide.
[0020] A "fragment" refers to a nucleic acid sequence that is preferably at least about nucleic acids in length, more preferably about 40 nucleic acids, and most preferably about 100 nucleic acids in length and encompasses, for example, fragments consisting of nucleic acids 1-100, 300-400, 500-600, 800-900 of SEQ ID NOs:1-1558 or fragments of similar length at the 3' end of SEQ ID NOs:1-1558. A "fragment" can also mean a stretch of at least about 100 consecutive nucleotides that contains one or more deletions, insertions or substitutions. A "fragment" can also mean the whole coding sequence of a gene and may include 5' and 3' untranslated regions. A "fragment" can also refer to polypeptide sequences which are preferably at least about 5 to about 15 amino acids in length, most preferably at least about 10 amino acids
Jong, and which retain some biological activity or immunological activity of a sequence.
[0021] The term "gene" or "genes" refers to the partial or complete coding sequence of a gene. The term also refers to 5' or 3' untranslated regions of a transcript. The phrase "gene differentially expressed in osteoarthritis" refers to a gene whose amount of mRNA expressed from that gene or the amount of gene product translated from the mRNA is detectably different, i.e. either greater or lesser, in cells from subjects having osteoarthritis or in pre-osteoarthritic subjects compared to the amount of mRNA or translated gene product in cells from normal subjects which are neither osteoarthritic nor pre-osteoarthritic. As used herein, “pre- osteoarthritis” or “pre-osteoarthritic” is intended to mean that a subject is predisposed to developing osteoarthritis at a later date, but may not have any overt signs or symptoms of osteoarthritis. Preferably, the abundance of transcription or translation products of a differentially expressed gene derived from an osteoarthritic or pre-osteoarthritic sample differs by least about 1.15 fold, more preferably at least about 1.2 fold, more preferably at least about 1.3 fold, more preferably at least about 1.4 fold, more preferably at least about 1.5 fold, , more preferably at least about 1.6 fold, more preferably at least about 1.75 fold, more preferably at
Jeast about 2 fold, more preferably at least about 3 fold, more preferably at least about 10 fold, more preferably at least about 20 fold than that in a normal sample. The phrase "gene differentially expressed in osteoarthritis” also refers to genes that are not detectable in the normal transcript profile but are preferably at levels of at least about 2 copies per cell, more preferably at least about 3 copies per cell, in the osteoarthritic or pre-osteoarthritic tissue transcript profile.
[0022] The terms “osteoarthritis (OA)-related” and “osteoarthritis (OA)-associated genes” refer to genes that are differentially expressed in osteoarthritis as defined herein.
[0023] As used herein, the terms "reporter," "reporter system," "reporter gene," or "reporter gene product” refer to an operative genetic system in which a nucleic acid comprises a gene that encodes a product that when expressed produces a reporter signal that is a readily measurable, e.g., by biological assay, immunoassay, radioimmunoassay, or by colorimetric, fluorogenic, chemiluminescent or other methods. The nucleic acid may be either RNA or DNA, linear or circular, single or double stranded, antisense or sense polarity, and is operatively linked to the necessary control elements for the expression of the reporter gene product. The required control elements will vary according to the nature of the reporter system and whether the reporter gene is in the form of DNA or RNA, but may include, but not be limited to, such elements as promoters, enhancers, translational control sequences, poly A addition signals, transcriptional termination signals and the like.
[0024] The terms "transform," "transfect," "transduce," refer to any method or means by which a nucleic acid is introduced into a cell or host organism and may be used interchangeably to convey the same meaning. Such methods include, but are not limited to, transfection, electroporation, microinjection, PEG-fusion and the like.
[0025] The term "functional” as used herein implies that the nucleic or amino acid sequence is functional for the recited assay or purpose.
[0026] The phrase "consisting essentially of" when referring to a particular nucleotide or amino acid means a sequence having the properties of a given SEQ ID NO. For example, when used in reference to an amino acid sequence, the phrase includes the sequence per se and molecular modifications that would not affect the basic and novel characteristics of the sequence.
[0027] A "vector" is a replicon, such as a plasmid, cosmid, bacmid, phage, artificial chromosome (BAC, YAC) or virus, into which another genetic sequence or element (either DNA or RNA) may be inserted so as to bring about the replication of the attached sequence or element.
A "replicon" is any genetic element, for example, a plasmid, cosmid, bacmid, phage, artificial chromosome (BAC, YAC) or virus, that is capable of replication largely under its own control. A replicon may be either RNA or DNA and may be single or double stranded.
[0028] The term "probe" as used herein refers to either a probe for a nucleic acid or a probe for a protein. When used in connection with nucleic acids, a “probe” refers to an oligonucleotide, polynucleotide or nucleic acid, either RNA or DNA, whether occurring naturally as in a purified restriction enzyme digest or produced synthetically, which is capable of annealing with or specifically hybridizing to a nucleic acid with sequences complementary to the probe. A probe may be either single stranded or double stranded. The exact length of the probe
B will depend upon many factors, including temperature, source of probe and method of use. For example, for diagnostic applications, depending on the complexity of the target sequence, an oligonucleotide probe typically contains about 10-100, preferably about 15-50, more preferably about 15-25 nucleotides. In certain diagnostic applications, a polynucleotide probe preferably contains about 90-1150 nucleotides, more preferably about 300-600 nucleotides, more preferably about 300 nucleotides. The probes herein are selected to be "substantially" complementary to different strands of a particular target nucleic acid sequence. This means that the probes must be sufficiently complementary so as to be able to "specifically hybridize" or anneal with their respective target strands under a set of pre-determined conditions. Therefore, the probe sequence need not reflect the exact complementary sequence of the target. For example, a non complementary nucleotide fragment may be attached to the 5' or 3' end of the probe, with the remainder of the probe sequence being complementary to the target strand. Alternatively, non complementary bases or longer sequences can be interspersed into the probe, provided that the probe sequence has sufficient complementarity with the sequence of the target nucleic acid to anneal therewith specifically. When used in connection with a protein, a “probe” is a protein binding substance capable of specifically binding a particular protein or protein fragment to the substantial exclusion of other proteins or protein fragments. Such binding substances may be any molecule to which the protein or peptide specifically binds, including DNA (for DNA binding proteins), antibodies (as described in greater detail herein), cell membrane receptors, peptides, cofactors, lectins, sugars, polysaccharides, cells, cell membranes, organelles and organellar membranes.
[0029] "Array" refers to an ordered arrangement of at least two probes on a substrate.
At least one of the probes represents a control or standard, and the other, a probe of diagnostic interest. The arrangement of from about two to about 40,000 probes on a substrate assures that the size and signal intensity of each labeled complex formed between a probe and a sample nucleic acid or protein binding substance is individually distinguishable.
[0030] A "hybridization complex" is formed between nucleic acid molecules of a sample when the purines of one molecule hydrogen bond with the pyrimidines of the complementary molecule, e.g, 5'.A-G-T-C-3' base pairs with 3'-T-C-A-G-5'. The degree of complementarity and the use of nucleotide analogs affect the efficiency and stringency of hybridization reactions.
[0031] The term "specifically hybridize" refers to the association between two single stranded nucleic acid molecules of sufficiently complementary sequence to permit such hybridization under pre determined conditions generally used in the art (sometimes termed
BN "substantially complementary"). For example, the term may refer to hybridization of a nucleic acid probe with a substantially complementary sequence contained within a single stranded DNA or RNA molecule according to an aspect of the invention, to the substantial exclusion of hybridization of the nucleic acid probe with single stranded nucleic acids of noncomplementary sequence.
[0032] "Sample" is used in its broadest sense as containing nucleic acids, proteins, antibodies, and the like. A sample may comprise, for example, a bodily fluid; the soluble fraction of a cell preparation, or an aliquot of media in which cells were grown; a chromosome, an organelle, or membrane isolated or extracted from a cell; genomic DNA, RNA, or cDNA in solution or bound to a substrate; a cell; a tissue or a tissue biopsy; a tissue print; a fingerprint, buccal cells, skin, or hair; and the like.
[0033] A “standard” refers to a control sample that comprises material from a source in a normal (as opposed to OA-related) biological state. An OA-related biological state may include, for example, one in which the source has OA, is predisposed to develop OA, or exhibits certain biological characteristics of OA. For example, a standard sample may comprise nucleic acids or proteins from a normal subject that is not osteoarthritic or pre-osteoarthritic. Standard samples may also include samples from normal cells or tissue that have not been treated to elicit an immune response that may model certain aspects of OA.
[0034] "Specific binding" refers to a special and precise interaction between two molecules which is dependent upon their structure, particularly their molecular side groups. For example, the intercalation of a regulatory protein into the major groove of a DNA molecule, the hydrogen bonding along the backbone between two single stranded nucleic acids, or the binding between an epitope of a protein and an agonist, antagonist, or antibody.
[0035] The term "primer" as used herein refers to a nucleic acid molecule, either RNA or DNA, either single stranded or double stranded, either derived from a biological system, generated by restriction enzyme digestion, or produced synthetically which, when placed in the proper environment, is able to functionally act as an initiator of template-dependent nucleic acid synthesis. When presented with an appropriate nucleic acid template, suitable nucleoside tripnosphate precursors of nucleic acids, a polymerase enzyme, suitable cofactors and conditions such as appropriate temperature and pH, the primer may be extended at its 3' terminus by the addition of nucleotides by the action of a polymerase or similar activity to yield an primer extension product. The primer may vary in length depending on the particular conditions and requirement of the application. For example, in diagnostic applications according to particular embodiments of the invention, a primer may be an oligonucleotide primer, preferably about 15 - ) 25 or more nucleotides in length. The primer must be of sufficient complementarity to the desired template to prime the synthesis of the desired extension product, that is, to be able anneal with the desired template strand in a manner sufficient to provide the 3' hydroxyl moiety of the primer in appropriate juxtaposition for use in the initiation of synthesis by a polymerase or similar enzyme. It is not required that the primer sequence represent an exact complement of the desired template. For example, a non complementary nucleotide sequence may be attached to the 5' end of an otherwise complementary primer. Alternatively, non complementary bases may be interspersed within the oligonucleotide primer sequence, provided that the primer sequence has sufficient complementarity with the sequence of the desired template strand to functionally provide a template primer complex for the synthesis of the extension product.
[0036] Amino acid residues described herein are preferred to be in the "L" isomeric form. However, residues in the "D" isomeric form may be substituted for any L amino acid residue, provided the desired properties of the polypeptide are retained. All amino acid residue sequences represented herein conform to the conventional left-to-right amino terminus to carboxy terminus orientation.
[0037] A “fragment” or "portion" of a polypeptide means a stretch of amino acid residues of at least about five to seven contiguous amino acids, often at least about seven to nine contiguous amino acids, typically at least about nine to thirteen contiguous amino acids and, most preferably, at least about twenty to thirty or more contiguous amino acids. Fragments of the polypeptide sequence, antigenic determinants, or epitopes are useful for eliciting immune responses to a portion of the protein amino acid sequence.
[0038] Different "variants" of the differentially expressed polypeptides exist in nature.
These variants may be alleles characterized by differences in the nucleotide sequences of the gene coding for the protein, or may involve different RNA processing or post translational modifications. The skilled person can produce variants having single or multiple amino acid substitutions, deletions, additions or replacements. These variants may include, inter alia: (a) variants in which one or more amino acids residues are substituted with conservative or non conservative amino acids, (b) variants in which one or more amino acids are added to the polypeptide, (c) variants in which one or more amino acids include a substituent group, and (d) variants in which the polypeptide is fused with another peptide or polypeptide such as a fusion partner, a protein tag or other chemical moiety, that may confer useful properties to the polypeptide, such as, for example, an epitope for an antibody, 2 polyhistidine sequence, a biotin moiety and the like. Other polypeptides of the invention may include variants in which amino acid residues from one species are substituted for the corresponding residue in another species, either at the conserved or non conserved positions. In another embodiment, amino acid residues at non conserved positions are substituted with conservative or non conservative residues. The techniques for obtaining these variants, including genetic (suppressions, deletions, mutations, etc.), chemical, and enzymatic techniques are known to the person having ordinary skill in the art. To the extent such allelic variations, analogues, fragments, derivatives, mutants, and modifications, including alternative nucleic acid processing forms and alternative post translational modification forms result in derivatives of the differentially expressed polypeptide that retain any of the biological properties of the differentially expressed polypeptide, they are included within the scope of this invention.
[0039] The term "isolated protein” or "isolated and purified protein” refers primarily to a protein produced by expression of an isolated nucleic acid molecule according to an aspect the invention. Alternatively, this term may refer to a protein that has been sufficiently separated from other proteins with which it would naturally be associated, so as to exist in "substantially pure" form. "Isolated" is not meant to exclude artificial or synthetic mixtures with other compounds or materials, or the presence of impurities that do not interfere with the fundamental activity, and that may be present, for example, due to incomplete purification, addition of stabilizers, or compounding into, for example, immunogenic preparations or pharmaceutically acceptable preparations.
[0040] The term "substantially pure" refers to a preparation comprising at least about 50-60% by weight of a given material (e.g., nucleic acid, protein, etc.). More preferably, the preparation comprises at least about 75% by weight, and most preferably about 90-95% by weight of the given compound. Purity is measured by methods appropriate for the given material (e.g. chromatographic methods, agarose or polyacrylamide gel electrophoresis, HPLC analysis, and the like).
[0041] The term "tag," "tag sequence” or "protein tag" refers to a chemical moiety, either a nucleotide, oligonucleotide, polynucleotide or an amino acid, peptide or protein or other chemical, that when added to another sequence, provides additional utility or confers useful properties, particularly in the detection or isolation, of that sequence. Thus, for example, a homopolymer nucleic acid sequence or a nucleic acid sequence complementary to a capture oligonucleotide may be added to a primer or probe sequence 0 facilitate the subsequent isolation of an extension product or hybridized product. In the case of protein tags, histidine residues (e.g., 4 to 8 consecutive histidine residues) may be added to either the amino or carboxy terminus of a protein to facilitate protein isolation by chelating metal chromatography.
Alternatively, amino acid sequences, peptides, proteins or fusion partners representing epitopes or binding determinants reactive with specific antibody molecules or other molecules (e.g., flag epitope, ¢ myc epitope, transmembrane epitope of the influenza A virus hemagglutinin protein, _ protein A, cellulose binding domain, calmodulin binding protein, maltose binding protein, chitin binding domain, glutathione S transferase, and the like) may be added to proteins to facilitate protein isolation by procedures such as affinity or immunoaffinity chromatography. Chemical tag moieties include such molecules as biotin, which may be added to either nucleic acids or proteins and facilitates isolation or detection by interaction with avidin reagents, and the like.
Numerous other tag moieties are known to, and can be envisioned by, the trained artisan, and are contemplated to be within the scope of this definition.
[0042] An "antibody" or "antibody molecule" is any immunoglobulin, including antibodies and fragments thereof, that binds to a specific antigen. The term includes polyclonal, monoclonal, chimeric, and bispecific antibodies. As used herein, antibody or antibody molecule contemplates both an intact immunoglobulin molecule and an immunologically active portion of an immunoglobulin molecule such as those portions known in the art as Fab, Fab', F(ab')2 and
F(v). :
[0043] As used herein, the term “subject” or “patient” refers to both humans and animals, unless specified that the “subject” or “patient” is an animal or a human. Animal subjects are preferably vertebrates, and more preferably, mammals.
[0044] “Therapeutic modality” refers to any means of treating and/or preventing a disease, condition or disorder.
[0045] In one aspect of the present invention, a number of genes have been identified that are differentially expressed in osteoarthritic subjects as compared to non-osteoarthritic subjects. These genes and gene fragments, as well as their encoded proteins and fragments, may be used, for example, in a variety of diagnostic and prognostic assays, as well as assays useful in screening test substances for effectiveness in treatment modalities for osteoarthritis.
[0046] In certain embodiments of the invention, expression of at least one differentially expressed gene may be measured. In preferred embodiments, expression of two or more differentially expressed genes may be measured, providing a gene expression pattern or gene expression profile. More preferably, measurement of a multiplicity of differentially expressed genes may be performed, providing additional information for a gene expression pattern or profile.
[0047] In various embodiments of the present invention, changes in gene expression may be measured in one or both of two ways: (1) measuring transcription through detection of mRNA produced by a particular gene; and (2) measuring translation through detection of protein i produced by a particular transcript.
[0048] Decreased or increased expression can be measured at the RNA level using any of the methods well known in the art for the quantitation of polynucleotides, such as, for example, PCR (including, without limitation, RT-PCR and gPCR), RNase protection, Northern blotting and other hybridization methods. The genes that are assayed or interrogated according to the present invention are typically in the form of mRNA or reverse transcribed mRNA. The genes may be cloned and/or amplified. The cloning itself does not appear to bias the representation of genes within a population. However, it may be preferable to use polyA+ RNA as a source, as it can be used with fewer processing steps.
[0049] Tn accordance with aspects of the present invention, 1558 genes have been identified whose functions are closely associated with osteoarthritis (OA). The association is determined by comparing expression of the genes in normal tissue and tissue from subjects oo diagnosed with OA. The genes so identified fall into two broad categories. The first category comprises known genes, many of whose association with OA had heretofore been unappreciated.
These genes are listed in Table 6, along with their corresponding gene ID numbers and SEQ ID
NOs.
[0050] According to another aspect of the invention, a second category comprises nucleic acid segments that do not demonstrate homology to previously identified sequences.
Thus, this category is believed to include one or more novel genes. One preferred embodiment of the invention relates to an isolated nucleic acid molecule comprising a novel OA-associated gene, mRNA or cDNA produced from the OA-associated gene.
[0051] One aspect of the present invention relates to a combination of 1558 polynucleotide molecules that are differentially expressed in an osteoarthritic subject or in a pre- osteoarthritic subject compared to expression in subjects which are not osteoarthritic or pre- osteoarthritic. In one embodiment of the invention described herein, segments of 1558 OA- related genes from canine cartilage were obtained by employing differential display. The nucleotide sequences of these polynucleotides are set forth herein asSEQ ID NOs:1-1558 (Table 1 shows the correlation between SEQ ID NO. and Gene ID Number). BLAST analysis of these sequences identified homologies with of a number of nucleic acid sequences previously identified (Table 2) These include a number of previously identified nucleic acid sequences with no identified homologies to known genes. BLAST analysis also identified sequences showing homology to previously-identified genes; information including names of genes as well as database accession numbers for respective homologs of these is provided in Tables 2A and 2B.
Table 2A
Gene ID Transcript ID No. Loc.
FE ES IS— i 1002b
I-50 EE I E— I 1002b
CaMax: | ENSG00000138709 | ENST00000264584 4 q28.2
Coll
ENST00000326639
CaMax. | ENSG00000152518 | ENST00000282388 | BUTYRATE RESPONSE 2 p21 1006b FACTOR 2 (TIS11D
PROTEIN) (EGF-RESPONSE
FACTOR 2) (ERF-2). [Source:SWISSPROT;Acc:P47 974]
CaMax: | ENSG00000152518 | ENST00000282388 | BUTYRATE RESPONSE 2 p21 1007a FACTOR 2 (TIS11D
PROTEIN) (EGF-RESPONSE
FACTOR 2) (ERE-2). [Source:SWISSPROT ;Acc:P47 974] er 1008a
FE A I
1008a
CaMax: | ENSG00000122912 | ENST00000265870 | GRAVE'S DISEASE 10 q21.3 1009¢ CARRIER PROTEIN (GDC) : (GRAVE'S DISEASE
AUTOANTIGEN) (GDA) (MITOCHONDRIAL SOLUTE
CARRIER PROTEIN
HOMOLOG). [Source:SWISSPROT;Acc:P16 260
Sl 1011a
ST fl I oe | 1 1016b
CaMax: | ENSG00000160961 | ENST00000292530 | ZINC FINGER PROTEIN 333. | 19 pl3.12 1019a [Source:SWISSPROT;Acc:Q96
JL9) 1020a RELATED PEPTIDE TYPE 1
RECEPTOR PRECURSOR
(CGRP TYPE 1 RECEPT OR).
Eel 602]
I I EN a 1026b ©} 1026b
El I I I 1028¢c
FI I I
1028¢
CaMax: | ENSG00000171567 | ENST00000304782 TIGGER TRANSPOSABLE 2 q37.1 1029a ELEMENT DERIVED 1;
JERKY (MOUSE)
HOMOLOG-LIKE. [Source:RefSeq;Acc:NM_1457 02] fl EE PE ER I 103a
CaMax: | ENSG00000041880 | ENST00000045065 | POLY [ADP-RIBOSE] 3 p21.2 1044c "| POLYMERASE-3 (EC 2.4.2.30) (PARP-3) (NAD+)
ADP-
RIBOSYLTRANSFERASE-3) ‘ (POLY[ADP-RIBOSE]
SYNTHETASE-3) (PADPRT- 3) (HPARP-3) (IRT1). [Source: SWISSPROT; Acc:Q9
Y6F1]
CaMax: | ENSG00000169045 | ENST00000326748 | HETEROGENEOUS 5 q35.3 104a ENST00000329433 | NUCLEAR
RIBONUCLEOPROTEIN H
(HNRNP H). [Source:SWISSPROT;Acc:P31 043] fi —
Lo ——
I I
CaMax: | ENSG00000138336 | ENST00000260906 | LEUKEMIA-ASSOCIATED q21.3 : 1061a PROTEIN WITH A CXXC
DOMAIN. [Source:SPTREMBL;Acc:Q8N
FU7] '
CaMax:
EA
CaMax: | ENSG00000167996 | ENST00000301775 | FERRITIN HEAVY CHAIN 11 ql2.3 106a (FERRITIN H SUBUNIT). (Source:SWISSPROT;Acc:P02 794]
FH
Fa
FE eae |]
TC A NS ES — RS i ES BE I 108a
I EE A RN
1090d
I EN ES EE A
1094b 17-2 EE ER Ri 1094b
CaMax: | ENSMUSG0000003 | ENSMUST0000003 7 B2 — 1095a 0693 2941
ENSMUST0000001 4058
CaMax: | ENSMUSG0000003 | ENSMUST0000003 7 B2 1096a 0693 2941
ENSMUST0000001 4058 fl al: I LA il 1098a ENST00000257883
Fld I A 109a ENST00000306802
CaMax: | ENSG00000119396 | ENST00000238339 | RAS-RELATED PROTEIN q33.2 1105a RAB-14. [Source:SWISSPROT;Acc:P35 287]
Fl stil ill NA GR Gi 1106a
CaMax: | ENSG00000133121 | ENST00000255486 | STAR-RELATED LIPID 13 ql3.1 1108a TRANSFER PROTEIN 13 (STARDI13) (START
DOMAIN- CONTAINING
PROTEIN 13) (46H23.2). [Source:SWISSPROT;Acc:Q9
Y3MS8] i I EN EN 1110b
I A EE
1110b
CaMax: | ENSG00000080546 | ENST00000302071 | SESTRIN 1 (P53- q21 1111b ENST00000237504 | REGULATED PROTEIN
PA26). [Source:SWISSPROT;Acc:Q9
Y6P5]
Fd iil WO 1112a fl I
CaMax. | ENSGO00000113384 | ENST00000265070 | GOLGI PHOSPHOPROTEIN | 5 pl13.3 1120a 3; GOLGI PROTEIN; GOLGI
PERIPHERAL MEMBRANE
PROTEIN 1, 34 KDA; GOLGI- .
ASSOCIATED PROTEIN;
COAT-PROTEIN. {Source:RefSeq;Acc:NM_0221 30] i pe 1121a fl —
Eni
CaMax: | ENSGO0000081189 ENST00000325423 | MYOCYTE-SPECIFIC 5 ql4.3 : ENHANCER FACTOR 2C. [Source: SWISSPROT; Acc:Q06 413]
CaMax: | ENSG00000128573 ENST00000324462 | FORKHEAD BOX PROTEIN | 7 g3l.l 1135a | BENST00000265436 | P2 (CAG REPEAT PROTEIN
ENST00000324544 | 44) (TRINUCLEOTIDE
REPEAT- CONTAINING
GENE 10 PROTEIN). [Source:SWISSPROT;Acc:015 4091
FE I A
1137b
FE I I I
1138a ee 1139a
CaMax: | ENSG00000106817 | ENST00000311316 | COLLAGEN ALPHA XV) q22.33 1145a CHAIN PRECURSOR. 059]
FE I i A 1145a =i EE 1146a
I EO I I
1159b
CaMax: | ENSG00000169045 | ENST00000326748 | HETEROGENEOUS 5 q35.3 104a ENST00000329433 | NUCLEAR
RIBONUCLEOPROTEIN H
(HNRNP H). ’ [Source:SWISSPROT;Acc:P31 943]
CaMax: | ENSG00000140416 | ENST00000267996 | TROPOMYOSIN 1 ALPHA 15 q22.2 116%9b ' ENSTO00000334895 | CHAIN (ALPHA-
ENST00000288398 | TROPOMYOSIN).
ENST00000317516 | [Source:SWISSPROT;Acc:P09 493] '
CaMax: | ENSG00000100839 | ENST00000262237 | DYNEIN HEAVY CHAIN, 14 q32.32 1177c CYTOSOLIC (DYHC) (CYTOPLASMIC DYNEIN
HEAVY CHAIN 1) (DHC1) ( (FRAGMENT). [Source:SWISSPROT;Acc:Ql4 204]
CaMax: | ENSG00000156299 | ENST00000286827 | T-LYMPHOMA INVASION 21 q22.11 1184a AND METASTASIS
INDUCING PROTEIN 1 (TIAM1 PROTEIN). [Source:SWISSPROT;Acc:Q13 009]
EE
1184a
CaMax: | ENSMUSG0000003 | ENSMUST(0000004 17 C 1190b 8954 3985
ENSMUST0000005 0630
CaMax: | ENSMUSGO0000003 | ENSMUST0000004 17 Cc
LE
ENSMUSTO0000005 0630 me 1 [ 11b or) 120a
I< EE 120a
Se 1212b
CaMax. | ENSG00000134215 | ENST00000280840 1213d [Source: SWISSPROT; Acc:Q9
UKW4]
FE I EA
1217a
Sa 1220b 1-21 EN A I Bo 1226d 1-3 I EN 1226d gh 123¢c aE I EN I 123¢ 12432 ENSTO00000309112 | [Source:SWISSPROT;Acc:Q9
UNX4]
FE I Wo 1245b
Fl id I A i 1246a 1 1248b
Fl nd IS A i 1253a
FE EE I
1257b }
El 1257b iE EE 1260c
Flt ad I A 1263b | 5004 1907
CaMax. | ENSG00000175198 | ENST00000310787 | PROPIONYL-COA 13 932.3 1267a CARBOXYLASE ALPHA
CHAIN, MITOCHONDRIAL
PRECURSOR (EC 6.4.1.3) (PCCASE ALPHA SUBUNIT) (PROPANOYL-
COA:CARBON DIOXIDE
LIGASE ALPHA SUBUNIT). [Source:SWISSPROT;Acc:POS 165]
CaMax. | ENSGO0000175198 | ENST00000310787 | PROPIONYL-COA 13 9323 1267a CARBOXYLASE ALPHA
CHAIN, MITOCHONDRIAL : ; PRECURSOR (EC 6.4.1.3) (PCCASE ALPHA SUBUNIT) (PROPANOYL-
COA:CARBON DIOXIDE
LIGASE ALPHA SUBUNIT). : [Source:SWISSPROT;Acc:P05 _23-
— 1 1 Tel
Fr al il IN 0 Gil 1270a
CaMax. | ENSGO0000113615 | ENST00000265341 | PROTEIN TRANSPORT 5 q31.1 1272a ENST00000322887 | PROTEIN SEC24A (SEC24-
RELATED PROTEIN A) (FRAGMENT). (Source:SWISSPROT;Acc:095 486]
J: I I A A ] 1273b _
I I I I I
1276a oer 127b 1 EE I I WN 127b
I EE IN I SO A
1282b
I I I i 1284b
CaMax: | ENSG00000164190 | ENST00000296607 | IDN3 PROTEIN ISOFORM A. } 5 pl3.2 1287¢ ENST00000282516 | [Source:RefSeq;Acc:NM_1334 33]
CaMax: | ENSG00000164190 | ENST00000296607 | IDN3 PROTEIN ISOFORM A. | 5 pl3.2
Ed) = al 33]
CaMax: | ENSMUSGO0000002 | ENSMUST0000002 | HEAT SHOCK PROTEIN HSP | 17 Cc 128a 3944 4739 90-BETA (HSP 84) (TUMOR
SPECIFIC
TRANSPLANTATION 84
KDA ANTIGEN) (TSTA). [Source:SWISSPROT;Acc:P11 499]
CaMax: | ENSG00000079246 | ENST00000328063 | ATP-DEPENDENT DNA 2 q35 1292¢ HELICASE II, 80 KDA
SUBUNIT (LUPUS KU 1 AUTOANTIGEN PROTEIN
P86) (KU86) (KU80) (86 KDA
SUBUNIT OF KU ANTIGEN) (THYROID- LUPUS
AUTOANTIGEN) (TLAA) (CTC BOX BINDING
FACTOR 85 KDA SUBUNIT) ' (CTCBF) (CTC85) (NUCLEAR FACTOR IV) (DNA-REPAIR PROTEIN
XRCCS). [Source:SWISSPROT;Acc:P13 ‘ 010]
CaMax: | ENSG00000136628 | ENST00000259146 | BIFUNCTIONAL 1 q4l 1294b ENSTG0000335149 | AMINOACYL-TRNA
SYNTHETASE [INCLUDES:
GLUTAMYL-TRNA
SYNTHETASE (EC 6.1.1.17) (GLUTAMATE--TRNA
LIGASE); PROLYL-TRNA
SYNTHETASE (EC 6.1.1.15) (PROLINE--TRNA LIGASE)]. [Source:SWISSPROT;Acc:P0O7 8141
CaMax: | ENSG00000163625 ENST00000295888 | WD REPEAT AND FYVE 4 q21.23 1299¢ ENST00000322366 | DOMAIN CONTAINING 3
ISOFORM 1. {Source:RefSeq;Acc:NM_0149 91] ol EN EN ESS SN 129b fl EE EN I 129b eT = 12a 1301a 9076 8033
CaMax: | ENSG00000168952 | ENST00000323944 | AMISYN; SYNTAXIN 14 ql2 1304a BINDING PROTEIN 6. 78]
El 1308c
El I EE 1308¢
Fal EE EB 130b
ES EE
1316b
EE I
1318a
EI I I
1320
CaMax: | ENSRNOG0000000 UDP-N- 21 q31 1322¢ 3359 ACETYLGLUCOSAMINE--
PEPTIDE N-
ACETYLGLUCOSAMINYLT
RANSFERASE 110 KDA
SUBUNIT (EC 2.4.1.-) (O-
GLCNAC TRANSFERASE
P110 SUBUNIT). [Source:SWISSPROT;Acc:P56 : 558)
EA
1323br
EA
1323br
Ll 1324a
EA EE
1324a oa]
ESI
CaMax: | ENSG00000166923 | ENST00000300177 | CYSTEINE KNOT 15 ql3.3 1341a ENST00000322805 | SUPERFAMILY 1, BMP
ANTAGONIST 1; GREMLIN. [Source:RefSeq;Acc:NM_0133 72] fl I 1354a ELEMENT DERIVED 1;
JERKY (MOUSE)
HOMOLOG-LIKE.
EEE] 02]
FE BR I I
1355a
I I EN EA
1355a
CaMax: | ENSG00000033170 | ENST00000315759 ALPHA-(1,6)- 14 q23.3 1361a ENSTO00000261677 FUCOSYLTRANSFERASE (EC 2.4.1.68) _ (GLYCOPROTEIN 6-ALPHA-
L-
FUCOSYLTRANSFERASE) (GDP-FUCOSE--
GLYCOPROTEIN ‘
FUCOSYLTRANSFERASE) (GDP-L-FUC:N-ACETYL-
BETA-D-GLUCOSAMINIDE
ALPHALG-
FUCOSYLTRANSFERASE) (ALPHAI1-6FUCT) (FUCOSYLTRANSFERASE 8). i Source: SWISSPROT; Acc:Q9
BYC5] mer 1364d
El EE 1364d
CaMax: | ENSG00000064205 | ENST00000190983 | CONNECTIVE TISSUE 20 ql3.12 1366a GROWTH FACTOR-LIKE
PROTEIN PRECURSOR
(CTGF-L) (WNT1
INDUCIBLE SIGNALING
PATHWAY PROTEIN 2) (WISP-2) (CONNECTIVE
TISSUE GROWTH FACTOR-
RELATED PROTEIN 58). [Source:SWISSPROT;Acc:076 076] oe pe | [0 1368a 0871 3159
CaMax: | ENSG00000119326 | ENST00000325551 | CATENIN (CADHERIN- g31.3 1371a ENST00000325580 | ASSOCIATED PROTEIN), . | ALPHA-LIKE 1; ALPHA-
CATULIN.
Of [Source:RefSeq;Acc:NM_0037 98]
CaMax: | ENSG00000083771 | ENST00000218546 | M-PHASE 13 ql2.11 137b } PHOSPHOPROTEIN 8 (FRAGMENT). [Source:SWISSPROT;Acc:Q99 549] {7 I I A 1381a
EE
1381a
CaMax: ENSGO00000067208 | ENST00000263785 | ECOTROPIC VIRAL 1 p22.1 1383a INTEGRATION SITE 5;
NEUROBLASTOMA STAGE
4S GENE.
I EE il I
CaMax: | ENSG00000099194 | ENST00000266053 | ACYL-COA DESATURASE | 10 q24.31 13842 (EC 1.14.19.1) (STEAROYL-
COA DESATURASE) (FATTY ACID
DESATURASE) (DELTA(9)-
DESATURASE). [Source:SWISSPROT;Acc:000 7671
Ei I EE EE 1391a fl EE EO I I 1394b
CaMax: | ENSG00000111912 | ENST00000229634 | NUCLEAR RECEPTOR q22.32 1397b ENST00000318575 | COACTIVATOR 7;
ESTROGEN RECEPTOR
ASSOCIATED PROTEIN 140
KDA. [Source:RefSeq;Acc:NM_1817 82]
EN ES a 1399a
EN EN IS FR
13a
Fal EE 1400a
CaMax: | ENSG00000109756 | ENST00000264431 | PDZ DOMAIN CONTAINING | 4 g32.1 1401c GUANINE NUCLEOTIDE
EXCHANGE FACTOR (GEF) 1; RA(RAS/RAPIA-
ASSOCIATING)-GEF; PDZ
DOMAIN CONTAINING
GUANINE NUCLEOTIDE
EXCHANGE
FACTOR(GEF)1;
RARAS/RAPLA-
ASSOCIATING)-GEF; PDZ
DOMAIN CONTAINING
GUANINE NUCLEOTIDE
EXCHANGE
FACTOR(GEF)1. {Source:RefSeq;Acc:NM_0142 47)
Il
Fl 1406a
CaMax: | ENSG00000166170 | ENST00000299204 | BAG-FAMILY MOLECULAR | 14 q32.32 1409b CHAPERONE REGULATOR- 5 (BAG-5). [Source:SWISSPROT;Acc:Q9 . UL15]
CaMax: | ENSGO0000058272 | ENST00000261207 | PROTEIN PHOSPHATASE 1, | 12 q21.2 1411a ENST00000312727 | REGULATORY (INHIBITOR)
SUBUNIT 12A; MYOSIN
PHOSPHATASE, TARGET
SUBUNIT 1. [Source:RefSeq;Acc:NM_0024 801 : CaMax. | ENSMUSG0000003 | ENSMUST0000005 | [4 C7
1415b 4794 4209
Er I 6558 {7-3 EE I EN SN 1416a 0 A I EO RI 1419a de 141c fl EN I IN FN 141c i A I 142.1c
El I EE EE 142.1c
CaMax: | ENSG00000128845 | ENST00000267809 | CELL CYCLE 15 q21.3 [Source:RefSeq;Acc:NM_0207 39]
CaMax: | ENSG00000172175 | ENST00000313958 | MUCOSA ASSOCIATED 18 q21.31 1421a ENST00000303708 | LYMPHOID TISSUE
LYMPHOMA
TRANSLOCATION PROTEIN : 1 (EC 3.4.22.-) (MALT-
LYMPHOMA ASSOCIATED
TRANSLOCATION) (PARACASPASE). [Source:SWISSPROT;Acc:Q9
UDYE]
I EE I a 1423b
CaMax: | ENSG00000152583 | ENST00000282470 | SPARC-LIKE PROTEIN 1 4 q22.1 : 143.2¢ PRECURSOR (HIGH ‘ ENDOTHELIAL VENULE
PROTEIN) (HEVIN) (MAST 9). ' [Source: SWISSPROT; Acc:Ql4 515]
CaMax: | ENSG00000152583 | ENST00000282470 | SPARC-LIKE PROTEIN 1 4 q22.1 143.2¢c PRECURSOR (HIGH
ENDOTHELIAL VENULE :
PROTEIN) (HEVIN) (MAST 9). [Source:SWISSPROT;Acc:Q14 515]
FE I A BH
1431a 7 EE A NS 144.2a
FI IE
144.2a
CaMax: | ENSG00000154430 | ENST00000284618 | TESTICAN-3 PRECURSOR. 4 qQ32.3 al —
BQI16]
CaMax: | ENSG00000170631 | ENST00000276816 | ZINC FINGER PROTEIN q24.3 1449a ENST00000317284 | CLONE 647.
ENST00000332620 [Source:SWISSPROT;Acc:P15
ENST00000317099 | 622] :
ENST00000333589
ENST00000276823
ENST00000332158 _28.-
mmm TTT
ENSTO00000331465
CaMax. | ENSGO0000170891 | ENST00000307746 | CYTOKINE-LIKE PROTEIN | 4 pl6.2 1450a C17 PRECURSOR. [Source:SWISSPROT;Acc:Q9
NRR1] rl I I I Ni 1452a a I EE EE 1457b
CaMax: | ENSG00000113387 | ENST00000265073 | ACTIVATED RNA 5 pl3.3 1459¢ POLYMERASE II
TRANSCRIPTIONAL
COACTIVATOR P15 (PC4) (P14). [Source:SWISSPROT;Acc:P53 999] 17:2 EE EE RN 1459¢
CaMax: | ENSG00000147403 | ENST00000276371 | 60S RIBOSOMAL PROTEIN 24 q28 145b 1.10 (QM PROTEIN) (TUMOR
SUPPRESSOR QM) (LAMININ RECEPTOR
HOMOLOG). [Source:SWISSPROT;Acc:P27 635]
FE EE
1460a
I I I
1460a {5 I I SE 1461a fl I A I 1461a
FE f= I
CaMax: | ENSMUSG0000004 | ENSMUST0000006 | UPREGULATED DURING 20 A2 1469a 6599 0592 SKELETAL MUSCLE
GROWTH 5. [Source:RefSeq;Acc:NM_0232 11] dil I LAN Ca 146b
CaMax: | ENSMUSGO0000004 | ENSMUST0000006 | UPREGULATED DURING 20 A2 1469a 6599 0592 SKELETAL MUSCLE
GROWTH 5. [Source:RefSeq;Acc:NM_0232 11]
CaMax:
FE a 1476a INHIBITOR ID-4. [Source:SWISSPROT; Acc:P47 928] 1477a INDUCIBLE ANTI-
PROLIFERATIVE PROTEIN msvsnosern [Source:SWISSPROT ;Acc:P78
Cal I I I BN 147b
CaMax: | ENSG00000105997 ENST00000317201 | HOMEOBOX PROTEIN 7 p52 [Source:SWISSPROT;Acc:043 365]
FE lcd A GE 14822 13 I EE A Rn 1484b
CaMax: | ENSG00000122566 | ENST00000265398 HETEROGENEOUS 7 pl5.2 1488b ENST00000312091 | NUCLEAR
RIBONUCLEOPROTEINS
A2/B1 (HNRNP A2 / HNRNP
BI). {Source:SWISSPROT;Acc:P22 626] fu EE I SR 148a
Ex EE 1497¢
Ea 1497¢
IF EE — — 1500b
EF
1504d
FA
1506d
IE —
CaMax: | ENSG00000106853 | ENST00000333580 | NADP-DEPENDENT q31.3 150a ENST00000309195. | LEUKOTRIENE B4 12-
HYDROXYDEHYDROGENA
SE (EC 1.1.1.5). ‘ [Source: SWISSPROT; Acc:Q14 914] :
Er ed ll IR GR 1516a a — =~
To
CaMax: | ENSG00000165421 | ENST00000333218 | PROTEIN PHOSPHATASE 11 ql34 1521b ENST00000327431 | METHYLESTERASE-1.
ENST00000328257 | [Source:RefSeq;Acc:NM_0161 47] on |] fa I or 1
I I DE NE
1532a
I A IN
1532a 1534b ENST00000322687
ENST00000256013 1:75 A A IN RN 1534b
Eo EE RE EE NA — 1535a _
Fl I I I a 1541a
CaMax: [| ENSG00000151012 ENST00000280612 CYSTINE/GLUTAMATE 4 q28.3 1546b TRANSPORTER (AMINO
ACID TRANSPORT SYSTEM
XC-) (XCT) (CALCIUM
CHANNEL BLOCKER
RESISTANCE PROTEIN
CCBR1). [Source:SWISSPROT;Acc:Q9
UPYS5] :
EE EN IN
1548¢c h 1 1549a
CaMax: | ENSG00000179454 | ENST00000324772 | BTB (POZ) DOMAIN 14 q21.2 1551a CONTAINING 5. [Source:RefSeq;Acc:NM_0176 58]
EI EE
1554¢
El 1574b
El 1574b
CaMax: | ENSG00000144785 | ENST00000273308 TRANSMEMBRANE 12 qi3.3 1577a PROTEIN 4. [Source:RefSeq;Acc:NM_0142 55]
Ex
El I 157b
El
ER
Ll 1591a fl I 1594a fl — fl — 1596b
Fr
Fl I EN EN NN 159a
I A SS EE I SO
159a td ER A GI 15b de RR ll ge 1604a
SO i il IO 0 il 1626¢ .
EE
1628d
I-21 EN I A Bn 1629a 1-31 EE ES RN 1629a
F752 I ES I RH 1630b f52 E E NN 1630b
CaMax: | ENSG00000083290 | ENST00000261504 UNC-51-LIKE KINASE 2. 17 pli2 al — 83]
CaMax: | ENSG00000083290 | ENST00000261504 UNC-51-LIKE KINASE 2. 17 pll2 e em EE 83]
CaMax: | ENSG00000083290 | ENST00000261504 | UNC-5 1-LIKE KINASE 2. 17 pli.2 e | [7 83]
I EE
1639a
I I EE I I
1639a Pp
Fall I A i 163a ENST00000326636
Fld cet I VR Lil 1646a
Ei id I LN 1648a 3207 6069
CaMax: | ENSG00000163734 | ENST00000296026 | MACROPHAGE 4 ql33 164c INFLAMMATORY
PROTEIN-2-BETA j PRECURSOR (MIP2-BETA) (CXCL3) (GROWTH
REGULATED PROTEIN
GAMMA) (GRO-GAMMA). [Source:SWISSPROT;Acc:P19 876]
EA
IE al ha I BE 166a
Cor
Fr
1675a i EN EE EE a 1676a 17 EE A I NN 1676a 3 I EE A— 1678a a I EE I 1682a i I I NS 168c
CaMax: | ENSRNOG0000001 CYTOCHROME C OXIDASE | 19 ql2 1690a 7817 SUBUNIT IV ISOFORM 1,
MITOCHONDRIAL
PRECURSOR (EC 1.9.3.1) (COX IV-1) (CYTOCHROME
C OXIDASE POLYPEPTIDE
Vv). {Source: SWISSPROT ;Acc:P10 888]
Fal cl I LA 1691b
CaMax: | ENSRNOGO0000001 CYTOCHROME C OXIDASE | 19 ql2 1692a 7817 SUBUNIT IV ISOFORM 1,
MITOCHONDRIAL
PRECURSOR (EC 1.9.3.1) (COX IV-1) (CYTOCHROME
C OXIDASE POLYPEPTIDE
Iv). [Source:SWISSPROT;Acc:P10 888]
CaMax: | ENSG00000066468 | ENST00000263455 | FIBROBLAST GROWTH 10 q26.13 1693b ENST00000310977 | FACTOR RECEPTOR 2
ENST00000263451 | PRECURSOR (EC 2.7.1.112)
ENST00000263454 | (FGFR-2) (KERATINOCYTE
ENST00000328075 | GROWTH FACTOR
ENST00000310973 | RECEPTOR 2).
ENSTO00000263453 | [Source:SWISSPROT;Acc:P21
ENST00000332961 | 802] 175 EN I I . 1696a [£5 1696a fl 16b
CaMax: | ENSG00000132357 | ENST00000254691 | CASPASE RECRUITMENT 5 pl3.1 1705a DOMAIN PROTEIN 6. [Source:SWISSPROT;Acc:Q9
BX69]
Ex 1709a 1714a
EI
1715a
CaMax: | ENSG00000179010 | ENST00000320912 | T-CELL ACTIVATION 4 pl6.1 1717a PROTEIN. [Source:RefSeq;Acc:NM_0332 96} [CaMax. | ENSG00000021355 | ENST00000229479 | LEUKOCYTEELASTASE [6 [p252
1721a INHIBITOR (LED (MONOCYTE/NEUTROPHIL
ELASTASE INHIBITOR) (M/NEI) (EI). [Source:SWISSPROT;Acc:P30 740]
CaMax: | ENSG00000144674 ENST00000273176 | GOLGI AUTOANTIGEN, 3 p22.3 1722a GOLGIN SUBFAMILY A
MEMBER 4 (TRANS-GOLGI
P230) (256 KDA GOLGIN) — (GOLGIN-245) (72.1
PROTEIN). [Source:SWISSPROT;Acc:Q13 439]
CaMax- | ENSG00000143147 | ENST00000271357 G-PROTEIN COUPLED 1 q24.2 1724a RECEPTOR. [Source:RefSeq;Acc:NM_1538 32] 1:5 EE I a A 1725a
EA I I
1726a
EAI I I
1726a
CaMax: | ENSG00000131355 | ENST00000253673 EGFE-LIKE MODULE- 19 pl3.12 1727a CONTAINING MUCIN-LIKE
RECEPTOR 3 ISOFORM A. [Source:RefSeq;Acc:NM_0325 711 :
EA
1730a
ES
1738b
EIR
1741a
CaMax: | ENSG00000109883 | ENST00000227288 | LEUCINE-RICH REPEAT- 11 pl4.1 1744a CONTAINING G PROTEIN- .
COUPLED RECEPTOR 4
PRECURSOR (G PROTEIN-
COUPLED RECEPTOR 48). [Source: SWISSPROT; Acc:Q9
BXB1]
EI
1744a
CaMax: | ENSG00000139688 | ENST00000267164 | TRANSCRIPTION 13 ql4.12 174a INITIATION FACTOR IIF,
BETA SUBUNIT (TFIIF-
BETA) (TRANSCRIPTION
INITIATION FACTOR
RAP30). : [Source:SWISSPROT;Acc:P13 984]
Fa 174a
I
Eni
ET
Eo EE EA EE I RR
SETI I I EA NE
CaMax: | ENSG00000104852 ENST00000221448 | Ul SMALL NUCLEAR 19 ql3.33 1758a RIBONUCLEOPROTEIN 70
KDA (U1 SNRNP 70 KDA) (SNRNP70) (U1-70K). [Source:SWISSPROT;Acc:P08 621]
CaMax: | ENSG00000179454 ENST00000324772 | BTB (POZ) DOMAIN 14 q2l.2 1759b CONTAINING 5. ’ [Source:RefSeq;Acc:NM_0176 _ 58]
FI I
1760c
ES EE EN
1760c ey 1772a
CaMax: | ENSG00000179562 | ENST00000321407 GOLGI COILED COIL 7 q32.1 1775a PROTEIN |.
CN9]
CaMax: | ENSG00000179562 | ENST00000321407 | GOLGI COILED COIL 7 g32.1 1775a PROTEIN 1. :
CN9]
EN I NS
1778c
CaMax: | ENSGO0000184880 | ENST00000332933 | OK/SW-CL.87. 11 q23.3 i — 168] !
CaMax: | ENSG00000135457 | ENST00000257915 TRANSCRIPTION FACTOR 12 | q13.12 178a ENST00000307660 | CP2; TRANSCRIPTION
FACTOR CP2, ALPHA : 1 GLOBIN. [Source:RefSeq;Acc:NM_0056 53]
Ea EE EI 1794a
Eni EE 1794a
El I 17a 1 1800a
CaMax: | ENSG00000166855 | ENST00000300107 | ATP-DEPENDENT CLP 15 q22.31 1801b PROTEASE ATP-BINDING
SUBUNIT CLPX-LIKE,
MITOCHONDRIAL
PRECURSOR. [Source:SWISSPROT;Acc:076 031]
CaMax: | ENSG00000171567 | ENST00000304782 | TIGGER TRANSPOSABLE 2 q37.1 180a ELEMENT DERIVED 1;
JERKY (MOUSE)
HOMOLOG-LIKE. [Source:RefSeq;Acc:NM_1457 02]
Fl i LA il 1810a .
El I
CaMax: | ENSG00000105492 | ENST00000270604 | SIALIC ACID BINDING IG- | 19 qi3.41 1812b LIKE LECTIN 6
PRECURSOR (SIGLEC-6) (OBESITY- BINDING
PROTEIN 1) (OB-BP1) (CD33
ANTIGEN-LIKE 1). [Source: SWISSPROT; Acc:043 699]
CaMax: | ENSG00000145730 ENSTO00000304400 PEPTIDYL-GLYCINE 5 q21.1 1814c ENST00000304406 ALPHA-AMIDATING — ENST00000282992 | MONOOXYGENASE
ENST00000325306 | PRECURSOR (EC 1.14.17.3)
ENST00000274392 | (PAM). [Source:SWISSPROT;Acc:P19 021]
FE I I
1814c
FE EN I
1818a
CaMax: | ENSMUSG0000002 | ENSMUST0000005 PROTEOGLYCAN LINK 13 C3 1828b 1613 3227 PROTEIN PRECURSOR ‘ ENSMUSTO0000002 | (CARTILAGE LINK 2108 PROTEIN) (LP). [Source:SWISSPROT;Acc:Q9
QUPS]
ES EE I
1834b
IF EE
1849d
IE EE
1852a
CaMax: | ENSRNOGO0000001 SPLICEOSOMAL PROTEIN q31 1853a 3516 SAPI155 (FRAGMENT). [Source:SPTREMBL;Acc:Q9E
T34]}
CaMax: | ENSRNOGO0000001 CYTOCHROME BS. 18 ql2.3 1857¢ 5205 [Source:SWISSPROT;Acc:P00 173]
CaMax: | ENSG00000055609 | ENST00000312661 | MYELOID/LYMPHOID OR 7 q36.1 1859a ENST00000262189 | MIXED-LINEAGE
LEUKEMIA 3; ALR-LIKE
PROTEIN. [Source:RefSeq;Acc:NM_0212 30]
Fl 1863c fi I I 1863c¢
CaMax: | ENSMUSG0000003 | ENSMUST0000004 8 -1 D3 1864b 3732 2012
ENSMUST0000005 4613 186a ENST00000326685 fl I 1874b
Er EE 1874b
FR
IS EE EE NN RN ER wr 1 [i A A EE Ni 1881b il ail IR 1894a
Fl EE DR 18a
ES A SR
1912a
I~ I I A — 1912a i
FI EN IN EN
1913a fA I A 1913a
CaMax: | ENSG00000146414 | ENST00000275233 | SNF2 HIST ONE LINKER q24.3 1917f ENST00000334592 | PHD RING HELICASE. [Source:RefSeq;Acc:NM_1730 82]
CaMax: | ENSG00000057019 | ENST00000326857 | ENDOTHELIAL AND 3 gql2.1 1919a ENST00000326840 | SMOOTH MUSCLE CELL-
DERIVED NEUROPILIN-
LIKE PROTEIN;
COAGULATION FACTOR
V/VHI-HOMOLOGY
DOMAINS PROTEIN 1. [Source:RefSeq;Acc:NM_0809 27}
CaMax: | ENSMUSGO0000002 | ENSMUST0000005 16 BS
ENSMUST0000002 3327
I I EE A NA I
1928a
Fd tl A A Gi 1929c
Flt A ial 1930a
CaMax: | ENSG00000116957 | ENST00000264180 | BETA-TUBULIN 1 q42.3 1940e COFACTORE. {Source:RefSeq;Acc:NM_0031 93]
CaMax: | ENSG00000070214 | ENST00000185520 | CDW92 ANTIGEN; q31.1 1941e CHOLINE TRANSPORTER-
LIKE PROTEIN. [Source:RefSeq;Acc:NM_0805 46]
CaMax: | ENSG00000154553 | ENST00000284770 | ALPHA-ACTININ-2- 4 q35.1 1943a ENST00000284771 | ASSOCIATED LIM
ENST00000284767 | PROTEIN; ENIGMA ,
HOMOLOG. [Source:RefSeq;Acc:NM_0144 76]
Eni
Se rr 1944a
I I I ER
1945a
FH
1:5 EE I I NN 1948b get 1948b 2 A ES I 1949a
I-58 A A NO i 1949a
CaMax. | ENSG00000134215 | ENST00000280840 1950a [Source: SWISSPROT; Acc:Q9 - UKw4]
CaMax: | ENSG00000138386 | ENST00000321041 NGFI-A BINDING PROTEIN j 2 q32.2 1953a 1 (EGR-1 BINDING PROTEIN 1) (TRANSCRIPTIONAL ‘ REGULATORY PROTEIN
P54). . [Source:SWISSPROT;Acc:Q13 506] a EE 1954
CaMax: | ENSG00000157077 | ENST00000287722 MOTHERS AGAINST 1 p32.3 1961e ENST00000287727 | DECAPENTAPLEGIC
HOMOLOG INTERACTING
PROTEIN (MADH-
INTERACTING PROTEIN) ’ (SMAD ANCHOR FOR
RECEPTOR ACTIVATION) : (RECEPTOR ACTIVATION
ANCHOR) (HSARA) (NOVEL
SERINE PROTEASE) (NSP). (Source:SWISSPROT;Acc:095 405]
CaMax: | ENSG00000080469 | ENST00000328494 | ANTIGEN PEPTIDE p21.32 1967a ENST00000190846 | TRANSPORTER 2 (APT2) , (PEPTIDE TRANSPORTER
TAP2) (PEPTIDE
TRANSPORTER PSF2) (PEPTIDE SUPPLY FACTOR 2) (PSF-2) (PEPTIDE
TRANSPORTER INVOLVED
IN ANTIGEN PROCESSING
2). [Source:SWISSPROT;Acc:Q03 519]
CaMax: | ENSG00000138063 | ENST00000260632 | PELLINO PROTEIN. 2 pl4 1968a [Source:RefSeq;Acc:NM_0206 51]
CaMax: | ENSG00000060718 | ENST00000305302 | COLLAGEN ALPHA 1(XI) 1 p21.1 1982a ENST00000193186 | CHAIN PRECURSOR.
ENST00000314022 [Source:SWISSPROT; Acc P12
ENSTO00000305262 | 107]
FE
CaMax: | ENSG00000166974 | ENST00000300249 | MICROTUBULE- 18 qi2.1 1990a ASSOCIATED PROTEIN,
RP/EB FAMILY, MEMBER 2;
T-CELL ACTIVATION
PROTEIN, EB1 FAMILY;
APC-BINDING PROTEIN
EBI1. [Source:RefSeq; Acc:NM_0142
— 1 Te&
Er I EE EE EE 1991d
Fal I ER I la
IN NE EE Ri 2002c¢
Se ms || [7 2003a
CaMax: | ENSMUSG0000002 | EN SMUSTO0000002 | PINS. 3 F3
El i 22]
CaMax: | ENSG00000180530 | ENST00000318948 NUCLEAR FACTOR RIP140 | 21 qll.2 2013a (NUCLEAR RECEPTOR
INTERACTING PROTEIN 1). [Source: SWISSPROT; Acc:P48 552]
Fi A IE I Na 2014f
CaMax: | ENSG00000174444 ENST00000307961 | 60S RIBOSOMAL PROTEIN 15 22.31 2015e 14 (L1). [Source:SWISSPROT;Acc:P36 578]
CaMax: | ENSG00000011566 | ENST00000263881 MITOGEN-ACTIVATED 2 p22.1 2020b PROTEIN KINASE KINASE : KINASE KINASE 3 (EC 2.7.1.37) (MAPK/ERK
KINASE KINASE KINASE 3) (MEK KINASE KINASE 3) (MEKKK 3) (GERMINAL
CENTER KINASE RELATED
PROTEIN KINASE) (GLK). [Source:SWISSPROT;Acc:Q8I
VHS] fl I 2020b
CaMax: | ENSG00000020577 | ENST00000305831 14 q22.2 2022a ENST00000251091
ENST00000321411
EI
IS I I
2023b
CaMax: | ENSG00000172155 | ENST00000326233 | LATE ENVELOPE PROTEIN | 1 q21.3 2034a . 4. [Source:RefSeq; Acc:NM_1783 52]
CaMax: | ENSG00000161980 | ENST00000293860 | DNA-DIRECTED RNA 16 pl33 2035d POLYMERASES III 12.5 KDA
POLYPEPTIDE (EC 2.7.7.6) (RNA POLYMERASE II C11
SUBUNIT) (HSC11P) (HRPC11) (MYO10
PROTEIN). [Source:SWISSPROT;Acc:Q9
Y2Y1]
BN [Eee]
DOMAIN. [Source:SWISSPROT;Acc:P42 ol 694] 2059
I EN NAS I
205a
CaMax: | ENSG00000129116 ENST00000261509 | PALLADIN; CGI-151 4 q32.3 2070a ENST00000335213 | PROTEIN. - ENST00000333488 [Source:RefSeq;Acc:NM_0160 81] 1 I I I I 2073b
I= I ES A NN 2073b
CaMax: | ENSG00000124406 | ENST00000264449 POTENTIAL 4 pl3 2074b PHOSPHOLIPID-
TRANSPORTING ATPASE
IA (EC3.6.3.1) (CHROMAFFIN GRANULE
ATPASE II) (ATPASE CLASS
I TYPE 8A MEMBER 1). [Source:SWISSPROT;Acc:Q9
Y2QO0]
CaMax: | ENSG00000138709 | ENST00000264584 4 q28.2 or
ENST00000326639 (20 I EN NR EN 2076¢
CaMax: | ENSG00000122545 | ENST00000322406 | SEPTIN7 (CDCIO PROTEIN | 7 pld.2 2078a HOMOLOG). [Source:SWISSPROT;Acc:Q16 181]
CaMax: | ENSG00000085449 ENST00000233055 | WD REPEAT AND FY VE 2 q36.1 2083e ENST00000272881 | DOMAIN CONTAINING 1
ISOFORM 1,
PHOSPHOINOSITIDE-
BINDING PROTEIN SR1;
WD40 AND FY VE DOMAIN
CONTAINING 1. [Source:RefSeq;Acc:NM_0208 : 30]
Fl I A i 2088a
ES
Som
Fal
CaMax: | ENSG00000166147 | ENST00000316623 | FIBRILLIN 1 PRECURSOR. 15 q21.1 2100b [Source:SWISSPROT;Acc:P35 553]
Er ER A ES RR ER
Sem 11 2 A ER I NN 2108b
Fa I NO I 2109a
CaMax: | ENSG00000180837 | ENST00000318177 | ZINC FINGER PROTEIN 345 | 19 ql3.12 2110a (ZINC FINGER PROTEIN
HZF10). [Source:SWISSPROT;Acc:Q14 585]
SN i ESS EA ES I 2113a
CaMax: | ENSG00000103222 | ENST00000263013 MULTIDRUG RESISTANCE- | 16 pl3.11 211b ENST00000263018 | ASSOCIATED PROTEIN 1.
ENST00000263015 | [Source:SWISSPROT;Acc:P33
ENST00000263019 | 527]
ENST00000263017
ENST00000263014
ENST00000263016
FE NS I
2122a
CaMax: | ENSG00000139370 | ENST00000266771 | PEPTIDE-HISTIDINE 12 q24.32 2123a TRANSPORTER 4. {Source:RefSeq;Acc:NM_1456 48]
CaMax: | ENSG00000143415 | ENST00000271682 | SMALL PROTEIN 1 q21.3 2129a EFFECTOR 1 OF CDC42. [Source:RefSeq;Acc:NM_0202 39
EI
EA
2135d ~
EA
2136b
Fr I— eT fr I
Elid | a 2161c ENST00000326703
ENST00000326639
Fl I— [2 I £3 —
Fo I
Cue TT ca 1
Erd a EE
Sel
Eh TT
Fe al LA i 2222b
Io A I EE a I 2223a
CaMax: | ENSG00000116690 ENST00000251819 | PROTEOGLYCAN 4; 1 g31.1 229244 MEGAKARYOCYTE . STIMULATING FACTOR;
PROTEOGLYCAN 4, (MEGAKARYOCYTE
STIMULATING FACTOR, _ | ARTICULAR SUPERFICIAL } ZONE PROTEIN); JACOBS
CAMPTODACTYLY- ’ ARTHROPATHY-
PERICARDITIS
SYNDROME;
CAMPTODACTYLY,
ARTHROPATHY, COXA
VARA, PERICARDITIS
SYNDROME. [Source:RefSeq;Acc:NM_0058 07]
Fl ad NR 0 ilk 2225b
CaMax: | ENSMUSG0000003 | ENSMUST(0000003 | THYROTROPIN- Cy 15 D1 2234a 8760 8856 RELEASING HORMONE
RECEPTOR (TRH-R) (THYROLIBERIN
RECEPTOR). [Source:SWISSPROT; Acc:P21 761]
FE I NR
2235a !
FE NE IN Hi 2235a
CaMax: | ENSG00000172572 | ENST00000325802 CGMP-INHIBITED 3',5'- 12 pl2.2 2238a CYCLIC ' PHOSPHODIESTERASE A (EC 3.14.17) (CYCLIC GMP
INHIBITED
. PHOSPHODIESTERASE A) (CGI-PDE A). [Source:SWISSPROT;Acc:Q14 432]
CaMax: | ENSG00000172572 | ENST00000325802 | CGMP-INHIBITED 3'5'- 12 pl2.2 2241a CYCLIC
PHOSPHODIESTERASE A
(EC 3.1.4.17) (CYCLIC GMP
INHIBITED
PHOSPHODIESTERASE A) (CGI-PDE A). [Source:SWISSPROT;Acc:Q14 432]
CaMax: | ENSG00000172572 | ENST00000325802 | CGMP-INHIBITED 3'5" 12 pl2.2 2238a CYCLIC
PHOSPHODIESTERASE A
(EC 3.1.4.17) (CYCLIC GMP
INHIBITED
PHOSPHODIESTERASE A) (CGI-PDE A). [Source:SWISSPROT;Acc:Q14
— [vem [57 I ES ES 2242
Fi I A I I 2251d
Sie em [ro | JT] 2252b
I I I
2258a
I= ES EE ES — 2258a
El a EE EN 2258a ’
I EE
I I NE I i 2264b
FI EN I SS
2264b
FI I I
2266b
CaMax: | ENSG00000137801 | ENST00000260356 THROMBOSPONDIN 1 15 ql4 2267a PRECURSOR. [Source:SWISSPROT;Acc:P0O7 996]
FE I A i 231a
Fl EE A a I 2331c
Fl a EN A ic 2341b
El I EE I Nh 2351c
Fi I a 2351c
CaMax: | ENSGO00000172572 | ENST00000325802 | CGMP-INHIBITED 3',5- 12 pi2.2 2241a CYCLIC
PHOSPHODIESTERASE A
(EC 3.14.17) (CYCLIC GMP
INHIBITED
PHOSPHODIESTERASE A) (CGI-PDE A). [Source:SWISSPROT;Acc:Q14 432]
Ed DE 235a
CaMax: | ENSG00000137801 | ENST00000260356 | THROMBOSPONDIN 1 15 ql4 2374a PRECURSOR. [Source:SWISSPROT;Acc:P07 996]
El I 238a
CaMax: | ENSG00000119363 | ENST00000238302 | SPECTRIN ALPHA CHAIN, g34.11 239a BRAIN (SPECTRIN, NON-
ERYTHROID ALPHA
CHAIN) (ALPHA-II
SPECTRIN) (FODRIN
ALPHA CHAIN). [Source:SWISSPROT; Acc:Q13 813]
CaMax: | ENSG00000162419 ENST00000294409 | GLUCOCORTICOID 1 p35.3 23a MODULATORY ELEMENT , BINDING PROTEIN 1 (GMEB-1) (PARVOVIRUS
INITIATION FACTOR P96) (PIF P96) (DNA BINDING
PROTEIN P96PIF). [Source:SWISSPROT;Acc:Q9
Y 692]
Fi cd NO LI 240a fo EN I NO 243a
Fld I J 245a
Fa il I LL 248a
FE I A I
24a
FE I I ER
258a
Fl EN I ER 26l1¢
El AS EN I NN 261c
CaMax: | ENSG00000041982 | ENST00000265131 | TENASCIN PRECURSOR q33.1 267d : (TN) (HEXABRACHION) (CYTOTACTIN) (NEURONECTIN) (GMEM) : (0D (MIOTENDINOUS
ANTIGEN) (GLIOMA-
ASSOCIATED- ;
EXTRACELLULAR MATRIX
ANTIGEN) (GP 150-225) (TENASCIN-C) (TN-C). [Source:SWISSPROT;Acc:P24 821]
CaMax: | ENSG00000141642 | ENST00000269466 | ELAC HOMOLOG 1. 18 q21.1 272d [Source:RefSeq; Acc:NM_0186 96]
Er I 27a
Fal
CaMax: ENSGO00000141378 | ENST00000311824 | PROTEIN CGI-147. 17 q23.2 307b [Source:SWISSPROT;Acc:Q9
Y3ES5]
CaMax: | ENSGO0000116745 | ENST00000262340 | RETINAL PIGMENT 1 p31.2 308c EPITHELIUM-SPECIFIC
PROTEIN 65KDA; RETINAL
PIGMENT EPITHELIUM-
SPECIFIC PROTEIN (65KD);
RETINITIS PIGMENTOSA 20 (AUTOSOMAL RECESSIVE). {Source:RefSeq;Acc:NM_0003 29]
CaMax:
El fo
Ir A EE ER ER
TET I EN I EE fl A NN EN 3l4a
Fo A NN NS NA 319b
CaMax. | ENSG00000090989 | ENST00000317642 | EXOCYST COMPLEX 4 ql2 3202 ENST00000333951 | COMPONENT SEC3 (BM- 012). [Source: SWISSPROT; Acc:Q9
NV70]
SR iE A EH 320a me 1 322a
Fl il NN GN 324a
CaMax. | ENSMUSGO0000002 | ENSMUST0000002 | MICROSOMAL SIGNAL 7 D2 326e 5724 6818 PEPTIDASE 18 KDA
SUBUNIT (EC 3 4.-.-) (SPASE 18 KDA SUBUNIT) (SPC18) (ENDOPEPTIDASE SP18). [Source:SWISSPROT;Acc:Q9
ROP6]
EE A ES
327f
Ea 327f
CaMax. | ENSGO00000129116 | ENST00000261509 | PALLADIN; CGI-151 4 q32.3 328b ENSTO00000335213 | PROTEIN.
ENSTO00000333488 | [Source:RefSeq;Acc:NM_0160 81) fowl TT 33a
Ea I 33a
El I 340a
Jew] “| 343b fa I 343b
Fall
CaMax: | ENSGO00000167996 | ENST00000301775 | FERRITIN HEAVY CHAIN 11 ql2.3 106a (FERRITIN H SUBUNIT). [Source:SWISSPROT;Acc:P02 794] 106a (FERRITIN H SUBUNIT). {Source:SWISSPROT; Acc:P02 794)
Fl
To I REN ER
EY A EN I — NE
CaMax: | ENSG00000182944 ENST00000331029 | RNA-BINDING PROTEIN 22 ql22 364a ENST00000329871 | EWS (EWS ONCOGENE) (EWING SARCOMA
BREAKPOINT REGION 1
PROTEIN). [Source:SWISSPROT;Acc:Q01 844]
I I R— 370a
CaMax: | ENSG00000136938 ENST00000277182 | ACIDIC LEUCINE-RICH q22.33 374a . NUCLEAR
PHOSPHOPROTEIN 32
FAMILY MEMBER B
(PHAPI2 PROTEIN) (SILVER-STAINABLE
PROTEIN SSP29) (ACIDIC
PROTEIN RICH IN
LEUCINES). [Source: SWISSPROT; Acc:Q92 688]
Eu 375d al I 379a
CaMax: | ENSG00000145216 | ENST00000306932 FIP1-LIKE 1; REARRANGED | 4 ql2 38a ENST00000273816 {| IN HYPEREOSINOPHILIA. [Source:RefSeq;Acc:NM_0309 17]
CaMax:
El EE BE ol —
El
Ea
El
ES
El Fad I EE SE 3c 6864 on
CaMax: | ENSG00000134001 | ENST00000256383 | EUKARYOTIC 14 q23.3 415b TRANSLATION INITIATION
FACTOR 2 SUBUNIT 1 (RUKARYOTIC
TRANSLATION INITIATION
: FACTOR 2 ALPHA
SUBUNIT) (EIF-2-ALPHA) (EIF- 2ALPHA) (EIF-2A). [Source:SWISSPROT; Acc: P05 198] _46 -
El I I EE 421a
Fil el I A hil 43a
Il I I IN NN 446f
Fc EN I I Si 44c¢
Fal EE 44¢
Se 45.1b ‘
Fa I EN IR 45.1b
Fa I I RS i 450a
Fa I ES I BE 450a
Fl I I IN i 452a
FE EE RN NN
455¢ er 455¢c
Fl I EN Na I 457c¢c
CaMax: | ENSG00000102908 | ENST00000317142 | NUCLEAR FACTOR OF 16 q22.1 459a ACTIVATED T CELLS 5 (T
CELL TRANSCRIPTION
FACTOR NFATS5) (NF-ATS) (TONICITY-RESPONSIVE
ENHANCER-BINDING
PROTEIN) (TONE- BINDING
PROTEIN) (TONEBP). [Source:SWISSPROT;Acc:094 916]
Fil EY I I 461a 461a
CaMax: | ENSG00000035687 | ENST00000263828 ADENYLOSUCCINATE 1 qd4 464b SYNTHETASE (EC 6.3.4.4) (IMP--ASPARTATE LIGASE) (ADSS) (AMPSASE). [Source: SWISSPROT; Acc:P30 520]
CaMax: | ENSGO0000064309 | ENST00000263577 | SURFACE GLYCOPROTEIN, | 11 q24.2 465b 1G SUPERFAMILY
MEMBER. i [Source:RefSeq;Acc:NM_0169 . 52]
Ea EE 46a
El 472a
Ex EE 472a !
CaMax: | ENSG00000165169 | ENST00000297871 | T-COMPLEX ASSOCIATED- | 24 plld 478a TESTIS-EXPRESSED 1-LIKE (PROTEIN 91/23). [Source:SWISSPROT; Acc:P51 _47 -
— 1 Teg _________T [
CaMax: | ENSG00000165169 | ENST! 00000297871 | T-COMPLEX ASSOCIATED- | 24 plié4 479% TESTIS-EXPRESSED 1-LIKE (PROTEIN 91/23). [Source:SWIS SPROT;Acc:P51 808] > EN IS I 482a
CaMax: | ENSG00000116584 ENSTO00000313695 | RHO GUANINE 1 q22 487a ENSTO00000313667 | NUCLEOTIDE EXCHANGE
FACTOR 2 (GEF-H1
PROTEIN) (PROLIFERATING CELL
NUCLEOLAR ANTIGEN
: P40). [Source: SWISSPROT; Acc:Q92 974]
CaMax: | ENSG00000159399 | ENST00000290573 HEXOKINASE, TYPEII (EC | 2 pl2 488a 2.7.1.1) (HK II) MUSCLE
FORM HEXOKINASE). [Source:SWISSPROT;Acc:P52 ! 789]
CaMax:
Fal EE
Fal
El I
Fal I
Fal oul I—
Ell I
Fal s0.1c ol
Bal
El
Esl I
Ia I
Ell IE —
Fl
Fall
CaMax: | ENSG00000179454 | ENST00000324772 | BTB (POZ) DOMAIN 14 q21.2 520a CONTAINING 5. [Source:RefSeq;Acc:NM_0176 58]
CaMax. | ENSG00000081189 |} ENST00000325423 MYOCYTE-SPECIFIC 5 ql4.3 521b ENHANCER FACTOR 2C. [Source:SWISSPROT;Acc:Q06 413]
Fi IY IS I I 523a
Fl A A AS NN A 52a
CaMax: | ENSG00000100567 | ENST00000216455 PROTEASOME SUBUNIT 14 q23.1 530b ALPHA TYPE 3 (EC 3.4.25.1) _ (PROTEASOME
COMPONENT C8) (MACROPAIN SUBUNIT C8) (MULTICATALYTIC
ENDOPEPTIDASE
COMPLEX SUBUNIT C8). [Source:SWISSPROT;Acc:P25 788]
A I
CaMax: | ENSG00000133059 | ENST00000255422 | HDCMD38P. i q32.1 ie re Ee 1S5])
El I I A NB 540a
El EE I 543a
CaMax: | ENSGO00000144785 | ENST00000273308 | TRANSMEMBRANE 12 ql3.3 545a PROTEIN 4. [Source:RefSeq;Acc:NM_0142 55]
Fl tl I 547c
Fl I LA cl 548c
CaMax: | ENSG00000133226 | ENST00000334537 | SER/ARG-RELATED 1 p36.11 550a ENST00000323848 | NUCLEAR MATRIX
PROTEIN (PLENTY OF . PROLINES 101-L; SER/ARG- . RELATED NUCLEAR
MATRIX PROTEIN (PLENTY }
OF PROLINES 101-LIKE). [Source:RefSeq;Acc:NM_0058 39] 552a
FE ld I LA il 553b
CaMax: | ENSG00000005812 | ENST00000281993 | F-BOX AND LEUCINE-RICH | 13 q22.3 555b REPEAT PROTEIN 3A; F-
BOX PROTEIN FBL3A. {Source:RefSeq;Acc:NM_0121 58]
Fa I I
IE I
Fall I—
Fall I ge 560b % I EN SN 561b
Fl I I I i 568a
I EN A I
568a
FE I EN
56a
Sa EEE EE SS I 56a
CaMax: | ENSG00000143924 | ENST00000318522 ECHINODERM 2 p21 571a MICROTUBULE-
ASSOCIATED PROTEIN-
LIKE 4 (EMAP-4) (RESTRICTEDLY
OVEREXPRESSED
PROLIFERATION- ' ASSOCIATED PROTEIN) . (ROPP 120). [Source:SWISSPROT;Acc:Q9
HC35] fa I NE I i I 574a
CaMax: | ENSG00000124193 | ENST00000244020 | SPLICING FACTOR, 20 ql3.11 579a ARGININE/SERINE-RICH 6 (PRE-MRNA SPLICING
FACTOR SRPS5). [Source:SWISSPROT;Acc:Q13 247]
CaMax: | ENSG00000091409 | ENST00000264107 | INTEGRIN ALPHA-6 2 q31.1 57a : ENST00000264106 | PRECURSOR (VLA-6) (CD49F). {Source:SWISSPROT;Acc:P23 229]
CaMax: ENSG00000115112 | ENST00000263707 | LBP-9. 2 ql42 581a [Source:RefSeq;Acc:NM_0145 53]
CaMax: | ENSMUSGO0000002 | ENSMUSTQ000005 1 C3 583e 6193 5226
ENSMUSTO0000005 9577
ENSMUSTO0000002 7385
Fall I 58a
CaMax: | ENSG00000171634 | ENST00000306378 | FETAL ALZHEIMER 17 q24.2 597c ENST00000335221 | ANTIGEN (FETAL ALZ-50-
ENST00000321866 | REACTIVE CLONE 1).
ENST00000321892 | [Source:SWISSPROT;Acc:Q12 8301
Eel I 59a
El 59a
Full
Fv I I
I I SE ER EE SE
Fr ER EE SS — 622a ’
CaMax: | ENSG00000140575 ENST00000268182 | RAS GTPASE-ACTIVATING- 15 q26.1 623a LIKE PROTEIN IQGAP1
P1935). . [Source:SWISSPROT; Acc:P46 940]
Sal I I EE 624b
BE I I E— 626a
F--5 AS— I 626a
CaMax: | ENSG00000183762 ENST00000327813 | KREMEN PROTEIN 1 22 gl2.1 628a PRECURSOR (KRINGLE-
CONTAINING PROTEIN
MARKING THE EYE AND ‘
THE NOSE) (DICKKOPF
RECEPTOR). [Source:SWISSPROT 1Acc:Q96
MU8]
CaMax: | ENSG00000133226 | ENST00000334537 SER/ARG-RELATED 1 p36.11 635a ENST00000323848 | NUCLEAR MATRIX
PROTEIN (PLENTY OF
PROLINES 101-L; SER/ARG-
RELATED NUCLEAR
MATRIX PROTEIN (PLENTY .
OF PROLINES 101-LIKE). [Source:RefSeq;Acc:NM_0058 39]
CaMax: | ENSG00000165169 | ENST00000297871 T-COMPLEX ASSOCIATED- | 24 pll4 638b TESTIS-EXPRESSED 1-LIKE (PROTEIN 91/23). \ {Source:SWISSPROT;Acc:P51 808]
Ful 639a
Fl EE I IS HN 63a
Fil I A EE 63a
Filial NO I ill 64.2a
CaMax: | ENSG00000125149 | ENST00000219139 UPF0183 PROTEIN. 16 gq22.1
Fl I ee
BSU1]
Fa 690a al I 690a
CaMax: | ENSG00000171567 | ENST00000304782 TIGGER TRANSPOSABLE 2 q37.1 692a ELEMENT DERIVED 1;
JERKY (MOUSE)
HOMOLOG-LIKE. [Source:RefSeq;Acc:NM_1457 02]
FE I I LN ali 697a 7325 a=]
Cl
Er all>il (A 701a 2077 6099
CaMax: | ENSG00000119509 ENST00000262457 | INVERSIN. q22.33 704b ENST00000262456 [Source:RefSeq;Acc:NM_0144 25] ,
CaMax: | ENSG00000119509 | ENST00000262457 pram 704b ENST00000262456 [Source:RefSeq;Acc:NM_0144
El I I 70d
CaMax: | ENSG00000123500 | ENST00000243222 COLLAGEN ALPHA 1(X) q22.1 710a CHAIN PRECURSOR. 6921
EE A I RN
71lla
Fo I IN i 71la
I I I I
713a
I I EE A
713a
Fr EE I BN 714a
Ser 718a
Ed I EN SE 720a
CaMax: | ENSG00000133454 | ENST00000335473 22 ql2.1 725a ENSTO00000335460
ENST00000335471
ENST00000335359
CaMax: | ENSG00000122912 | ENST00000265870 | GRAVE'S DISEASE 10 q21.3 726b CARRIER PROTEIN (GDC) (GRAVE'S DISEASE
AUTOANTIGEN) (GDA) (MITOCHONDRIAL SOLUTE
CARRIER PROTEIN
HOMOLOG). [Source:SWISSPROT;Acc:P16 260]
Fal I 72a
Fal I— 72a
Fall I 731a
Ea
CaMax: | ENSG00000130066 | ENST00000252349 | DIAMINE 24 p22.11 736a ACETYLTRANSFERASE (EC 2.3.1.57) (SPERMIDINE/SPERMINE
N(1)-
ACETYLTRANSFERASE) (SSAT) (PUTRESCINE
ACETYLTRANSFERASE). [Source:SWISSPROT;Acc:P21 673]
Fl al) I ll iil 739a ENST00000319212
CaMax: | ENSG00000112473 ENST00000230235 HISTIDINE-RICH p21.32 73b ENST00000325843 | MEMBRANE PROTEIN KE4. [Source:SWISSPROT;Acc:Q92 504)
Ei I I EE I 745a :
CaMax: | ENSG00000164190 ENST00000296607 | IDN3 PROTEIN [ISOFORM A. | 5% pi32 747a ENST00000282516 [Source:RefSeq;Acc:NM_1334 33]
FE ER I
- 749a {2 A I I
Tdc
Fr ial i IN A i 753b 9203 6300 [a EE I 759b ) {ol I I I I 759b
I I ES I
764b (= I EE I I 764b
El al NR Ll 765a ENST00000281496
E- I 768a ey 76b , [CaMax: | ENSG00000171867 | ENST00000305832 | MAJOR PRION PROTEIN 20 pl3 785b PRECURSOR (PRP) (PRP27- 30) (PRP33-35C) (ASCR) (CD230 ANTIGEN). [Source: SWISSPROT; Acc:P04 156]
Evil A A a 788a toc IS LL 780a
CaMax: | ENSGO0000123096 | ENST00000242729 | SARCOSPAN (K-RAS 12 pl2.1 794a ONCOGENE-ASSOCIATED
PROTEIN) (KIRSTEN-RAS-
ASSOCIATED PROTEIN). ) [Source:SWISSPROT;Acc:Q14 : 714]
Fi i I LA C8 7952
Fl 813a
Fal I 815a
Fal 8la
FE EE
820a
I EE RA RE RR NR
SC A NE ES ES EE
Ch I I I I 827b
I IS ES
828a
Fi I NS ES NN 82b
I I ES i 831a
Fi I I EO Hi 831la
CaMax: | ENSMUSGO0000002 | ENSMUST0000005 1 C3 832a 6193 5226
ENSMUST0000005 9577
ENSMUST0000002 7385
Fill I ill 833a f= I I EA i 835¢
Fa el I GN ial 839a fl I I i A 841b fl EI I I HN A 841b
I EE I i 847a
CaMax: | ENSG00000136003 | ENST00000311893 | NITROGEN FIXATION 12 q23.3 85.1c _ENST00000228459 CLUSTER-LIKE. [Source:RefSeq;Acc:NM_0143 01]
Fl tl A 85.2b
El EE 850a
El 851a’
CaMax: | ENSG00000060982 | ENST00000261192 BRANCHED-CHAIN AMINO | 12 pi2.1 856¢ ENST00000334327 | ACID
AMINOTRANSFERASE,
CYTOSOLIC (EC 2.6.1.42) (BCAT(C)) (ECA39
PROTEIN). {Source:SWISSPROT;Acc:P54 687}
CaMax: | ENSMUSG0000002 | ENSMUST0000002 | ZINC FINGER PROTEIN 16 B1 863c 2676 3356 SLUG (NEURAL CREST ) TRANSCRIPTION FACTOR
SLUG) (SNAIL HOMOLOG 2). [Source:SWISSPROT;Acc:P97 469]
CaMax: | ENSG00000175582 | ENST00000310653 | RAS-RELATED PROTEIN 11 ql34 890a ENST00000334372 | RAB-6A (RAB-6). ’ [Source:SWISSPROT;Acc:P20 340]
FE I ER
8a
FS I RS ER A EN
TY I ES ES —
FI EE I— 906a
Foi I NE N— a 907a
CaMax: | ENSG00000145730 ENST00000304400 PEPTIDYL-GLYCINE 5 q21.1 909a ENST00000304406 ALPHA-AMIDATING
ENST00000282992 MONOOXYGENASE
ENST00000325306 | PRECURSOR (EC 1.14.17.3)
ENST00000274392 | (PAM).
B [Source:SWISSPROT;Acc:P19 021]
CaMax: | ENSMUSG0000002 | ENSMUST0000002 HEAT SHOCK PROTEIN HSP | 17 C 90c 3944 4739 90-BETA (HSP 84) (TUMOR
SPECIFIC
TRANSPLANTATION 84
KDA ANTIGEN) (TSTA). {Source:SWISSPROT;Acc:P11 499]
FA SS NO
Olla
RN A
9lla
FE I I i 912b
FE I IN
914a
Fv A I a 914a
El DE 915a
Fr I I 915a
CaMax: | ENSG00000104177 | ENST00000267836 | MYELIN GENE 15 q21.1 919b ENST00000324324 | EXPRESSION FACTOR 2. [Source:RefSeq;Acc:NM_0161 32]
Fal EE 91f
Ea 91f
CaMax: | ENSG00000104177 | ENST00000267836 | MYELIN GENE 15 g2l.1 919b ENST00000324324 | EXPRESSION FACTOR 2. [Source:RefSeq;Acc:NM_0161 32]
CaMax: | ENSG00000084676 | ENST00000288599 | NUCLEAR RECEPTOR 2 p23.3 92¢ ENST00000326011 | COACTIVATOR 1 ISOFORM 1. [Source:RefSeq; Acc:NM_0037 43]
CaMax: | ENSG00000125953 | ENST00000246165 | CHURCHILL PROTEIN 14 q23.3 935b (MY015 PROTEIN). [Source:SWISSPROT;Acc:Q8
WUHI1]
El 936b
EA
Fa I I A Sal 945a 1175 ve eT 1 1 I" [
FN EN IV
947a :
Fld 1:25 I A ilk 949c ENSTO00000273079 al i 953a 1290 1719 PROTEOLIPID. [Source:SWISSPROT;Acc:P56 kal 379] 963c [Source:RefSeq;Acc:NM_0146 76]
Fl ES A 96e
Fi EN I I 981a
Fl I EE I 084a
Fv EN I Ni 984a 986a [Source:SWISSPROT;Acc:P30 279]
CaMax: | ENSG00000125398 | ENST00000245479 | TRANSCRIPTION FACTOR 17 q24.3 990a SOX-9. 436]
El RR 992a
CaMax: | ENSG00000005700 | ENST00000306270 | INHIBITOR OF BRUTON'S qld.l 994b TYRSOINE KINASE; BTK-
BINDING PROTEIN. ' [Source:RefSeq;Acc:NM_0155 25]
CaMax: | ENSG00000008988 | ENST00000009589 | 40S RIBOSOMAL PROTEIN ql2.1 996a S20. [Source:SWISSPROT;Acc:P17 075] {
Table 2B
CaMax | Swissprot | OMIM | RefSeq InterPro Sig. | TMBHMM | HUGO
ID
FE A HH
1002b 00244769 om [ow 1002b | 00244769
CaMax: NM_178043 | PF05383 | IPR0O01199
Cll i
NM_018078
FE rR I ill 1006b | MAN PF00642 | IPRO07635 0 al 1 ial 1007a MAN PF00642 | IPROO7635
F- H 1008a 00245479
Foal I 1008a | 00245479
Fc 1 I wd 1009¢c MAN TPRO02167
IPRO02067
Fira I NN I A 1011a 012223_1
CaMax: | Transcript 1011a :ENSRNO
T0000003 3408
Fal I NN HH — 1013a 00326567 _ ii dN NO EF 1015d
CaMax: | Transcript 1016b :ENST000 00330345 1019a MAN PF00096 | IPRO07086
IPR001909
CaMax: | CGRR_H | 114190 | NM_005795 | PF02793 | IPRO00832 | Sigp Tmhmm CALCRL 1020a UMAN PF00002 | TPR003287
IPR003289
IPRO01688
IPRO01879
Fi I A wn 1026b 012223_1
CaMax: { Transcript 1026b :ENSRNO
T0000003 5961
IE El EE I A A 1028¢c RBP1_1
EE I I EE
1028¢ 00260780
FO 7 1 I 1029a PF03184 | IPR0O06695
Fr I 103a 00287239
ME
1044c MAN PF02877 | IPR004102
PF00644 rl = I I I I 1050a 00322598 (E- I N 1054a 00261710
IESE
1057b 012223_1
Fd I FN 1060a 2489
CaMax: PF02008 | IPRO02857 il EN I cl cl I I
ESE I I I
1063b 00277359 oe | an HE
CaMax: | Transcript
Lil. 00322595 lI I HF BL 1072a 09953_1
Fl I NA 1072a 00295955
Seg 1 10894 | 790758 108a 00297846
CaMax: | swiss|ATP 1090d 6_CANF
A
Ell I EE 1094b | 790758
CaMax: | ENSMUS
ST
6525
CaMax: NM_019974 | PF00089 | IPR001254 | Sigp Prss20- 1095a NM_133712 IPRO01314 pending 2300002A1 3Rik
CaMax: NM_019974 | PFO0089 | IPR0O01254 | Sigp Prss20- 1096a NM_133712 IPR0O01314 pending 2300002A1 3Rik
FE cd NO FH 1098a
FE cc HO id A 109a
Od 4 I 1105a MAN TPRO01806
FE ied HO Ol i 1106a a El I 1 1108a | MAN PF01852 | IPR0O00198
PR0O02913
FA I WE
1110b 790758 (FE 4 I 1110b | 790758
Ce a | [ors [ee Eon || [ 1111b | MAN 0 EO al OO 1 cd I NO 1112a IPR0O01472
CaMax: | Transcript 00327492
F730 ad tl al 1120a
IPR000566
SE I
1131b | 790758
FE FI
1132a 43360_1
CaMax: | FXP2_HU | 605317 | NM_148898 | PF00904 | IPRO07087 FOXP2 1135a | MAN 602081 | NM_148899 | PF00250 | IPR0O01766
NM_148900 IPR000354
NM_014491 rl EN I A I 11370 | 00256429 cE EE A A I A 1138a | 00261765
Erik I I NN I 1139a | 00245479 1145a | UMAN PFO1391 | IPR0O03129
TPRO01791 7 I NH - 1 11452 | UMAN 2 IY I HO 1146a | 00308148
Fs HE SH 11596 | 00296084 ll HO a 104a UMAN 7 le all cl NN 11696 | UMAN alt ll a a 1177¢ | UMAN IPRO00169
IPR0O04273
CaMax. | TIAM_H | 600687 | NM_003253 | PF00169 | IPRO01331 TIAM1 1184a | UMAN PF02196 | IPRO0D1849
PF00595 | IPR001478
PF00621 | IPRO00219
IPR0O03116
IPRO01472
Fatal I NN NS NN I 1184a | UMAN 5 A i cl IN A 1190b 2 cl cc NR 1192b
El I HN A I HO 11b 00307407
CaMax: | swiss|UB1 a I
N .
I
1212b | 00235420
CaMax: | VAV3_H | 605541 | NM_006113 | PF00307 | IPR002086 VAV3 1213d | UMAN PFO0621 | IPR002219
PF00169 | IPR001331
PF00130 | IPROC0980
PF00017 | IPRO01452
PFO0018 | IPRO03096
IPR0O01849
IPRO01715
IPR0O00219
EAE
1217a | 00305327
CaMax: | Transcript 1220b | :ENST000 00333521 [Al 1226d | 00244769
CaMax |ENSTOOO | | | 1 | 1 ped Towa | 11 1 i 4 I I I I A 123¢ 027883_1 fl 1 EN HA 123c 00313779
UMAN PF04003 | IPR007148 fl EN HN A HO 1245b 00319046 0H I cd A OH 1246a _ ls I A 1248b 00263196
FE cd NO FF 1253a
FE I I A
1257b 043468_1
CaMax: | Genscan: 1257b ACO07365 5.26.1.188 105.67776 .86719
FE NE HO HR
1260c 00325918
Ol I 1263b TPR0O00694
CaMax: | PCCA_H | 232000 | NM_000282 | PF00289 | IPR0O01882 PCCA 1267a UMAN 606054 PF02786 | IPR0O05479
PF02785 | IPRO05481
PF00364 | IPR0O0008S
IPR0O05482
CaMax: | PCCA_H 232000 { NM_000282 | PF00289 | IPR0O01882 PCCA 1267a UMAN 606054 PF02786 | IPR005479
PF02785 | IPR005481
PF00364 | IPRO00089 :
TPR005482
Fad cl 1270a
CaMax: | S24A_HU | 607183 PF04810 | IPRO07123 SEC24A 1272a MAN PF04811 | IPRO0689S
PF04815 | IPR006896
PF00626 | IPRO06900
IPR000694
FE FS HH
1273b 012223 1
EEA
1276a 012223_1
Frill 7 A HN 127b 027883_1 (all A — I 127b 00313779
CaMax: | Genscan: 1282b CAAAQI12 09745.1.1. 24557.315 9.16476
CaMax: | ENSRNO
El 3862
CaMax. | | I~Nmuis333] [oo 1
Ee Twos] TT [ 11 NH FO 1288a | NM_015384
Far M3 I 128a OUSE PF00183 | IPR0035%94 ar [sar ee Teed) | [ 1292c¢ UMAN PF02735 | TPR005160
PF03730 | TPR0O05161
CaMax: | SYEP_H . | 138295 | NM_004446 PF00749 | IPRO0D1589 \ EPRS 1294b UMAN PF03950 | IPR001412
PF00458 | IPRO00738
PF00587 | IPR000924
PF03129 | TPR002316
PF00043 | IPR004046
IPR002314
PRO04 154 ems es | 7 1299¢ NM._178583 | PFO0400 | IPRO00306
PF01363 | IPROQ0409
CaMax: | tremblnew 129b |AX40003 9_1
EE] I '129b 00265677 aE I 12a 00288263
FO al FO 1301a
FE cl OH ia 1304a
FF EH A
1308¢ 012223_1
EEE EE
1308¢c 00297641
CaMax: | ENSRNO
Cal I A 1463
CaMax: | ENSRNO
Elem 4354
Fr 1318a MAN — oe aa il ad 1322c AT [ESE 1323br | 09953_1
FEE I I
1323br | 00295955
Ea 1324a 09953_1
I
Cow lmeer 1335b 4087
EE
1335b 00321183 i cll NO a 1341a IPR001472 1
Fl DH HN FO 1352b | CCO or Rad: I NO hal 1354a PF03184 | IPR006695 rH FF 1355a 318340_1 iE I EE I 1355a 00324229
CaMax. | FUT8_HU | 602589 | NM_178157 | PF00018 IPRO01452 | Sigp | Tmhmm FUT 1361a MAN NM_178154 [PRO01472
NM_178155
NM_178156
NM_004480 fl EI A A 1364d 012223_1
Fc HO EO RE 1364d | 00304487
CaMax: | CTGL_H | 603399 | NM_003881 | PF00219 | IPR0O01525 Sigp WISP2 1366a UMAN PFO0093 | IPRO0086T
PF00090 | IPRO01007
IPRO00884
FE cl I il 1368a IPR000924 1Rik
Fl ld al il 1371a IPR0O06077
CaMax: | MPP8_H PF00385 | IPRO00953 137b UMAN PF00023 | IPR002110
TPRO01472 7 A NF 1381a 7350_1
FE I NH
1381a 00228938
CaMax: 602942 | NM_005665 | PF00566 | IPRO01687 EVI5 1383a IPRO00S1S [PRO00195 = 1384a UMAN IPRO05804 (EEE A I 1391a 00222271 vl 3 I NH wn 1394b | 00256429 1397b
FETE I WO
1399a 00318060
FENG NE
13a 00295709 [AE A 1400a 012223_1
CaMax: NM_014247 | PF00027 | IPR000595 PDZGEF1 1401c PF00595 | IPR0O01478
PF00788 | IPRO01895
PF00617 | IPROC0651
PF00618 | IPRO00159 fio Loomis 1403a 00231061
CaMax: | Transcript 1406a :ENST000 00298992 [CaMax: | BAGS H | 603885 | NM 004873 | PFO2179 [TPROO3103 | | [BAGS aos [oman | 1. 1 1 1 [ ere fom 1411a rc I NN Nhl 1415b 1Rik 1416a :ENSTO000 00336483
Fra I 1419a 00325584 ) a br d EE I I I I 141c 018999_1
CaMax: | Transcript 141c :ENST000 00307901
CaMax: | tremblnew 142.1¢c |AK00130 1.1
FE HN ON
142.1¢c 00311713
Fo El NO 1420¢ NM_020739 IPR(004238
CaMax: | MLTI_H | 604860 | NM_006785 | PF00531 | IPR007110 MALT 1421a UMAN NM_173844 | PF00047 | IPRO00488
PF00656 | IPR0O01309
FES HH HY A
1423b 790758 a ll i 1 ll I 1432¢ | MAN IPR0O01999
IPR002350
CaMax: | SPL1_HU | 606041 | NM_004684 | PFO0050 | IPR002048 | Sigp SPARCL1 1432¢ | MAN IPR001999
IPR002350
Ei I 1431a :ENST000 00296858
Fi 5 EH HY 144.2a 157990_1
Fred r H 144.2a | 00249297 ore 1448a MAN PF00086 | IPR002350
CaMax: | Z271_HU | 604754 | NM_006958 | PF00096 | IPRO01687 ZNF271 1449a MAN 601262 | NM_003415 { PF01352 | IPR0O07087 ZNF16
ZN16_HU | 606024 IPR007086 ZNF268 1 MAN 604753 IPRC00294
Z268_HU IPR001909
MAN
ZF64_HU
MAN
1450a MAN
Fl A I 1452a° | 00261976 1457b 69 real cad HEE EE BE BR
Fl lal al cl 145b MAN 1460a U93567_2 oral NW BE 1460a 00322543
Frail: iN I HH 1461a 049156_1
CaMax: | ENSMUS 1461a TO000003 - 0311
I
1466b 325902_1 fl I A 1466b 00222271
Fo dH i Gc 1469a
CaMax: | Y441_HU NM_014797 | PFO0651 | IPRO0O7087 ZNF450 146b MAN PF02178 | IPR000345
PF00096 | IPR0O07086
IPR000210
TPRO00637
FE ccd il 1469a
FE NH
1472a 00296084
Fala a 1475a AT
FE dl I Ga 1476a MAN IPRO00694
FE li lal NN 1477a UMAN '
Fil I HH NO 147b 00317517
CaMax: | HXA3_H | 142954 | NM_030661 | PFO0046 | IPR001356 HOXA3 1481c UMAN NM_153631 | - IPR001827
NM_153632 IPR002965
IPR0O00047
IPR000694 id NO Li 1482a
Fi I I 1484b UMAN
Fela ll WO RO Fd 1488b UMAN NM_031243 1
Fra 148a 00271717
CaMax: | swiss|SEC
Fc I
N
FE A
1497c¢ 00317675
FEE I NN
1500b 00322519
FEE 1 I EE 1504d 00278824
FEE I
1506d 061884 _1
Ea ER 1506d 00229488
FE id al NO si 1502 UMAN
Ea i I sd I I 1516a
Fd I A 15192 | 39
Fo WH DO A 1519a | 00311733
Con [msto0 |] 151b 00281131
BR i EE I 15202 | 267013_1 fH NN 1520a | 00261435
CaMax: NM_016147 TPR000734 11 15216 IPR003089
IPRO00639
IPRO00379
FE-57 H H 15220 | 154463_1
I OH
1531c | 154463_1
Comes 1 1532a | 0384221
FE I HH
1532a | 00272761
FE Ed 4 I 1534b | MAN NM_025114 IPR0O03900
CMe gpRo lL 1534b | VIN
FE A
15352 | 00277895
FE FH
1541a [oe [a | [ 1546b | MAN IPRO02293
FEA
1548¢c | 00254926 ,
EEA
15492 | 00294618
FE cl i HO NO 1551a
Fi A HH 1554c | 012223_1
FE cd cl RN A 1573a :
F730 A 1574b | 0122231
Fc NL 1574b | 00310739
Fr al id NO 1c 1577a IPRO08139
ENE ] 15782 | 28
Fl NN A 157b 7350_1
Foca: 1 I 157b 00228938
ESE ad HI NN ID ona | 8
CaMax: | Transcript 1591a ‘ENSRNO
T0000001 0671
SEE
1594a T0000006 0486
I NH HH
1596b 081111 _2 seme | 1 [1 1 1596b :ENSTO000 00319237
Fal NH HH HO 1598a CCO
Fal FY A A NO 159a AAE_1
Sel 159a :ENSTO00 00311190
FE oll il A 15b
Fo ce NO I NO 1602a
CaMax: | ENSDAR
Fa I 4018
FE ld 1626¢
Fa A A 1628d 00325761 rls) | [0 1629a [BCO2153 51
Fl EN 1629a 00229238
CaMax: | tremblnew 1630b |BCO2153 5_1
FE EE
1630b 00229238
CaMax: NM_014683 | PF00069 | IPRO00719 ULK2 1631d IPR0O02290
IPR0O01245
CaMax: NM_014683 | PFO0069 | IPR0O00719 ULK2
CA el
IPR001245
CaMax: NM_014683 | PFO0069 | IPRO00719 ULK2
CI ed (EE
IPR001245
FRG
1639a 8096
CaMax: | Transcript 1639a :ENSTO000 00329369 ;
NM_017967 er] [Tm me mm 1646a PF02882 | IPR000672 1
PF01268
Cai] | | vrooso |TROO0E [Sep
ST TT I A RA A SU EU — I
CaMax. | MI2B_HU | 139111 | NM_002090 | PF00048 EE I 164c MAN IPR002473 [PR001811 crear ol I I RE I 1659a | 7162_1 lv I NH EO 1659a | 00316200
Fl I cad ll OY I AR HN 166a [ii 2 I tH 1671b | 012223_1
CaMax: | Transcript 1671b | :ENST000 00329369 [EAE + I NN I HF 1675a | 00321491
Fak NN I NN 1676a | 081104 2
FEE HE NN I A
1676a | 00299933
EEE 4 NN NE A 1678a | 00307746
BEE
16822 | TOO00001 5118
FSi HH 168¢c MAN
Fl lil NO il 1690a | T
FF al al 1691b IPR0O02562 7d dc il NO cl 1692a | T
CaMax: | FGR2_H | 176943 | NM_022971 | PF00047 | IPRO00719 | Sigp | Tmhmm | FGFR2 1693b | UMAN 101200 | NM_022974 | PF0O0069 | IPR001245
BFR2_HU | 101600 | NM_022976 IPRO07110
MAN 123150 | NM_022969 123500 | NM_022972 ‘ NM_022973
NM_000141
NM_023028
NM_023029
NM_022975
NM_022970
NM_023031
NM._023030 72d HH 1696a | 32 fl EH A 1696a | 00259146
EE
16b 00303924
CaMax: | CAR6_H NM_032587 | PFO0619 | [PRO01687 CARD6 17052 | UMAN IPRO01315
IPR001472
CaMax: | Genscan: 1709a | AC09196 6.3.1.9129 6.20868.4 6788
CaMax: NM_018227 | PF00899 | IPRO0C0594 wl] PEER
IPRO00205
Fl NT NS HB 1715a 00299230 '
El a I EE 1717a rd Md Bd I tah 1721a MAN IPRO01472
CaMax: | GOA4_H | 602509 | NM_002078 | PF00904 | IPRO06162 GOLGA4 17222 UMAN 270150 PF01465 | TPRO01990
IPRO00354
IPR0O00237
IPR0O01472 rl I 1 el i NO 1724a NM_007369
FE A
1725a 00026952
F=f I A 1726a 012223 _1 [EEE 8 I NH 1726a 00325761
CaMax: 606101 | NM _032571 | PF01825 | IPRO00152 1} Sigp | Tmhmm 1727a NM_152939 | PF00002 | IPROO1881
PEO0008 | IPRO01740 ' IPRO00332
PRO03056
IPRO06209
IPR0O00203
FE A HH
1730a 00222271
ENE
1738b 00318296
Fil 2 I I 1741a 00221700
CaMax: | LGR4_H 606666 | NM_018490 | PF01462 | IPR007087 | Sigp | Tmhmm GPRA48 1744a UMAN PF00560 | IPR002131
PF00001 {| IPRO00276
IPROO1611
TPRO00372 a le 1744a UMAN
Cores
Fd ta | MAN
Fa 1750a 00282228 oe loan 1751a 00319353
CaMax: | Genscan: 1755a AL.109926 .9.1.11429 8.7096.11 4020 = sie | MAN HE
CaMax: |__| | NM 017658 | PFO0651 [IPR000210 [ | ~~ ~~ [BTBD5
SUF TS ES ES RS NA ER ER EE
1760c 648027_1 8 I I I I 1760c 00326555 wre | | 1 [[ [ 1772a TO000005 3459
Fd el 1775a UMAN
Fl id dO A cB 1775a UMAN
CaMax: | Transcript 1778c :ENSTO000 00315390 a i al
Fn I al I ed id il 4 BO i 178a | IPR001472
See 1794a 09
Fal A A HO 1794a 00310739
Fr A HH 17a 012223_1
Fl HE A FO 1800a 00320480
CaMax: | CLPX_H NM_006660 | PFO0004 | IPROO1687 | Sigp CLPX
Cl d= ad I
IPR0O03959
Fl I i FA I I 180a PF03184 | IPRO06695 a HO il 1810a
Fad A HH 1811b 4087
CaMax: | SIL6_HU | 604405 | NM_001245 | PE00047 | IPR003006 | Sigp | Tmhmm SIGLEC6 for eg
IPR0OQ1472
CaMax: | AMD_HU | 170270 | NM_000919 | PF01082 | IPR002086 | Sigp | Tmhmm PAM 1814c MAN NM_138766 | PF03712 | IPR0O0C0323
NM_138822 | PF01436 | IPR000720
NM_138821 IPR0O01258
FETE ul HN I A EE 1814c VIN
Fal NI NH NO 1818a 00324450
FE Sa a cl I li 1828b USE PF00193 | IPR0O03006
Fa 1834b 293286_1
I
1849d 790758
CaMax: | Transcript
Lil 00333606
EE OO cd I 1853a
CaMax: 606833 | NM_170606 | PF02178 | IPR000194 MLL3 185%a NM_021230 | PFO0S04 IPR000345
PF00628 | IPRO00637
PF00505 | IPR0OC0910
PF05964 | IPR001965
PF05965 | [PRO01214
PF00856 | IPR000354
IPR001472
TPR000694
CaMax: | swiss[PEN
Bd
N
Ina EN I I I 1863c 00222266 = wo 186a PF02209 | IPRO03128
Fr 1874b 648027_1
Fl A 1874b 00326555
Fe 1d 1879a 648027_1 fl I 1879a 00326555
Flt WO A 1881b | 00253814 -
CaMax: NM_021927 | PFO0O009 | IPRO01687 1894a PF03144 | TPRO00795 - | PFO0679 | IPRO01806
IPR000640
IPR004161
Fl A 18a 012223_1
Fl I NF 1912a 019022 _1
Fall WE 1912a 00318072
CaMax: | swiss|CO ck 1
AN
FE A NN BW
1913a 00299886
CaMax: NM_173082 | PFO0176 | IPRO00345 SHPRH 1917f PF00538 | IPR0O01841
PF00628 | IPR0O00330
PF00271 | IPR0O01650
IPRO05818
TPR0O01965
CaMax: NM_080927 | PF00431 | IPR0O00859 Tmhmm 1919a PF03815 | IPRO00421
PF00754 | TPR004043
E25 I I EN I A 1920a
CaMax: | ENSMUS dal 1864 1929¢ MAN [CaMax: | | | ~— |PFooi68 [PRO00008 | [Tmhmm
(19302 | SS A A DE SU — i d= 1 I FO 1940e PF00560 | TPRO00938
Sel [oe gg re [ov [TE] 1941e | NM_080546 rl dl 1 I 1943a IE PEO0412 | IPR0O01478
A I NE FO
1944a | 025270_1 rl EN I NN 1944a | 00319557
Fa J EI A EE 1945a | 748505
Fl I HF 1945a | 00312037 fll I A A A 1048b | 748505 fl EE IN EO NE 1948b | 00312037
Fl FH EH 1949a | 86 {alt EN NN A 1949a | 00320480
CaMax- | VAV3_H | 605541 | NM_006113 | PR00307 | IPR002086 VAV3 1950a | UMAN PF00621 | IPRO02219
PF00169 | IPRO01331
PE00130 | IPR000980
PF00017 | IPR001452
PFO0018 | IPRO03096
IPRO01849
IPRO01715
IPRO00219 [me 1953a | UMAN PF04905 | IPRO06988
PF04002 | TPRO0698Y
Fil HN EN 1954¢ | 00321787
CaMax. | MADL H | 603755 | NM_007323 | PF01363 | IPR0O00345 MADHIP 1961e | UMAN NM_004799 IPRO00306
NM_007324
CaMax. | TAP2 HU | 170261 | NM_000544 | PFO0664 | IPRO0L687 | Sigp | Tmhmm | TAP2
J [BE
IPR001140
FH ih WO HN 1968a
CaMax. | CAIB_H | 120280 | NM_080629 | PF02210 | IPRO0IGBT | Sigp COL11Al 19822 | UMAN 604841 | NM _080630 | PF01391 | IPR001230 154780 | NM_001854 | PF0O1410 | IPRO08160
TPRO008SS
TPR003129
IPRO01791
Ey 1989b | 030650_1
Fadil Fr I ial 1990a PF03271 | IPRO04953
Fil EH I A 1991d | 00244096 aE - la 00322438
EE ESO I EE SE RS EN I
Gl NN NE
So Ec NH NO
PF02188 | IPR003109 sending
Fld od IO ci il 20132 | MAN
CaMax: | ENSMUS 2014f | T0000002 8222
CaMax- | RLA_HU | 180479 | NM_000968 | PF0O0573 EX 2015e | MAN IPRO02136
IPRO01472 rl al al A tA il 2020b | UMAN PF00780 | TPRO01180
Fl Sal A HN I 20206 | OUSE
FH cd li i I il 2022a
Fl A HF 2023b | 008100_1
Fl NN NE 2023b | 00312547
Fl 8 I NE EO 2024a | 00314543
Fl cl 2034a [Se 2035d | UMAN PE01096 | IPRO01529 ee 11 TT 1 204a 00276230
Fl ad td al I 2056d | UMAN IPRO00571
Ex IE 2059b | 00282218
EEA
205a 00276230
CaMax: NM _016081 | PFO0047 | IPRO00634 2070a IPRO07110
IPRO02965
IPRO00694
Fa i I I I NF 2073b | 012223_1
CaMax: | Transcript
Eu I 00320621
CaMax: | ASAl_H NM_006095 | PR00702 | IPR001687 Tmhmm | ATP8A1 2074b | UMAN PF00122 | IPRO01757
IPRO08250
IPRO05834
CaMax: NM _178043 | PF05383 | IPR001199
NM_018078 [EAE + I I 2076c | 00324643
Fd la 2078a | MAN IPRO0C0038
FE
2083e NM_178350 | PEO1363 | IPRO00306
7 dt ial RY 2088a 2092¢ 790758
A HH
2095a 00258969 elem | [1 2099%a SF30_HU
MAN a I I A NO = 2099%a 00239010 lH HO NR 20a 001284 1
Fl HH HE 20a 00318446
CaMax: | FBN1_H 134797 | NM_000138 | PF00008 | IPRO00152 ‘| Sigp FBNI1 2100b UMAN 154700 PF00683 | IPR006209
IPR0O07087
IPR0O01881
JPR001438
IPR002212
Fars NN NH 2105a 00319412
CaMax: | Transcript [dl A 00314393
Ei: I NN NO 2109a 00324450
Fi da + A NO ial 2110a MAN IPR0O07086
Fil IN I 2113a 00324450
CaMax: | MRP1 H | 158343 | NM_004996 | PF00664 | IPRO01687 Tmhmm ABCC1 211% UMAN NM_019901 | PFO0005 | IPRO00719
NM_019902 TPR003439
NM_019898 IPRO01140
NM_019862
NM_019900
NM_019899
Ea EE 2122a 00321873
FI ad i i ia 2123a TPR0O00109
CaMax: NM_020239 | PF00786 | IPRO0009S
El I ad a il I I
FE NY I
2132a 00175091
Ea a 2135d 00325604
ENE
2136b 00294665
CaMax: | ENSMUS
Cl 0642
CaMax: | Genscan: 2142a CAAAO010 04319.1.1. 45274.201 6.41736
Same ENSTOO | [1 rr = EN NE SS NS A ES
Cl id I 2161c NM_032239
FH
2165a 00244769
Fall I I NE 2167a 00278483
Fall NB 2189b 00309655
Em 2198b T0000000 0642 (El I 2201a 00244769 (5 lH 2201a 00244769
FE 2 NI A I 2205a 00274054 [al I HO 2210a 00244769 1 cfd al 2222b
HEE
2223a :ENST000 00228330
CaMax: 604283 | NM_005807 | PF01033 | IPRO00585 | Sigp PRG4 2224a PF05001 | IPRO01212
PF02818 | IPR002965
PFO0045 | IPRO04168
TPRO00684
IPR0O01472
FI id A 2225b IPR0O06663
Fl ad a += al 2234a QUSE TPR002120
Ell EE 2235a 00296412
FE NO NO
2235a 00296412
CaMax: | CN3A_H | 123805 | NM_000921 | PF00233 IPRO02073 Tmhmm PDE3A
Sr os ep
IPRO01917
CaMax: | CN3A_H 123805 | NM_000921 | PF00233 | IPRG02073 Tmhmm PDE3A 2241a UMAN IPRO05829
IPRO01917
CaMax: | CN3A_H | 123805 | NM_000921 | PF00233 IPR002073 Tmhmm PDE3A 2238a UMAN IPR0O05829
TPRO01917
Foal I JE 224a F8L1B_1
CaMax: | swiss|LIN 2251d 1_NYCC 8) £5 cd 2252b — 2258a | 00245479
El — 2258a 00245479
7 I I I HA 2258a 00245479
Cal I NA I a EE 2254 16
CaMax: | ENSMUS 2264b T0000000 0642
CaMax: | ENSMUS 2264b T0000000 0642 ll I NH NO 2266b 00306715
CaMax: | TSP1_HU | 188060 NM _003246 | PF02210 | IPR006209 Sigp THBSI1 2267a MAN PF00093 | IPRO01007
PFO0090 | IPRO00884
PFO0008 | IPRO03129
PF02412 } TPR0O03367 . PF05735 | IPRO01791
Fa I AH A 231a 00317584
Fa BB OL 2331c 00296412
Si EE A 2341b
FE
2351c 00319965
Fi NO A HE 2351c 00319965
CaMax: | CN3A_H | 123805 | NM_000921 | PF00233 IPR002073 Tmhmm PDE3A 2241a UMAN IPRO05829
IPR0O01917
CaMax: | Genscan: 235a RNORO10 69968.119 47.48582
CaMax: | TSP1 HU | 188060 | NM_003246 | PF02210 IPR0O06209 | Sigp THBS1 2374a MAN PF00093 | IPR001007
PF00090 | IPRO00884
PF00008 | IPR003129
PF02412 | IPR003367
PF05735 | IPRO01791
CaMax: | Genscan: 238a AC01660 1.7.1.1452 64.1553.2 0016
CaMax: | SPCN_H 182810 | NM_003127 | PF00435 | [PR002048 SPTANI1 2392 UMAN PF00018 | IPR000276
PF00036 | [PRO01452
PR0O02017
Ea al al ve Ml al WO I Si 23a UMAN NM_024482
FO c+ 240a PF05965
FN ES
243a 012223_1
CaMax: NM_144972 | PF00056 | IPRO0L557 245a PF02866 | IPR001236
IPR0O00205
IPR000594
Cac |_| |i oszil [procore |PROOSO4 | {Tf
ST TT wee a NI HN 24a 00239392 [Eat J I NO A NO 258a 790758
Frat A HH HH 261c 50
Fall I FO FO 261c 00322543
CaMax: | TENA_H | 187380 NM_002160 | PFO0008 TPR006209 | Sigp | Tmhmm TNC 267d UMAN PF00041 | IPR002049
PF00147 | TPR0O03961 .
IPR002181
FO cd acd OO ci 272d
EES
27a TO000000 6484
CaMax: | Genscan: 28s NA26110. 1.701.151
Fl dl ll i 307b UMAN
FE lc aN ad 308c
Ea Er I EE I 310h OUSE
Ea EE I 311c 00315874
CaMax: { Genscan: 313a AL136225 .8.1.42171 .4910.172 . 11
Eom I I NO 314a 00303575
CaMax: | ENSRNO 3190 T0000002 2117
Fel] I 320a MAN NM_178237
Eada a 320a MAN
Ee [ 322a T0000002 2117
Ev al 41 HN I il 324a PF02809 | IPR0O03903 i er | fr [eT 326e OUSE IPR0O01733 pending
Elta 327% 62
EN HF
327% 00315821
CaMax: NM_016081 | PF00047 | IPR000634 328b IPRO07110
TPR002965
IPRO00694
Forres A A EA RA I EN DU RE
FETT I I NS SS SA RU I
FH NN HA I
33a 024093_1
CaMax: | ENSRNO
Eo I HE 6836
CaMax: | swiss|PTN 340a 3_HUMA
N
Fl I 340a 00262539
FE I
343b 033094_1
FE I HE NO
343b 00269073
Fd I HF NO 34a 17
Fv I FO I A 34a 00316410
Fl le ld NO 106a MAN
Fl ed lal NO NO 106a MAN
CaMax: | tremblnew 360a [AK 09446 1.1
Fa I A NA 360a 00291220
CaMax: | EWS_HU | 133450 | NM_005243 | PFO0076 TPR0O01064 EWSR1
Ell al
IPRO01876 alin In 370a ANFA
Con [Aum RU] |NMOGRI[EO0SD [ERO] | [MR 374a MAN
Edi 375d ANFA
Ea 379a 00278407
Fa oad id 38a
Ei 2 EE I HR 391a 00293648
CaMax: | tremblnew
Ea
S5_1
Fl 392a 00319311
Foal a — 395a 051886_1 on on 395a 00323751
Coal E225 I — 397b UMAN
Ea
Co wg] 406a-r X3_CAN :
Caen | Tramerpt | 1 [
ia 3 NE I A NE 00332194
Fa I HF FO 408a UMAN
Eka NN 409a UMAN
Fall ced ili ia 415b MAN rll NH WS 421a 790758
Ee pee Ee 43a
Fa NR 446f 00239392
Fl dH NH NN 44c 019226_1
Fl HF HH 44c 00264258
Fl A HE 45.1b 007837_1
Fal NY I 45.1b 00314138
CaMax: | tremblnew
El I I 132_1
Fora A I NH 450a 00325086
Ful I I NH 452a 00218713
FE oN NF 455¢ 028178_1
Fall I NH 455¢ 00317856
FE I NH
457¢ U93569_1
CaMax: | NFT5_HU | 604708 | NM_006599 | PF00554 IPRO00451 NFAT5 459a MAN NM_138713 | PF01833 | IPR002909 : NM_138714 IPRO01472
NM_173214
NM_173215
CaMax: | swissnew 461a SF30_HU
MAN
FE NH I
461a 00239010
Fl ad dll NO Cli 464b UMAN
Fl 5 lal 465b PF00041 | IPRO07110
Fl I HH EN 46a 00282493
CaMax: | tremblnew 472a [BCO1981 0_1
Een 472a 00327301 ia | OviAR Ll
CaMax: | Genscan: 482a APO0S117 2.1.14879 0.13386.9 5160
CaMax. | ARH2_H | 607560 | NM_004723 | PFO0L30 me | 0 487a UMAN PFO0621 | IPR001849
PF00169 | TPR0O00219
Fr al NO 488a UMAN PF03727
Flo I EN I A 48b 019226_1
Fal I NN EO 48b 00264258
Fal I I 490c 088660_1
Sem 1 490c¢ T0000002 ‘ 5796
Fl I HH ROC 494a AB461_1
Se 494a 00324722 seme | | | [ 498a TO000001 1463
CaMax: | swiss|RL3 50.1¢c 1_HUMA
N
Fil EE 50.1¢c 00264258
CaMax: | ENSMUS 501b TO000005 0981 ove meme | |] [ 504a 00267434
Fl A I BH 505b 00248673
CaMax: | ENSRNO 507a TGC000001 6310
Ell 516¢ -ENSTO000 00328854
CaMax: | Transcript fal 00328854
Fld EW 51a 072691_1
Comme | | CT 51a 00321758
Erol EE I ll sll I I 520a
Ca
Fal 523a 00300162
El I 52a 00242208 oar | PSAs FU | T7690 | NM 15213 | PROGET |PROOGAsS | | | PSMAS so TWAN wees [voorm | [wromm [LT all NH A 538a 00283629
CaMax: PF00069 | IPR0O00719
ESTE
IPR001245 glad CI 540a 0033 all. lI HH BO 543a 74 545a TPR0O08139 . al ci d+ I 547¢c IPRO01472
I cd 1 HN 548c TPRO01472
CaMax: 605975 | NM_005839 | PF01480 IPR002965 SRRM1
Cl dl + I : IPR001472
Fv EH 552a 00318468
Fd oll NN 553b
Fd dl A 53 555b FBX1.3B
CaMax: | tremblnew 556b JHSM805 356_1
FE I I
557b MAN :
Foal I HW 558a 352051_1
Foal 1 HE I 558a 00319272
Fa 560b UMAN
Fl 561b 00296499
CaMax: | trembl|CF a I 1
Ele I I 568a 00225430
Eada 56a 511552
ERE EE
56a 00202773
CaMax: | EML4_H 607442 | NM_019063 | PF03451 | IPR002048 EMLA 571a UMAN PF00400 | IPR0O01254
TPRO01680
PRO0OO560
IPRO05108
Eval 4 EN I A 574a 00296412
Fld dc 579a MAN TPR0O01472 57a MAN 226730 PF00357
Fal NE
CaMax: PFO0030 | IPR006209 | Fal 583e PFO0041 | IPRO0CCO83
TPR0O02086
PR0O03962
TPR003961
Fa NI NN 58a 00313783
CaMax: | FALZ_H 601819 | NM_182641 | PR02791 PR0O01687 FALZ 597¢ UMAN NM_004459 | PF00628 PR000345 . PEO0439 | TPRO01487 ) IPR006209 : PRO01965
TPR004022
IPR0O00694 ms 59a SMO2_M
OUSE
Fal I EH I EO 59a 00230324
CaMax: | Genscan: 04784.371 6.7206
CaMax: | Transcript
Gill I I 00256653 -
Ea] 622a 52
CaMax: | Genscan: 622a AC10793 9.5.1.1452 64.83212. 131724
CaMax: | IQGI_HU | 603379 | NM_003870 PFO0307 | IPR001936 IQGAP1L 623a MAN PF00397 | IPR001202
PF00612 | IPRO01715
PF00616 | IPRO00048
PF03836 | IPRO00593
CaMax: | ENSMUS 624b T0000005 8265
Ea 626a 046507_1 commer | | [| [ 626a 00261631
EE ET hil hd I a Fall 628a UMAN NM_032045 B]
CaMax: 605975 | NM_005839 | PF01480 | IPR002965 SRRM1 635a TPR002483 .
IPR0O01472
Sy [ 638b UMAN
EE a 639a 00309558
Fl 4 I NS I 63a 259036_1
CaMax: | Transcript 63a :ENSTO000 00332194
Fd FH 64.2a MAN _81-
Fl i a il HL 685a MAN
AC EE I I NH I
690a 00244411
Flt I NF 690a 00244411 43-1 692a PF03184 | IPRO06695 rd I al 4 EO 697a CC IPR0O01394
QR ld HN NS HE 6b USE
Ft cs il 701a 11Rik 704b PF00612 | IPRO00048 po or a [ 704b IE PF00612 | IPRO0C0048
Ets: HE NE WO I 70d 00323467
EEE i I 710a UMAN 156500 PF00386 | IPRO08160 184250
Eval Ed EE I EN
Tila 019226_1
Campero 711a 00264258
Era of I I HB 713a 008338_1
Ea a 713a 00012559
CaMax: | Genscan: 714a AL391495 .16.1.1429 52.28457. 34558 a1 718a 00299020
Somme 1 1 1 720a ANFA
CaMax: PF00063 | IPROOL687
ET mmm
IPRO00048
CaMax: | GDC_HU | 139080 | NM_152707 | PF00153 IPR001993 SLC25A16 726b MAN TPR002167
IPR002067
BEEF
72a 007442_1
So es | ||| HE 72a 00250454
EE A HH
731a DNAW_I commer 1 1 731a 00275603
Cdl vio HO 736a UMAN el ll HO 739a
Fl dl al Ml Gl 73b MAN . IPR0O03689
Fc HI NO RO 7452 00315919 i 51H HH HL
Cafe] | | Naorsans
Cr a 749a 00294890
CaMax: | ENSRNO 0282 co I cd ll NO NO — 753b 2Rik
Fr I HH EN 759b 704781_1
Fl I I 759b 00261981
Eels I EE 764b 002413_1 ame | | | [1 764b T0000000 5190
El I cd I 765a '
EH EE NN
768a 00325727 eR oT 76b 00275248 ]
CaMax: | PRIO_HU | 176640 | NM_000311 | PF03991 | IPRO00817 Sigp | Tmhmm PRNP 785b MAN 123400 PF00377 600072 137440 603218 ; 245300 606688 welmeel | 1] 788a T0000002 9203
FY A Ol i 789a ia | MAN 1
EG ll dA 795a
Fc I lid 810a MAN a ee | |p 813a 00222567
CaMax: | Transcript 815a :ENST000 00272273
Fria I 8la 00252102
FE A EO
820a 012223_1 (oul 820a 00325761 (all rd I 827b 147999 _1 [Call I 827b 00269485
CaMax |BNSTOOO | 1 [
PTW 77 A I A NN I SS
EH HN NN I FN
82b 00252102
Ser LTT 831la 019226_1
Fra I I NN NW 83la 00264258
CaMax: PF0O0039 | IPR0O06209 Fnl 832a PFO0041 | IPROC00O83
TPR0O02086 - TPR003962
TPR0OO3961
FE lc OO HA cl BN 833a
Fl A I 835¢ CCO
FO ial NN 839a ;
Fd I I 841b 072691_1
Fl A 841b 00321758
Fe EF 847a 170044 _1
Fs cal ct , 85.1c
Ex I a 85.2b
CaMax: | Genscan: 850a AP000813 4.121081 6.38383.4 2179
CaMax: | Genscan: 851a AP000813 4.121081 6.38383.4 2179
FE ad Vl Ll 856¢ UMAN
Foal ld lA EO 863c OUSE : IPR007086
FES ld a 14 il 890a UMAN IPR0O01806
FG A I
8a 00254942
Ea 905a 00231061
EA
906a 790758
Fra I 907a UMAN : 909a MAN NM_138766 | PF03712 | [PR000323
NM_138822 | PFO1436 | IPR000720
NM_138821 TPR0O01258
Ell a a 90c OUSE PF00183 {| IPR00359%4
Fal HA 911a 012223_1 al I WR EO 911a 00292530
Il A NO 912b 83 ac HF NF I HO 914a 29 all HW 914a 00273342
CaMax: | swiss|AL 915a U6_HUM + | AN all I I A 915a 00262877
Fd cd ld 919%
FH EF
91f 8694_1
Fi EE 91f 00231004
Fl cil lil ll 919%b
El =A EC = I wl 92¢ NM_003743 | PF00989 | IPROC0014
NM_147223 IPRO01472
Fu id cal OO iil 935b UMAN
FE A
936b 008233_1
Fr i I I A I A 936b 00316232
FO cil 945a
Fd HO 947a 310153_1 . ill 947a TO000000 5605
Fd HO I 949¢ IPRO00OS51
I FT id I NO il 953a OUSE 4Rik 1 cc 963¢
Eid HE EE 96e MAN
FE EE
981a 790758
Fl 984a 7185
Ell Jl EE. 984a T0000004 8377 (Ell i= 4 ia 986a UMAN PF02984 | IPRO04367 ol oil ll =: I I 990a UMAN IPRO01472
CaMax: | remblnew wml 11] 1 [CaMax: | | 606457 | NM 015525 | Pro0o23 frrootes7 [| [| 0000 _85-
“TT | Tem]
PF00651 | IPR002110 [PR0O00210 996a MAN TPR001848
[0052] One embodiment of the invention relates to a combination comprising two or - more polynucleotide molecules selected from SEQ ID NOs:1-1558, or fragments thereof.
Preferably, the combination comprises about 10 or more polynucleotide molecules, more preferably about 50 or more polynucleotide molecules, more preferably about 200 or more polynucleotide molecules, more preferably about 400 or more polynucleotide molecules, more preferably about 1000 or more polynucleotide molecules.
[0053] In a preferred embodiment, the invention relates to a combination of 396 differentially expressed polynucleotide molecules, whose sequences are represented by SEQ ID
NOs:1-396. Table 3 identifies a list of gene sequences determined from clinical samples to be differentially expressed in OA versus normal subjects to a degree that is statistically significant (p <0.05). Table 3 includes the gene IDs, expression values, standard deviations, and fold difference of expression (OA versus normal). Preferably, the combination comprises two or more of polynucleotide molecules selected from SEQ ID NOs:1-396 or fragments thereof.
[0054] In a particularly preferred embodiment, the invention relates to a combination of 217 differentially expressed polynucleotide molecules, whose sequences are represented by SEQ
ID NOs:1-217. Table 4 identifies a list of gene sequences determined from clinical samples to be differentially expressed in OA versus normal subjects to a degree that is highly significant (p < 0.01). Table 4 includes the gene IDs, expression values, standard deviations, and fold difference of expression (OA versus normal). Preferably, the combination comprises two or more of polynucleotide molecules selected from SEQ ID NOs:1-217 or fragments thereof.
[0055] According to an aspect of the invention, one or more oligonucleotide or polynucleotide probes for interrogating a sample may be prepared using the sequence information set forth herein for any of the 1558 isolated gene fragments (SEQ ID NOs: 1-1558).
According to another aspect of the invention, probes may be prepared using the sequence information available for any of the genes or gene fragments identified in. The probes should be of sufficient length to specifically hybridize substantially exclusively with appropriate complementary genes or transcripts. Preferably, the oligonucleotide probes will be at least about 10, 12, 14, 16, 18, 20 or 25 nucleotides in length. In some embodiments, longer probes of at least about 30, 40, 50, 60, 70, 80, 90 or 100 nucleotides are desirable, and probes longer than about 100 nucleotides may be suitable in some embodiments. Preferably, a collection of two or more nucleic acid probes for detecting expression of gene products differentially expressed in
OA is provided, more preferably a collection of about 10 or more probes, more preferably a collection of about 50 or more probes, more preferably a collection of about 200 or more probes, more preferably a collection of about 400 or more probes, more preferably a collection of about 1000 or more probes.
[0056] In a preferred embodiment of the invention, one or more oli gonucleotide or polynucleotide probes may be prepared using the sequence information set forth for any of SEQ
ID NOs:1-396. Preferably, one or more oligonucleotide or polynucleotide probes may be prepared using the sequence information set forth for any of SEQ ID NOs:1-217.
[0057] In certain preferred embodiments of the present invention, immobilized nucleic acid probes may be used for the rapid and specific detection of nucleic acid molecules and their expression patterns. Typically, a nucleic acid probe is linked to a solid support and a target nucleic acid (e.g., a genomic nucleic acid, an amplicon, or, most commonly, an amplified mixture) is hybridized to the probe. Either the probe, or the target, or both, can be labeled, typically with a fluorophore or other tag, such as streptavidin. Where the target is labeled, hybridization may be detected by detecting bound fluorescence. Where the probe is labeled, hybridization is typically detected by quenching of the label. Where both the probe and the target are labeled, detection of hybridization is typically performed by monitoring a color shift resulting from proximity of the two bound labels. A variety of labeling strategies, labels, and the like, particularly for fluorescent based applications, are known in the art.
[0058] Another aspect of the invention relates to one or more probes comprising polypeptide binding agents that specifically bind to polypeptides produced by expression of one or more nucleic acid molecules comprising sequences selected from SEQ ID NOs:1-1558 or fragments thereof. According to another aspect of the invention, protein binding probes may be prepared using the sequence information available for any of the genes or gene fragments identified in Table 2. Preferably, a collection of two or more polypeptide probes for detecting expression of gene products differentially expressed in OA is provided, more preferably a collection of about 10 or more probes, more preferably a collection of about 50 or more probes, more preferably a collection of about 200 or more probes, more preferably a collection of about 400 or more probes, more preferably a collection of about 1000 or more probes.
[0059] In a preferred embodiment of the invention, probes comprising polypeptide binding agents specifically bind to polypeptides produced by nucleic acid molecules comprising sequences selected from SEQ ID NOs:1-396. In a particularly preferred embodiment, probes comprising polypeptide binding agents specifically bind to polypeptides produced by nucleic acid molecules comprising sequences selected from SEQ ID NOs:1-217.
[0060] Assay techniques that can be used to determine levels of a protein in a sample are also well known to those of skill in the art. Such assay methods include radioimmunoassays, competitive-binding assays, Western blot analysis and ELISA assays. In the assay methods utilizing antibodies, both polyclonal and monoclonal antibodies are suitable for use in the present invention. Such antibodies may be immunologically specific for a particular protein, or an epitope of the protein, or a protein fragment, as would be well understood by those of skill in the art. Methods of making polyclonal and monoclonal antibodies immunologically specific for a protein or peptide are also well known in the art.
[0061] Preferred embodiments of the present invention may utilize antibodies for the detection and quantification of proteins produced by expression of the polynucleotides described herein. Though proteins may be detected by immunoprecipitation, affinity separation, Western blot analysis and the like, a preferred method utilizes ELISA-type methodology wherein the antibody is immobilized on a solid support and a target protein or peptide is exposed to the immobilized antibody. Either the probe, or the target, or both, can be labeled. A variety of labeling strategies, labels, and the like, are known in the art.
[0062] In particularly preferred embodiments of the invention, expression patterns or profiles of a plurality of genes differentially expressed in osteoarthritis are observed utilizing arrays of probes for detecting target nucleic acids or proteins. In one embodiment, arrays of oligonucleotide or polynucleotide probes may be utilized, whereas another embodiment may utilize arrays of antibodies or other proteins that bind specifically to the differentially expressed gene products. Such arrays are commercially available (e.g,. through Affymetrix, Inc., Applied
Biosystems, Inc., Agilent, Inc.), or they may be custom made according to known methods, such as, for example, in-situ synthesis on a solid support or attachment of pre-synthesized probes to a solid support via micro-printing techniques. In preferred embodiments, arrays of nucleic acid or protein-binding probes are custom made to specifically detect transcripts or proteins produced by two or more of the 1558 differentially expressed genes or gene fragments described herein. In one embodiment of the invention, arrays of nucleic acid or protein-binding probes are custom made to specifically detect transcripts or proteins produced by two or more of the genes or gene fragments identified in Table 2. In a preferred embodiment, arrays of nucleic acid or protein- binding probes are custom made to specifically detect transcripts or proteins produced by two or more of the 396 differentially expressed genes or gene fragments identified in Table 3. Ina preferred embodiment, arrays of nucleic acid or protein-binding probes are custom made to specifically detect transcripts or proteins produced by two or more of the 217 differentially . expressed genes or gene fragments identified in Table 4. [0063) Preferably, a collection of two or more nucleic acid or polypeptide probes for detecting expression of gene products differentially expressed in OA is immobilized on a support in discrete locations, more preferably a collection of about 10 or more probes, more preferably a collection of about 50 or more probes, more preferably a collection of about 200 or more probes, more preferably a collection of about 400 or more probes, more preferably a collection of about 1000 or more probes.
[0064] Since chondrocytes represent the cellular component of cartilage, a tissue affected by OA, the construction of a chondrocyte array may represent a powerful tool to study the gene expression profile of osteoarthritic chondrocytes. The use of differential display for transcript selection was used by the present inventors to enrich the clones represented on an array for transcripts associated with OA.
[0065] In one aspect of the invention, methods are provided for assaying OA-associated nucleic acids in a sample. Preferably, a combination comprising one or more polynucleotide molecules selected from SEQ ID NOs:1-1558, more preferably selected from SEQ ID NOs:1- 396, more preferably selected from SEQ ID NOs:1-217, are used to prepare probes that are hybridized with nucleic acids of a test sample, forming hybridization complexes that are detected and compared with those of a standard, such that differences between the sample and standard hybridization complexes are indicative of differential expression of nucleic acids in the sample.
In a preferred embodiment, nucleic acid probes are made to specifically detect transcripts or fragments thereof produced by one or more of the genes or gene fragments identified in Table 2.
In certain preferred embodiments, the nucleic acids of the sample may be amplified prior to hybridization.
[0066] In another aspect of the invention, methods are provided for assaying OA- associated polypeptides in a sample. Preferably, polynucleotide sequences selected from SEQ
ID NOs:1-1558, more preferably selected from SEQ ID NOs:1-396, more preferably selected from SEQ ID NOs:1-217 are used to prepare protein-binding probes that specifically bind to translation products of those polypeptides or fragments thereof. These probes are reacted with a test sample, forming binding complexes that are detected and compared with those of a standard, such that differences between the sample and standard binding complexes are indicative of differential expression of polypeptides in the sample. In a preferred embodiment, protein- binding probes are made to specifically detect polypeptides or fragments thereof produced by one or more of the genes or gene fragments identified in Table 2.
[0067] According to certain preferred embodiments of the invention, the assays . described herein for the detection of OA-associated transcription and translation products may be used in methods useful for determining a diagnosis and/or prognosis for osteoarthritis in a patient. According to an embodiment of the invention, a typical diagnostic test will comprise obtaining a sample of cells or tissue from a patient in which OA-associated gene expression is expected to occur. Such cells or tissues include, but are not limited to, cartilage tissue and chondrocytes. The sample is then analyzed for either 1) increased or decreased expression of one or more selected genes, via detection of mRNA or protein, or 2) a particular gene expression profile, for example, via gene or protein array technology, as described herein. Such a diagnostic procedure should lead to a determination of whether indications of osteoarthritis are present in the patient.
[0068] In another embodiment of the invention, the diagnostic procedures described herein may also be extended to provide prognostic information regarding a patient’s recovery from OA, or to monitor a patient’s progress in response to a therapeutic regimen. In these situations, the diagnostic assay is performed at intervals during the patient’s recovery or course of treatment, and a change in expression of a target gene, or a particular change in the pattern of gene expression, is indicative of the patient’s level of recovery or improvement. : [0069] In one aspect of the invention, assays are provided for identifying substances effective in treatment modalities for osteoarthritis. In one embodiment of the invention, a method is provided for measuring the effect of a test substance on the expression profile of genes differentially expressed in osteoarthritis, comprising the steps of: a) obtaining a standard expression profile from a first sample by measuring transcription or translation products of two or more genes corresponding to two or more genes or gene fragments identified in Tables 1 and/or 2 in the absence of the test substance; b) obtaining a test expression profile from a second sample by measuring the transcription or translation products of two or genes or gene fragments identified in Tables 1 and/or 2 expressed in the presence of the test substance; ¢) comparing the standard expression profile the test expression profile, wherein a change in the test expression profile compared to the standard expression profile is indicative of an effect of the test substance on the expression profile of genes differentially expressed in osteoarthritis compared to a non- osteoarthritic condition. Preferably, the two or more genes or gene fragments correspond to two or more of the genes or gene fragments identified in Table 3 (SEQ ID NOs:1-396). More preferably, the two or more genes or gene fragments correspond to two or more of the genes or gene fragments identified in Table 4 (SEQ ID NOs:1-217). In certain preferred embodiments, the samples are obtained from cultured cells. In this case, the standard expression profile is obtained from cells that have not been contacted with the test substance, while the test expression profile is obtained from cells that have been contacted with 2 test substance.
[0070] Test compounds may include proteins, polypeptides, nucleic acids, small molecule pharmaceuticals, vitamins, minerals, fatty acids, polysaccharides, extracts, nutriceuticals, and the like. In a preferred embodiment, the test compounds are nutrients that may be added to food or other dietary substances, or that may be taken as a dietary supplement.
As exemplified herein, such nutrients include, but are not limited to, fatty acids such as omega-3 fatty acids (e.g., eicosapentaenoic acid) and omega-6 fatty acids (e.g., arachidonic acid), glucosamine, chondroitin sulfate and vitamin D derivatives such as 1a,25-dihydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3.
[0071] One type of assay according to an embodiment of the invention involves . measuring the activity of the protein encoded by one of the aforementioned OA-associated genes in the presence or absence of a candidate substance. Such activity assays are well known in the art. If a cell-free activity assay is available for the selected protein, such an assay is simply conducted on the purified protein in the presence or absence of the test substance. Candidate substances are selected based on their ability to positively or negatively regulate activity of the purified protein. It should be noted that assays of this type may be performed, for example, in a recombinant cellular system, as described below. They can also be performed, for example, in a cell-free system in some instances.
[0072] For such in vitro activity assays, it is desirable to have a source of the purified protein of interest. One or more of the protein products of the genes mentioned above may be commercially available, or purifiable in significant quantities from an appropriate biological source, e.g., cultured cells. Alternatively, the proteins may be recombinantly produced from an isolated gene or cDNA by expression in a suitable procaryotic or eucaryotic expression system, and thereafter purified, as is also well known in the art.
[0073] Another embodiment of the invention comprises ir vitro cellular assays for expression of OA-associated genes or activity of their encoded proteins. For these embodiments, a nucleic acid construct comprising an OA-associated gene according to an aspect of the invention is introduced into host cells. In a preferred embodiment, mammalian cell lines are utilized. Host cells contemplated for use include, but are not limited, to NIH3T3, CHO, HELA, and COS, as well as non-mammalian cells such as yeast, bacteria and insect cells. The coding sequences are operably linked to' appropriate regulatory expression elements suitable for the particular host cell to be utilized. Methods for introducing nucleic acids into host cells are well known in the art. Such methods include, but are not limited to, transfection, transformation,
calcium phosphate precipitation, electroporation and lipofection. The recombinant cells may be used to identify compounds which modulate expression of the OA-associated genes or activity of their encoded proteins.
[0074] For gene expression assays, it is preferred to prepare an artificial construct comprising the promoter of a selected OA-associated gene, operably linked to a reporter gene.
The reporter construct may be introduced a cultured cell, including, without limitation, the standard host cell lines described above, or other suitable cells, for example, cartilage-related cells such as chondrocytes. The assay is performed by monitoring expression of the reporter gene in the presence or absence of a test compound. Candidate substances are selected based on their ability to positively or negatively affect expression of the gene.
[0075] In another embodiment of the invention, OA-associated genes and gene fragments described herein may be used to manipulate the genome of non-human animal subjects. Methods of manipulating the genomes of a variety of animals are known to those of skill in the art. Such methods may include, without limitation, the production of transgenic and . gene-knockout animals. In a preferred embodiment of the invention, a gene or gene fragment identified in Table 2 is used to prepare a construct that is used to disrupt or “knock out” the corresponding endogenous gene in an animal, thus producing an animal having a null mutation for that gene locus. In some embodiments, the animals exhibit a reduction or complete elimination of the expression of one or more genes having a nucleic acid sequence selected from
SEQ ID NOs:1-1558. In some embodiments, the animals exhibit a reduction or complete elimination of the expression of one or more genes having a nucleic acid sequence selected from
SEQ ID NO: 1-396. In some embodiments, the animals exhibit a reduction or complete elimination of the expression of one or more genes having a nucleic acid sequence selected from
SEQ ID NO: 1-217. In other embodiments, the animals exhibit a reduction or complete elimination of the expression of one or more genes shown in Table 6. The transgenic animals are preferably mammals. In some embodiments, the transgenic animals are rodents (e.g., mice and rats). In other embodiments, the animals are, for example, goats, cats, dogs, cows, pigs, sheep, horses, non-human primates, rabbits, and guinea pigs. In some embodiments, small interfering
RNAs are used to functionally disrupt the genes. Briefly, gene expression is inhibited by a short interfering RNA (siRNA) through RNA interference (RNAI) or post-transcriptional gene silencing (PTGS) (see, for example, Ketting ef al. (2001) Genes Develop. 15:2654-2659). siRNA molecules can target homologous mRNA molecules for destruction by cleaving the mRNA molecule within the region spanned by the siRNA molecule. Accordingly, siRNAs capable of targeting and cleaving mRNA of the gene products shown in Table 6 may be used to decrease or eliminate expression of one or more of these genes. In other embodiments, siRNAs capable of targeting and cleaving mRNA of one or more of the genes shown in Table 1 (SEQ ID
NOS: 1-1558) may be used to decrease or eliminate expression of one or more of these genes.
[0076] In another embodiment of the invention, OA-associated genes and gene fragments described herein are used to design molecules that may be used to interfere with the expression of one or more OA-associated genes; such molecules may include, without limitation,
RNA interference probes and antisense molecules.
[0077] Another aspect of the invention features compositions of matter to facilitate practice of the assays described above. These compositions may comprise collections of two or more probes or primers for use in detecting differentially expressed OA-related genes, gene fragments and encoded proteins according to certain aspects of the invention. In one embodiment, the compositions may comprise collections of two or more oligonucleotides or polynucleotides that specifically hybridize with nucleic acid molecules selected from SEQ ID
NOS:1-1558. Preferably, the compositions may comprise collections of two or more oligonucleotides or polynucleotides that specifically hybridize with nucleic acid molecules selected from SEQ ID NOS:1-396. More preferably, the compositions may comprise collections of two or more oligonucleotides or polynucleotides that specifically hybridize with nucleic acid molecules selected from SEQ ID NOS:1-217. Preferably, the composition may comprise collections of two or more oligonucleotides or polynucleotides that specifically hybridize with genes and/or gene fragments selected from the genes and gene fragments identified in Table 2.
The collection may comprise a primer pair for amplifying the sequence. In certain preferred embodiments, amplification may be performed using Polymerase Chain Reaction (PCR), more preferably quantitative PCR (qPCR). In a preferred embodiment, the collection comprises a larger plurality of probes, e.g., about 10, 50, 200, 400, 1000 or more probes, each of which hybridizes specifically with part or all of one of the sequences of SEQ ID NOS:1-1558. In a preferred embodiment, nucleic acid probes are immobilized on a solid support. In a particularly preferred embodiment, they are immobilized in an array format, most preferably in a miniature or micro-array. Such micro-arrays are known in the art, and are sometimes referred to as “DNA chips,” “microchips,” “biological chips” and other similar terms, and may contain the entire array of genes or gene fragments altered by OA, in addition to those represented in Tables 1 and 2.
[0078] In another embodiment, these compositions comprise two or more protein binding substances capable of specifically binding proteins or protein fragments encoded by the genes and gene fragments identified in Tables 1 and 2. In a preferred embodiment the binding substances are antibodies and the collection comprises two of more antibodies for detecting two or more proteins or peptides encoded by SEQ ID NOS: 1-1558, respectively. Preferably, these compositions comprise two or more protein binding substances capable of specifically binding proteins or protein fragments encoded by the genes and gene fragments of SEQ ID NOS: 1-396.
More preferably, these compositions comprise two or more protein binding substances capable of specifically binding proteins or protein fragments encoded by the genes and gene fragments of
SEQ ID NOS:1-217. Such binding substances may be any molecule to which the protein or peptide specifically binds, including DNA (for DNA binding proteins), antibodies, cell membrane receptors, peptides, cofactors, lectins, sugars, polysaccharides, cells, cell membranes, organelles and organellar membranes. In a preferred embodiment, the collection comprises a larger plurality of antibodies, e.g., about 10, 50, 200, 400, 1000 or more, each of which binds immunospecifically with part or all of a protein or peptide encoded by genes or gene fragments identified in Tables 1 and/or 2. In a preferred embodiment, the antibodies are immobilized on a solid support. In a particularly preferred embodiment, they are immobilized in an array format, most preferably in a miniature or micro-array, as described above for oligonucleotide probes, and may contain the entire array of proteins altered by OA, in addition to genes or gene fragments identified in Tables 1 and 2.
[0079] Another embodiment of the present invention relates to substances or compounds identified in any of the methods described herein as having an effect on the . expression profile of genes differentially expressed in OA. Preferably, such substances will be effective in the treatment and/or prevention of OA.
[0080] Still another aspect of the invention features test kits for use in one or more of the assays described herein. One type of kit comprises one or more pairs of primers for amplifying nucleic acids corresponding to the OA-associated genes and gene fragments described herein. The kit may further comprise samples of total mRNA derived from tissue of various physiological states, for use as controls. The kit may also comprise buffers, nucleotide bases, and other compositions to be used in hybridization and/or amplification reactions. Each solution or composition may be contained in a vial or bottle and all vials held in close confinement in a box for commercial sale.
[0081] Another type of kit comprises one or more nucleic acid or protein-binding probes, wherein the nucleic acid probe hybridizes specifically with a OA-associated gene or gene fragment according to certain aspects of the invention, or the protein-binding probe specifically binds to a protein encoded by the OA-associated gene or gene fragment. Preferably, the protein- binding probe is an antibody that is immunologically specific for the protein encoded by the OA-
associated gene or gene fragment. In preferred embodiments, the nucleic acid or protein-binding probes are immobilized on a solid support. In a particularly preferred embodiment, the kit comprises immobilized arrays of nucleic acid or protein-binding probes, the arrays comprising probes specific for a plurality of the OA-associated genes or gene fragments described herein, or proteins encoded thereby. These kits also may contain appropriate control samples of mRNA or protein from tissues of known physiological state, to be used as controls in the assays. They may further comprise buffers and reagents for performing the assays. Each solution, reagent or composition in the kit may be contained in a vial or bottle and all vials held in close confinement in a box for commercial sale. Preferably, kits may further comprise instructions for performing an assay of gene expression.
[0082] In another aspect, the invention provides a method for altering biological profile of cells through inducing a change in the gene expression profile of the cells with respect to genes involved in OA. The method involves administering to cells an effective amount ofa compound that alters the expression of one or more genes having a nucleic acid sequence selected from SEQ ID NOs:1-1558. In some embodiments, the compound affects the expression of one or more genes having a nucleic acid sequence selected from SEQ ID NOs:1-396. In some embodiments, the compound affects the expression of one or more genes having a nucleic acid sequence selected from SEQ ID NOs:1-217. In other embodiments, the compound affects the expression of one or more genes having the gene products shown in Table 6. The invention also provides a method of affecting the expression of genes involved in OA comprising exposing cells to an effective amount of a compound that modulates expression of one or more genes having a sequence selected from SEQ ID NOs:1-1558. In some embodiments, the compound affects the expression of one or more genes having a nucleic acid sequence selected from SEQ
ID NOs: 1-396. In some embodiments, the compound affects the expression of one or more genes having a nucleic acid sequence selected from SEQ ID NOs: 1-217. In other embodiments, the compound affects the expression of one or more genes having the gene products shown in
Table 6.
[0083] In some embodiments the cells are cells associated with symptoms of osteoarthritis. In some embodiments the cells are chondrocytes. In some embodiments the compounds are administered to cells in vitro. In other embodiments the compounds are administered to cells in vivo. The compounds may be administered to subjects via any route of administration. Preferably, the subjects are vertebrates. More preferably, the subjects are mammals including dogs, cats and humans.
[0084] The change in gene expression is preferably at least a 1.01 fold difference.
More preferably, it is at least a 1.05, 1.10, 1.25,1.50, 1.75, 2.0, 2.25,2.50, 2.75, 3.0, 3.25, 3.50, 3.75, 4.0 fold difference or more.
[0085] Chondroitin sulfate was shown to have an effect on a wide variety of OA- associated genes as shown in detail in Tables 7-12. Glucosamine was also found to have an effect on a variety of OA-associated genes as shown in detail in Tables 13-18. 1a,25- dihydroxyvitamin D3 and 24R 25-dihydroxyvitamin D3 also affected the expression of OA- related genes as shown in Tables 19-20. Eicosapentaenoic acid (EPA) and arachidonic acid (AA) were also shown to affect OA-related genes as shown in Tables 21-23.
[0086] The following examples are provided to describe the invention in greater detail.
They are intended to illustrate, not to limit, the invention. :
EXAMPLE 1
Extraction of RNA from chondrocytes
[0087] Normal and osteoarthritic canine cartilage chondrocytes (N,-flash frozen) were obtained and stored at ~-80°C. Osteoarthritic chondrocytes originated from canines clinically diagnosed with osteoarthritis undergoing total hip replacement. 300 to 500 mg were ground in N» (mortar and pestle) and transferred to a clean, pre-chilled, 50 ml tube. Trizol (2ml/100mg) was added and the mixture was homogenized using a Polytron for 2 x 30 seconds, and 1 minute (high speed). The homogenate was then centrifuged at 10,000 x g for 10 minutes at 4° C. The supernatant was removed and 0.2 volumes chloroform added to the supernatant, vortexed, and centrifuged at 10,000 x g for 15 minutes at 4° C. The upper aqueous phase was removed and 5 volumes of 4 M Guanidine thiocyanate, 25 mM sodium citrate, 0.5% sarkosyl, 0.1 M beta- mercaptoethanol and .475 volumes of 100 % ethanol were added to the upper aqueous phase.
The solution was then applied to Qiagen RNAqueous mini-columns (cat # 74104), using a vacuum manifold (according to the manufacture’s directions) for further purification of the
RNA. The purified RNA was then ethanol precipitated to concentrate, resuspended in DEPC water and DNAse I treated to remove residual DNA. The DNA-free™ DNAse Treatment kit from Ambion (cat #1906) was used for DNAse I treatment according to the manufacture’s directions. iy
[0088] RNA was quantitated in a Beckman DU 640B spectrophotometer at 260 nm (Beckman Coulter, Inc.,4300 N. Harbor Boulevard, P.O. Box 3100, Fullerton, CA 92834-3100).
Absorbance of 1 at 260nm is equivalent to 40 ug RNA/ml. Typical yields were 0.65 to 0.8 pg/ul. Quality of RNA was determined by the absorbance at 260 nm/280 nm with a typical ratio of 1.7 — 2.0. Quality was also assessed by electrophoresis in a 1% agarose gel/formaldehyde/T. ris-borate-EDTA (TBE), pH 7.8 buffer (90mM Tris, 90mM boric acid, 2mM
EDTA). Approximately 1 to 3.5 ug RNA was loaded (2 to 5 ul) after being mixed with 15 ul gel loading solution (10mM Tris pH 7.5, ImM EDTA, 0.02% bromophenol blue, 10% glycerol).
The gel was run at 50 Volts for 3-4 hours, stained with SYBR Green I (Molecular Probes, Inc.,
PO Box 22010 Eugene, OR 97402-0469, 4849 Pitchford Ave., Eugene, OR 97402-9165 ) at a dilution of 1:10,000 for 30 minutes in the dark and scanned using a Hitachi FMBIO II
Fluorescent scanner at 505 nm (Hitachi Genetic Systems, 1201 Harbor Bay Parkway Ste. 150,
Alameda, CA 94502).
Example 2
Differential Display
[0089] Fluorescent differential display was performed using one of three anchored primers in combination with one of 80 arbitrary primers (GenHunter). In all, 240 PCR reactions were carried out. Reactions were separated using PAGE and visualized using a fluorescent scanner (FMBIOTI, Hitachi). Bands representing differentially expressed genes were excised, reamplified and run on an agarose gel to verify size. These were subsequently subcloned (PCR-
TRAP, GenHunter) and sequenced.
[0090] Differential display was performed using GenHunter’s RNAimage® kit or
RNAspectra™ green fluorescent mRNA differential display systems (GenHunter Corporation, 624 Grassmere Park Drive, Suite 17, Nashville, TN 37211). Approximately 200 ng of RNA was reverse transcribed in the following reaction (final concentration): RT buffer (25 mM Tris-Cl, pH 8.3, 37.6 mM KCl, 1.5 mM MgCl,, 5 mM DTT), 625 pM ea. dNTP, 50 pmol H-T11G primer (GenHunter) (5 AAGCTTTTTTTITTTG 3") (SEQ ID NO:1559), or H-T},C primer (GenHunter) (5 AAGCTTTTTITTTTTTC 3°) (SEQ ID NO:1560), or H-T;A primer (GenHunter) (5 AAGCTTTTTTITTITTA 3°) (SEQ ID NO:1561), in a total volume of 19 ul. 1p (100 units/ul) of MMLYV reverse transcriptase was added ten minutes into the 37°C step in a thermocycler (GeneAmp PCR System 9700, PE Applied Biosystems, 850 Lincoln Center Dr.,
Foster CA 94404) and the following reaction performed: 65°C 5 minutes, 37°C 60 minutes, 75°C minutes followed by a hold at 4°C. Two pl of the reverse transcription reaction was used in the following polymerase chain reaction: PCR buffer (10mM Tris-Cl, pH 8.4, 50 mM KCI, 1.5 mM MgCl, 0.001% gelatin), 50 uM each dNTP, 5 pmol Fluorescein-labeled H-T1;G primer (GenHunter) (Fluorescein-labeled primer, 5° AAGCTTTTTTTTTTTG 3’) (SEQ ID NO:1562),
or Fluorescein-labeled H-T;,C primer (GenHunter) (Fluorescein-labeled primer, 5°
AAGCTTTTITTITTTTC 3°) (SEQ ID NO:1563) or Fluorescein-labeled H-T11A primer (GenHunter) (Fluorescein-labeled primer, 5’ AAGCTTTTTTTTTTTA 3’) (SEQ ID NO:1564) one of the H-AP primers provided in the kit at 200 pM, 1 unit of Amplitaq DNA polymerase (PE
Applied Biosystems, 850 Lincoln Center Dr., Foster CA 94404) in a total of 20 pl.
[0091] The following thermocycler reaction was used: 40 cycles of 94°C 15 seconds, ) 40°C 2 minutes, 72°C 30 seconds, followed by 72°C 5 minutes and a 4°C hold.
[0092] 5 ul of each PCR sample was mixed with 5 ul blue dextran loading buffer and ul deionized formamide and electrophoresed on a 6% polyacrylamide gel at 55 watts for 3 hours in TBE buffer. The gel was scanned using a Hitachi FMBIO 1I at 505 nm. cDNA bands differentially expressed were excised with a razor, placed in a 1.5 ml tube, soaked in 100 pl sterile water for 10 minutes and then boiled for 15 minutes. Tubes were centrifuged for 2 "minutes at 10,000 x g and the supematant transferred to a new tube. 10 ul 3M sodium acetate, 5 ul glycogen (10 mg/ml) and 450 ul 100% ethanol was added to the supernatant and the tubes were placed at —80°C overnight. Samples were centrifuged at 10,000 x g for 10 minutes at 4 °C and the supernatant was removed. cDNA pellets were washed with cold (-20°C) 85% ethanol, spun as above for 1 minute and the supernatant was removed. cDNA pellets were resuspended in 10 pl sterile water.
[0093] Four pl samples of the cDNA extracts were amplified the same as in the above "PCR reaction with the following exceptions: 40 ul total reaction volume; 20 uM ea. dNTP; 200 pM unlabeled primer H-T1;G , H-T;;C, or H-TpA (GenHunter) and 2 units of Amplitag DNA polymerase (PE Applied Biosystems). PCR conditions were the same as above. 15 ul of the amplified cDNA extracts were mixed with 3 ul 6X loading dye (0.25% bromophenol blue, 0.25% xylene cyanol FF, 30% glycerol) and electrophoresed in a 1.5% agarose gel. The gel was run at 100 volts for 2 to 3 hours in TBE buffer, stained/visualized the same as above. Bands were excised with a razor and cDNA extracted according to Qiagen’s QIAEX® II Gel Extraction
Kit (Qiagen, Inc., 28159 Avenue Stanford, Valencia, CA 91355). Three hundred ul QX1 buffer and 10 pl QIAEX® II suspension was added to each gel slice in a 1.5 ml tube and incubated at 50°C for 10 minutes. Tubes were vortexed every 2 minutes during incubation. Tubes were centrifuged 10,000 x g for 30 seconds and the supernatant was discarded. Pellets were washed once with 500 ul Buffer QX1 and twice with buffer PE (vortexing and centrifuging as above for each wash). Pellet was air dried for 10 minutes and 20 ul sterile water was added. Tubes were incubated for 5 minutes at room temperature and CONA was eluted by centrifugation as above for 30 seconds. Supernatant was then transferred to 2 new 1.5 ml tube and stored at —20°C.
[0094] Amplified gel purified cDNA was subcloned according to GenHunter’s PCR-
TRAP® Cloning System Kit (GenHunter Corporation, 624 Grassmere Park Drive, Suite 17,
Nashville, TN 37211). 5 pl amplified gel purified cDNA was added to 300 ng PCR-TRAP® vector, ligase buffer (50 mM Tris-Cl, pH 7.8, 10 mM MgCl, 10 mM DTT, 10 mM ATP, 5 ug i BSA) and 200 units T4 DNA ligase, mixed, and incubated overnight at 16°C. GH competent cells (E. coli del(lac-pro) ara thi (080dlacZdelM15)) were transformed with ligation reaction by mixing 10 ul ligation reaction to 100 pl GH competent cells on ice in 1.5 ml tubes. Tubes were incubated on ice for 45 minutes, heat shocked at 42°C for 2 minutes and then incubated on ice for 2 minutes. 400 pl LB broth (Luria-Bertani, Difco) was added to each tube and the tubes were incubated at 37°C for 1 hour with shaking (250 rpm). 200 pl of these transformations were plated onto LB-agar-tet plates (LB-agar, Difco, tetracycline 20 pg/ml) and incubated overnight at 37°C.
[0095] Colonies were checked for insert using GenHunter’s colony lysate PCR protocol. Colonies were picked with a clean pipette tip and placed in 50 pl colony lysate buffer (GenHunter, TE with 0.1% Tween 20) in a microfuge tube. Tubes were boiled for 10 minutes, centrifuged at 10,000 x g for 2 minutes and the corresponding lysate (supernatant) was transferred to a new microfuge tube. 2.0 ul of lysate was added to PCR buffer, 20 uM ea. dNTP, 200, pmol ea. of Lgh (5 CGACAACACCGATAATC) (SEQ ID NO:1565) and Rgh (5°
GACGCGAACGAAGCAAC) (SEQ ID NO:1566) primers and 1 unit of Amplitag DNA polymerase (PE Applied Biosystems) in a total volume of 20 pl. The following thermocycler reaction was used: 30 cycles of 94°C for 30 seconds, 52°C for 40 seconds and 72°C for 1 minute followed by 72°C for 5 minutes and a 4°C hold. PCR products were analyzed in a 1.5% agarose gel the same as above.
[0096] 3-5 ml LB broth was inoculated with appropriate colonies and incubated overnight at 37°C at 250 rpm. Plasmids were isolated according to Qiagen’s QIlAprep Plasmid protocol. Bacteria were pelleted (10,000 x g, 30 seconds) using 2 x 1.5 ml inoculated broth and the supernatant was removed. Pelleted bacteria were resuspended in 250 pl buffer P1, 250 ul buffer P2 was then added and tubes were mixed by gentle inversion. 350 pl buffer N3 was added, tubes were mixed by gentle inversion and then centrifuged for 10 minutes. Supernatants were added to a QIAprep column and centrifuged for 30 seconds. Flow-throughs were discarded, 0.5 ml of buffer PB was added to column and tubes were centrifuged for 30 seconds. Columns were washed with 0.75 ml buffer PE and centrifuged for 30 seconds. Flow-throughs were discarded and tubes were spun an additional minute. DNA was eluted from the column by adding 50 ul sterile water to the column. The column was incubated at room temperature for 1 minute and then centrifuged for 1 minute. Resulting supernatant containing plasmid DNA was quantitated as above (absorbance of 1 at 260 nm equals 50 pg/ml) with a typical yield of 350 pg/ml and a 260nm/280nm ratio of 1.8. } [0097] Sequencing reactions used 200 to 500 ng plasmid DNA in the ABI Prism
BigDye Terminator Cycle Sequencing Ready Reaction Kit (PE Applied Biosystems, 850 Lincoln
Center Dr., Foster CA 94404). 0.8 pl of primer (0.16 pm final concentration of either Lgh or
Rgh, GenHunter) was added to plasmid DNA along with 4.0 pl Teminator Reaction Mix (containing AmpliTaqg DNA Polymerase, FS, deoxynucleoside triphosphates, MgCla, Tris-HCL buffer, pH 9.0, A-Dye Terminator labeled with dichloro(R6G), C-Dye Terminator labeled with dichloro(ROX), G-Dye Terminator labeled with dichloro(R110) and T-Dye Terminator labeled with dichloro(TAMRA)) and brought to a final volume of 10 pl with sterile water. The following thermocycler reaction was used: 25 cycles of 96°C for 10 seconds, 50°C for 5 seconds, 60°C for 4 minutes followed by a 4°C hold.
[0098] Unincorporated dye-terminators were removed from the sequencing reactions according to Qiagen’s DyeEx spin protocol. Prepared DyeEx spin columns were placed in 2.0 ml microfuge tubes and centrifuged at 750 x g for 3 minutes. Columns were placed in new tubes, sequencing reactions were added to columns and centrifuged, as above, for 3 minutes. The eluate was placed at 74°C until dry.
[0099] 5 ul of formamide/blue dextran (5:1 ratio) was added to each dried sequencing © pellets. 1.5 pl to 2.0 pl was then added to a 5% polyacrylamide gel (in TBE buffer) on a Perkin
Elmer ABI Prism 377 automated DNA sequencer.
[0100] Each isolated plasmid clone was sequenced 2-6 times (2-6 different sequencing reactions, 1-3 times for each primer, Lgh or Rgh). ‘Sequence files from the ABI 377 sequencer were transferred to Genetic Computer Group’s Wisconsin Package and a corresponding consensus sequence was determined.
[0101] Approximately 1750 clones were isolated using differential display. All genes that appeared to be differentially expressed were selected. A representational polyacrylamide gel image is shown in Figure 1. Panel A represents the gel prior to band excision and panel B represents the same gel after band excision. Sizes of clones ranged from 90 b.p. to 1150 b.p., with an average size of 300 b.p. After filtering the sequences for redundant sequences, dimers, E. coli fragments, fragments <100 b.p. etc., 1558 remained. Sequences obtained (SEQ ID NOs:1-
1558) are shown in Table 1, which is appended herewith and which forms part of the present specification.
[0102] The sequences obtained were BLASTed against the human, mouse and dog public domain genomes to get a first hit. To be considered a hit at this stage, the match had to cover more than 50% of the sequence and an Expect value (E value) of less than 0.002. The first hits were used to extend the sequence using the respective genome. The sequences were either extended 2Kkb to the 5' or 3' side of the hit. The extended sequences were then used to BLAST against public domain protein databases (Ensembl, swissprot/trembl). The respective hits (those with an Expect value of less than 0.002, in this case) were consolidated and used for the annotations. In some cases, this strategy did not give hits, and in these situations the original sequences were BLASTed directly against swissprot/trembl or Ensembl proteins. In this case, hits were considered when the Expect value was less than 0.002.
[0103] Results of BLAST analysis (as of 1/28/04) of sequences isolated by differential display are shown in Table 2, which is appended herewith and which forms part of the present specification. The sequences are listed in the leftmost column by the gene ID designations (clone numbers) employed by the inventors herein. Many sequences matched with a Description of a previously-identified gene; the Description column also includes the source database and the corresponding database accession number. Table 2 includes additional information from a number of databases, including Ensemble Gene IDs, Ensemble Transcript IDs,
Swissprot/Ensemble, OMIM (Online Mendelian Inheritance in Man), RefSeq, Pfam, InterPro and HUGO. Information is also shown regarding Chromosome Number (#) and Chromosome
Location for many of the sequences. Additionally, the column labeled “Signal peptide” indicates the sequences for which a predicted signal peptide occurs in the amino acid sequence; the column labeled “TMHMM” (Transmembrane Hidden Markov Model) indicates sequences for which a predicted transmembrane region occurs in a protein sequence.
Table 6 lists clones demonstrating homology to previously-identified genes.
Table 6
Gene ID i 1006b RESPONSE FACTOR 2) (ERF-2). [Source:SWISSPROT;Acc:P47974] 1007a RESPONSE FACTOR 2) (ERF-2). [Source:SWISSPROT;Acc:P47974]
CaMax: | GRAVE'S DISEASE CARRIER PROTEIN (GDC) (GRAVE'S DISEASE 905
PROTEIN HOMOLOG). [Source:SWISSPROT ;Acc:P16260]
CaM | CALCITONIN GENE RELATED PEPTIDE TYPE I RECEPTOR
[Source:SWISSPROT;Acc:Q1 6602]
GsMax | TIGGER TRANSPOSABLE ELEMENT DERIVED 1; JERKY (MOUSE) 1029a HOMOLOG-LIKE. [Source:RefSeq;Acc:NM,_145702]
CaMax: | POLY [ADP-RIBOSE] POLYMERASE-3 (EC 2.4.2.30) (PARP-3) 1044c (NAD(+) ADP- RIBOSYLTRANSFERASE-3) (POLY[ADP-RIBOSE] 1363
SYNTHETASE-3) (PADPRT-3) (HPARP-3) (IRT1). {Source:SWISSPROT;Acc:QIY6F 1] 104a H). [S ource:SWISSPROT;Acc:P31943] : 1061a [Source:SPTREMBL;Acc:Q8NFU7] , 106a {Source: SWISSPROT; Acc:P02754] 1105a
CaMax: | STAR-RELATED LIPID TRANSFER PROTEIN 13 (STARD13) (START 1108a DOMAIN- CONTAINING PROTEIN 13) (46H23.2). 1262 [Source:SWISSPROT;Acc:Q9Y3M8] 1111b [Source:SWISSPROT;Acc:Q9Y6PS]
CaMax: | GOLGI PHOSPHOPROTEIN 3; GOLGI PROTEIN; GOLGI 1120a PERIPHERAL MEMBRANE PROTEIN 1, 34 KDA; GOLGI 1366
ASSOCIATED PROTEIN; COAT-PROTEIN. [Source:RefSeq; Acc:NM_022130] 1134a [Source:SWISSPROT;Acc:Q06413]
CaMax: | FORKHEAD BOX PROTEIN P2 (CAG REPEAT PROTEIN 44) 1135a (TRINUCLEOTIDE REPEAT- CONTAINING GENE 10 PROTEIN). 1173 [Source:SWISSPROT;Acc:015409] 1145a [Source: SWISSPROT; Acc:P39059] 104a H). [Source:SWISSPROT;Acc:P31943] 1169b [Source:SWISSPROT; Acc:P09493]
CaMax: | DYNEIN HEAVY CHAIN, CYTOSOLIC (DYHC) (CYTOPLASMIC
DYNEIN HEAVY CHAIN 1) (DHCI) (FRAGMENT). [Source: SWISSPROT; Acc:Q14204 1184a 1 (TIAM1 PROTEIN). [Source:SWISSPROT;Acc:Q13009] 1213d . 1243a
CaMax: | PROPIONYL-COA CARBOXYLASE ALPHA CHAIN, 1267a MITOCHONDRIAL PRECURSOR (EC 6.4.1.3) (PCCASE ALPHA 874
SUBUNIT) (PROPANOYL-COA:CARBON DIOXIDE LIGASE ALPHA
SUBUNIT). [Source:SWISSPROT;Acc:P05165]
CaMax: | PROPIONYL-COA CARBOXYLASE ALPHA CHAIN, 1267a MITOCHONDRIAL PRECURSOR (EC 6.4.1.3) (PCCASE ALPHA 874
SUBUNIT) (PROPANOYL-COA:CARBON DIOXIDE LIGASE ALPHA
SUBUNIT). [Source:SWISSPROT;Acc:P05165] 1272a PROTEIN A) (FRAGMENT). [Source:SWISSPROT;Acc:095486] 1287c ' 1288a "CaMax. | HEAT SHOCK PROTEIN HSP 00-BETA (HSP 84) (TUMORSPECIFIC
[Source: SWISSPROT; Acc:P11499)
J CaMax: | ATP-DEPENDENT DNA HELICASE 11, 80 KDA SUBUNIT (LUPUS KU 1292¢ AUTOANTIGEN PROTEIN P86) (KU86) (KU80) (86 KDA SUBUNIT OF
KU ANTIGEN) (THYROID- LUPUS AUTOANTIGEN) (TLAA) (CTC 44
BOX BINDING FACTOR 85 KDA SUBUNIT) (CTCBF) (CTC85) (NUCLEAR FACTOR 1V) (DNA-REPAIR PROTEIN XRCCS). (Source:SWISSPROT; Acc :P13010]
CaMax: | BIFUNCTIONAL AMINOACYL-TRNA SYNTHETASE [INCLUDES: 1294b GLUTAMYL-TRNA SYNTHETASE (EC 6.1.1.17) (GLUTAMATE--
TRNA LIGASE); PROLYL-TRNA SYNTHETASE (EC 6.1.1.15) (PROLINE--TRNA LIGASE)]. (Source: SWISSPROT; Acc:P078 14] 1299¢ [Source:RefSeq :Acc:NM_014991] 1304a [Source:RefSeq :Acc:NM_014178]
CaMax: UDP-N-ACET YLGLUCOSAMINE-PEPTIDE N- 1322c ACETYLGLUCOSAMINYLTRANSFERASE 110 KDA SUBUNIT (EC 1372 2.4.1.2) (O-GLCNAC TRANSFERASE P110 SUBUNIT). [Source:SWISSPROT;Acc:P56558] 1341a GREMLIN. [Source:RefSeq :Acc:NM_013372] 1354a HOMOLOG-LIKE. [Source:RefSeq :Acc:NM_145702]
CaMax: | ALPHA-(1,6)-FUCOSYLTRANSFERASE (EC 2.4.1.68) 1361a (GLYCOPROTEIN 6-ALPHA-L- FUCOSYLTRANSFERASE) (GDP-
FUCOSE--GLYCOPROTEIN FUCOSYLTRANSFERASE) (GDP-L- 1189
FUC:N-ACETYL-BETA-D-GLUCOSAMINIDE ALPHAL,6-
FUCOSYLTRANSFERASE) (ALPHA1-6FUCT) (FUCOSYLTRANSFERASE 8). [Source:SWISSPROT;Acc:Q9BYC5]
CaMax: | CONNECTIVE TISSUE GROWTH FACTOR-LIKE PROTEIN 1366a PRECURSOR (CTGF-L) (WNT1 INDUCIBLE SIGNALING PATHWAY | 209
PROTEIN 2) (WISP-2) (CONNECTIVE TISSUE GROWTH FACTOR-
RELATED PROTEIN 58). [Source:SWISSPROT ;Acc:076076} 1371a ALPHA-CATULIN. [Source:RefSeq;Acc:NM_003798] 137b [Source: SWISSPROT; Acc:Q99549] 1383a STAGE 4S GENE. [Source:RefSeq ;Acc:NM_005665]
ERE OE |e 1384a DESATURASE) (FATTY ACID DESATURASE) (DELTA(9)- 1330
DESATURASE). [Source: SWISSPROT; Acc:000767] 1397b ASSOCIATED PROTEIN 140 KDA. [Source:RefSeq :Acc:NM_181782]
CaMax: | PDZ DOMAIN CONTAINING GUANINE NUCLEOTIDE EXCHANGE 1401c¢ FACTOR (GEF) 1; RA(RAS/RAP1A-ASSOCIATIN G)-GEF; PDZ
DOMAIN CONTAINING GUANINE NUCLEOTIDE EXCHANGE
FACTOR(GER)1; RA(RAS/RAP1A-ASSOCIATING)-GEF; PDZ 306
DOMAIN CONTAINING GUANINE NUCLEOTIDE EXCHANGE
FACTOR(GEF)1. [Source:RefSeq ;Acc:NM_014247] 1409b [Source:SWISSPROT;Acc:QIUL15] 1411a 12A; MYOSIN PHOSPHATASE, TARGET SUBUNIT 1. [Source:RefSeq :Acc:NM_0024801 1420c [Source:RefSeq;Acc:NM_020739] 1421a TRANSLOCATION PROTEIN | (EC 3.4.22.-) (MALT-LYMPHOMA 1248
ASSOCIATED TRANSLOCATION) (PARACASPASE).
— [SowcesWiSSPROTAGOUDYE [
CaMax: | SPARC-LIKE PROTEIN 1 PRECURSOR (HIGH ENDOTHELIAL 1432¢ | VENULE PROTEIN) (HEVIN) (MAST 9). 145 [Source:SWISSPROT;Acc:Q145 15]
CaMax: | SPARC-LIKE PROTEIN 1 PRECURSOR (HIGH ENDOTHELIAL 143.2¢ | VENULE PROTEIN) (HEVIN) (MAST 9). 145 [Source:SWISSPROT;Acc:Q14515]
TESTICAN-3 PRECURSOR. [Source:SWISSPROT;Acc:Q9BQ16] EE 1448a 1449a [Source:SWISSPROT;Acc:P15622] 1450a [Source:SWISSPROT;Acc:QINRR1]
CaMax- | ACTIVATED RNA POLYMERASE Il TRANSCRIPTIONAL 1459¢ COACTIVATOR P15 (PC4) (P14). [Source:SWISSPROT :Acc:P53999]
CaMax: | 60S RIBOSOMAL PROTEIN L10 (QM PROTEIN) (TUMOR
SUPPRESSOR QM) (LAMININ RECEPTOR HOMOLOG). [Source: SWISSPROT; Acc:P27635] 1469a [Source:RefSeq;Acc:NM_023211] 1469a [Source:RefSeq;Acc:NM,_02321 1] 1476a {Source:SWISSPROT;Acc:P47928] 1477a PC3). [Source: SWISSPROT ;Acc:P78543] 1481c [Source: SWISSPROT; Acc:043365] 1488b (HNRNP A2 / HNRNP B1). [Source: SWISSPROT; Acc:P22626]
CaMax: | NADP-DEPENDENT LEUKOTRIENE B4 12- [Source:SWISSPROT;Acc:Q14914] 1521b [Source:RefSeq;Acc:NM_016147]
CaMax: | CYSTINE/GLUTAMATE TRANSPORTER (AMINO ACID
TRANSPORT SYSTEM XC-) (XCT) (CALCIUM CHANNEL BLOCKER
RESISTANCE PROTEIN CCBR1). [Source:SWISSPROT;Acc:Q9UPY 5] 1551a [Source:RefSeq;Acc:NM_017658] 1577a 1631d 1635a 1635a
CaMax: | MACROPHAGE INFLAMMATORY PROTEIN-2-BETA PRECURSOR 465 164c (MIP2-BETA) (CXCL3) (GROWTH REGULATED PROTEIN GAMMA) (GRO-GAMMA). [Source:SWISSPROT;Acc:P19876]
CaMax: CYTOCHROME C OXIDASE SUBUNIT IV ISOFORM 1, 1690a MITOCHONDRIAL PRECURSOR (EC 1.9.3.1) (COX IV-1) 1379 (CYTOCHROME C OXIDASE POLYPEPTIDE IV). [Source:SWISSPROT ;Acc:P10888]
CaMax: | CYTOCHROME C OXIDASE SUBUNIT IV ISOFORM 1, (CYTOCHROME C OXIDASE POLYPEPTIDE IV). [Source:SWISSPROT;Acc:P10888]
CaMax: | FIBROBLAST GROWTH FACTOR RECEPTOR 2PRECURSOR (BC
RECEPTOR 2). [Source:SWISSPROT :Acc:P21802] 1705a [Source:SWISSPROT;Acc:QIBX69] : -1717a
CaMax: | LEUKOCYTE ELASTASE INHIBITOR (LED 1721a (MONOCYTE/NEUTROPHIL ELASTASE INHIBITOR) (M/NEI) (ED. [Source:SWISSPROT;Acc:P307 40]
CaMax: | GOLGI AUTOANTIGEN, GOLGIN SUBFAMILY A MEMBER 4 1722a (TRANS-GOLGI P230) (256 KDA GOLGIN) (GOLGIN-245) (72.1
PROTEIN). [Source:SWISSPROT;Acc:Q13439 1724a = 1727a ISOFORM A. [Source:RefSeq ;Acc:NM_032571]
CaMax: | LEUCINE-RICH REPEAT-CONTAINING G PROTEIN-COUPLED [Source:SWISSPROT;Acc:QIBXB1]
CaMax: | TRANSCRIPTION INITIATION FACTOR IF, BETA SUBUNIT (TFIIF- 174a BETA) (TRANSCRIPTION INITIATION FACTOR RAP30). 243 [Source: SWISSPROT; Acc:P13984] 1758a 70 KDA) (SNRNP70) (U1-70K). [Source:SWISSPROT;Acc:P08621] 1759b [Source:RefSeq :Acc:NM_017658] . 1775a 1775a 1782b 178a ALPHA GLOBIN. [Source:RefSe q;Acc:NM_005653]
CaMax: | ATP-DEPENDENT CLP PROTEASE ATP-BINDING SUBUNIT CLPX-
EE rer], [Source: SWISSPROT; Acc:07 6031} 180a HOMOLOG-LIKE. [Source:RefSeq;Acc:NM_145702]
CaMax: | SIALIC ACID BINDING IG-LIKE LECTIN 6 PRECURSOR (SIGLEC-6) 1). [Source: SWISSPROT; Acc:043699] 1814c PRECURSOR (EC 1.14.17.3) (PAM). [Source: SWISSPROT; Acc:P19021 1828b PROTEIN) (LP). [Source:SWISSPROT;Acc:Q9QUP5] 1853a [Source:SPTREMBL;Acc:QIET34] 1857¢c 1859a LIKE PROTEIN. [Source:RefSeq;Acc:NM._021230] 1917f [Source:RefSeq ;Acc:NM_173082]
Gill 1919a NEUROPILIN-LIKE PROTEIN; COAGULATION FACTOR V/VII- 150
HOMOLOGY DOMAINS PROTEIN 1. [Source:RefSeq ;Acc:NM_080927] 1940e
FO TE CVA E— 1 1943a HOMOLOG. [Source:RefSeq;Acc ‘NM _014476] 1950a
CaMax: | NGFI-A BINDING PROTEIN | (EGR-1 BINDING PROTEIN 1) [Source:SWISSPROT ; Acc :Q13506]
CaMax: | MOTHERS AGAINST DECAPENTAPLEGIC HOMOLOG _ 1961e INTERACTING PROTEIN (MADH-INTERACT ING PROTEIN) (SMAD | 1494
ANCHOR FOR RECEPTOR ACTIVATION) (RECEPTOR ACTIVATION
ANCHOR) (HSARA) (NOVEL SERINE PROTEASE) (NSP). [Source:SWISSPROT :Acc:095405] :
CaMax: | ANTIGEN PEPTIDE TRANSPORTER 2 (APT2) (PEPTIDE El 1967a TRANSPORTER TAP2) (PEPTIDE TRANSPORTER PSF2) (PEPTIDE 1083
SUPPLY FACTOR 2) (PSF-2) (PEPTIDE TRANSPORTER INVOLVED
IN ANTIGEN PROCESSING 2). [Source:SWISSPROT :Acc:Q03519] 1968a 1982a [Source:SWISSPROT; Acc :P12107]
CaMax: | MICROTUBULE-ASSOCIATED PROTEIN, RP/EB FAMILY, MEMBER 1990a 2; T-CELL ACTIVATION PROTEIN, EB1 FAMILY; APC-BINDING 1092
PROTEIN EB1. [Source:RefSeq;Acc:NM_014268] 2008a 2013a PROTEIN 1). [Source:SWISSPROT;Acc:P48552] 60S RIBOSOMAL PROTEIN L4 (L1). [Source:SWISSPROT;Acc:P36578] 2015¢
CaMax: | MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 2020b KINASE 3 (EC 2.7.1.37) MAPK/ERK KINASE KINASE KINASE 3) (MEK KINASE KINASE 3) (MEKKK 3) (GERMINAL CENTER KINASE | 284
RELATED PROTEIN KINASE) (GLK). [Source:SWISSPROT;Acc:Q8TVHSE] 2034a
CaMax: | DNA-DIRECTED RNA POLYMERASES IIT 12.5 KDA POLYPEPTIDE (HRPC11) (MY010 PROTEIN). {Source:SWISSPROT;Acc:Q9Y2Y 1] 2056d [Source:SWISSPROT;Acc:P42694] , 2070a
CaMax: | POTENTIAL PHOSPHOLIPID-TRANSPORTING ATPASE IA (EC 3.6.3.1) (CHROMAFFIN GRANULE ATPASE II) (ATPASE CLASS I
TYPE 8A MEMBER 1). [Source:SWISSPROT;Acc:Q9Y2Q0] 2078a [Source: SWISSPROT; Acc:Q16181]
S| ph MC ROR Se [i 2083e PHOSPHOINOSITIDE-BINDING PROTEIN SR1; WD40 AND FYVE 113
DOMAIN CONTAINING 1. [Source:RefSeq;Acc:NM,_020830] 2100b 2110a [Source:SWISSPROT;Acc:Q14585] 211b {Source: SWISSPROT; Acc:P33527] 2123a [Source:RefSeq; Acc:NM_145648]
RE a 2129a [Source:RefSeq;Acc:NM_020239]
CaMax: | PROTEOGLYCAN 4; MEGAKARYOCYTE STIMULATING FACTOR; 2224a PROTEOGLYCAN 4, (MEGAKARYOCYTE STIMULATING FACTOR,
ARTICULAR SUPERFICIAL ZONE PROTEIN); J ACOBS 215
CAMPTODACTYLY-ARTHROPATHY-PERICARDITIS SYNDROME;
CAMPTODACTYLY, ARTHROPATHY, COXA VARA, PERICARDITIS
SYNDROME. [Source:RefSeq;Acc:NM_005807] ’ 2234a (THYROLIBERIN RECEPTOR). [Source:SWISSPROT;Acc:P2 1761] ] CaMax: | CGMP-INHIBITED 3',5'-CYCLIC PHOSPHODIESTERASE A (EC 2238a 3.1.4.17) (CYCLIC GMP INHIBITED PHOSPHODIESTERASE A) (CGI-
PDE A). (Source: SWISSPROT; Acc:Q14432]
CaMax: | CGMP-INHIBITED 3'.5-CYCLIC PHOSPHODIESTERASE A (EC . 188
PDE A). [Source:SWISSPROT;Acc:Q14432]
CaMax: | CGMP-INHIBITED 3',5'-CYCLIC PHOSPHODIESTERASE A (EC 2238a 3.1.4.17) (CYCLIC GMP INHIBITED PHOSPHODIESTERASE A) (CGI-
PDE A). [Source:SWISSPROT;Acc:Q14432] .
Elles oR LA 2267a [Source:SWISSPROT;Acc:P07996] .
CaMax: | CGMP-INHIBITED 3',5-CYCLIC PHOSPHODIESTERASE A (EC
PDE A). [Source:SWISSPROT;Acc:Q14432] 2374a [Source:SWISSPROT;Acc:P07996] :
CaMax: | SPECTRIN ALPHA CHAIN, BRAIN (SPECTRIN, NON-ERYTHROID 239a ALPHA CHAIN) (ALPHA-II SPECTRIN) (FODRIN ALPHA CHAIN). 530 [Source:SWISSPROT;Acc:Q13813]
CaMax: | GLUCOCORTICOID MODULATORY ELEMENT BINDING PROTEIN 23a 1 (GMEB-1) (PARVOVIRUS INITIATION FACTOR P96) (PIF P96) (DNA BINDING PROTEIN P96PIF). [Source:SWISSPROT;Acc:Q9Y 692]
CaMax: | TENASCIN PRECURSOR (TN) (HEXABRACHION) (CYTOTACTIN) 267d (NEURONECTIN) (GMEM) (JD (MIOTENDINOUS ANTIGEN) 553 (GLIOMA-ASSOCIATED-EXTRACELLULAR MATRIX ANTIGEN) . (GP 150-225) (TENASCIN-C) (TN-C). [Source: SWISSPROT ;Acc:P24821] 272d 307b
CaMax: | RETINAL PIGMENT EPITHELIUM-SPECIFIC PROTEIN 65KDA; 308c RETINAL PIGMENT EPITHELIUM-SPECIFIC PROTEIN (65KD); 597
RETINITIS PIGMENTOSA 20 (AUTOSOMAL RECESSIVE). [Source:RefSeq;Acc:NM_000329] 320a [Source:SWISSPROT;Acc:QINV70]
Ee |r 326e (SPASE 18 KDA SUBUNIT) (SPC18) (ENDOPEPTIDASE SP18). 71 (Source: SWISSPROT; Acc:QSROP6] 328b 106a [Source:SWISSPROT;Acc:P02794]
Eales iC 364a SARCOMA BREAKPOINT REGION 1 PROTEIN). 640 [Source: SWISSPROT; Acc:Q01844]
CaMax- | ACIDIC LEUCINE-RICH NUCLEAR PHOSPHOPROTEIN 32 FAMILY 374a MEMBER B (PHAPI2 PROTEIN) (SILVER-STAINABLE PROTEIN 644
SSP29) (ACIDIC PROTEIN RICH IN LEUCINES). [Source: SWISSPROT; Acc:Q92688]
[38a | [SourceRefSeqAccNM 0300171 [7]
CaMax: | EUKARYOTIC TRANSLATION INITIATION FACTOR 2 SUBUNIT 1 415b (EUKARYOTIC TRANSLATION INITIATION FACTOR 2 ALPHA 913
SUBUNIT) (EIF-2-ALPHA) (EIF- 2ALPHA) (EIF-2A). . [Source:SWISSPROT;Acc:P05198]
CaMax: | NUCLEAR FACTOR OF ACTIVATED T CELLS 5 (T CELL 658 459a TRANSCRIPTION FACTOR NFAT5) (NF-ATS) (TONICITY-
RESPONSIVE ENHANCER-BINDING PROTEIN) (TONE- BINDING
PROTEIN) (TONEBP). [Source:SWISSPROT:Acc:094916] = 464b ASPARTATE LIGASE) (ADSS) (AMPSASE). 292 [Source: SWISSPROT; Acc:P30520] a [Source:RefSeq; Acc:NM_016952] . 91/23). [Source:SWISSPROT;Acc:P51808] 479¢c 91/23). [Source:SWISSPROT;Acc:P51808] ll CO 487a PROTEIN) (PROLIFERATING CELL NUCLEOLAR ANTIGEN P40). 668 [Source:SWISSPROT;Acc:Q092974] 488a HEXOKINASE). [Source:SWISSPROT;Acc:P52789] 520a [Source:RefSeq;Acc:NM_017658] 521b [Source:SWISSPROT;Acc:Q06413]
CaMax: | PROTEASOME SUBUNIT ALPHA TYPE 3 (EC 3.4.25.1) 530b (PROTEASOME COMPONENT C8) (MACROPAIN SUBUNIT C8) (MULTICATALYTIC ENDOPEPTIDASE COMPLEX SUBUNIT C8). [Source:SWISSPROT;Acc:P25788] 539a 545a :
CaMax: | SER/ARG-RELATED NUCLEAR MATRIX PROTEIN (PLENTY OF 550a PROLINES 101-L; SER/ARG-RELATED NUCLEAR MATRIX 1403
Rl teil [Source:RefSeq;Acc:NM_005839] 555b FBL3A. [Source:RefSeq;Acc:NM_012158]
CaMax: | ECHINODERM MICROTUBULE-ASSOCIATED PROTEIN-LIKE 4
ASSOCIATED PROTEIN) (ROPP 120). [Source:SWISSPROT;Acc:Q9HC35] 579a SPLICING FACTOR SRP55). [Source:SWISSPROT;Acc:Q13247] 57a [Source:SWISSPROT;Acc:P23229)
El ec 58la 597¢ 1). [Source:SWISSPROT;Acc:Q12830] 623a [Source:SWISSPROT;Acc:P46940]
CaMax: | KREMEN PROTEIN 1 PRECURSOR (KRINGLE-CONTAINING
RECEPTOR). [Source:SWISSPROT;Acc:Q96 MUS]
EERE yi Be PO 635a PROLINES 101-L; SER/ARG-RELATED NUCLEAR MATRIX 1404
[ER Et NN [Source:RefSeq;Acc:NM_005839] 638b 91/23). [Source:SWISSPROT ;Acc:P51808] 685a =
HOMOLOG-LIKE. [Source:RefSeq; Acc:NM_ 145702] 704b 704b .
Ho 710a {Source:SWISSPROT;Acc:Q03692)
CaMax: | GRAVE'S DISEASE CARRIER PROTEIN (GDC) (GRAVE'S DISEASE
PROTEIN HOMOLOG). [Source:SWISSPROT;Acc:P16260]
CaMax: | DIAMINE ACETYLTRANSFERASE (EC 2.3.1.57) 736a (SPERMIDINE/SPERMINE N(1)- ACETYLTRANSFERASE) (SSAT) 142 (PUTRESCINE ACETYLTRANSFERASE). [Source:SWISSPROT;Acc:P21673] 73b [Source:SWISSPROT;Acc:Q92504] 747a 785b (ASCR) (CD230 ANTIGEN). [Source:SWISSPROT;Acc:P04156]
CaMax: | SARCOSPAN (K-RAS ONCOGENE-ASSOCIATED PROTEIN) [Source:SWISSPROT;Acc:Q14714] 85.1c [Source:RefSeq;Acc:NM_014301]
CaMax: | BRANCHED-CHAIN AMINO ACID AMINOTRANSFERASE,
CYTOSOLIC (EC 2.6.1.42) (BCAT(C)) (ECA39 PROTEIN). [Source:SWISSPROT;Acc:P54687] ' all iil CI 863c FACTOR SLUG) (SNAIL HOMOLOG 2). 916 [Source:SWISSPROT;Acc:P97469] 890a [Source:SWISSPROT; Acc:P20340] , 909a PRECURSOR (EC 1.14.17.3) (PAM). [Source:SWISSPROT;Acc:P19021]
CaMax: | HEAT SHOCK PROTEIN HSP 90-BETA (HSP 84) (TUMOR SPECIFIC [Source:SWISSPROT; Acc:P11499] 919b [Source:RefSeq;Acc:NM_016132] 92¢ [Source:RefSeq;Acc:NM_003743] 935b [Source:SWISSPROT;Acc:Q8WUHI1] 953a [Source:SWISSPROT;Acc:P56379] 963¢ 986a 990a
(G54b__ | PROTEIN. [SourceRefSeqAcoiM 013528] sn
EXAMPLE 3
Preparation of Microarray 3 [0104] Microarray probes were generated by PCR-amplifying clones isolated from differential display. Probes were spotted in duplicate onto poly-L-lysine coated slides using a
GMS417 (Affymetrix) arrayer. Osteoarthritic cartilage samples were obtained from the femoral heads of clinically diagnosed canines undergoing total hip replacement. RNA was hybridized to the slides using the HC ExpressArray (Digene) kit and visualized using a GMS418 (Affymetrix) scanner. The Imagene (Biodiscovery) program was used for spot finding and subsequent data analysis was performed using GeneSight (Biodiscovery). Expression levels are represented after background subtraction, log (base 2) transformation and global slide signal normalization.
Microarray clone preparation
[0105] Culture blocks containing 1.5 mLs of Magnificent Broth (MB) plus tetracycline (50 mg/mL) were inoculated with appropriate clones from glycerol stocks and grown overnight with shaking at 37°C. These cultures were used to inoculate a second culture block that was grown for approximately 6 hours with shaking at 37°C. These 6-hour cultures were used to inoculate 2 replicate culture blocks which were grown overnight with shaking at 37°C. Cultures were centrifuged to pellet cells and plasmids isolated using the Qiagen 96-well culture system (Qiagen). Plasmid concentrations were determined using a spectrophotometer by measuring the absorbance at 260nm. All cDNA plasmid clones were amplified in duplicate using the following
PCR reaction (final concentration): 10X PCR buffer (10mM Tris-HCI, pH 8.3, 50mM KCl, 2.5mM MgCl), 500uM ea. dNTP, 600 nM Rgh primer, 600 nM Lgh primer, pL (Sunits/puL) of
Eppendorf Taq polymerase and 1pL (~100ng/ul) cDNA template in a total of 100uL. The reaction was performed in the following conditions: 94°C 30 seconds, 52°C 40 seconds, 72°C 1 minute for 40 cycles, followed by 72°C — Smin and 4°C - hold. Amplified products were verified on 1.5% agarose gel and purified using Minelute (Qiagen) protocol. The 200uL of PCR was added to the filter plate and vacuum was turned on to pull through all PCR reagents and liquid leaving only the cDNA bound to the filter. 30uL molecular grade water was added to the filter plate and incubated at room temperature on an orbital shaker at 900 rpm for 5 minutes. The supernatant containing the purified cDNA was aspirated from the filter plate. The cDNA’s were dried for 2hrs or to completion in a speed vac at 45°C. 30UL Corning Universal Printing Buffer was added to all cDNA’s and resuspended over night at room temperature on an orbital shaker. . 2uL’s transferred for concentration analysis and the appropriate amount of Corning Universal
Printing Buffer was added for a final concentration of 200 to 500 ng/uL. Plates were stored at — °C until and after each array printing.
Clone arraying
[0106] Microscope slides (Goldseal cati# 3010) were submerged in a 10% NaOH (Fisher cat#S318-500) 57% EtOH solution and incubated at room temperature in an orbital shaker at 50rpm for 2 hours. Slides were rinsed in Milli-Q water 5X for 30 seconds each. While the slides remain in the last water rinse a 10% Poly-L-Lysine (Sigma cat#P8920), 10% 1X PBS (GibcoBRL cat#70013-032) was brought to 700mLs using Milli-Q water in plastic ware. Slides were submerged in coating solution and incubated at room temperature in orbital shaker at 50rpm for 1 hour. Slides were rinsed in Milli-Q water 5X for 30 seconds each and spun at 500rpm for 1 minute. Slides were incubated in 55°C oven for 10 min and kept in dessicator for at least 14 days and no longer than 3 months prior to arraying. cDNA clones were arrayed using the GMS 417 arrayer (Affymetrix). All slides were placed in a room temperature dessicator to dry overnight. The slides were rehydrated over boiling Milli-Q water (steam) and snap dried
DNA side up on an 80°C heat block. To ensure efficient cross-linking the slides were baked for 2 hours at 80°C in an oven and then cross-linked with Stratalinker (120mJ, Stratagene). All slides were stored in a room temperature dessicator until used for cDNA hybridization. cDNA microarray hybridization
[0107] All RNA samples were reverse transcribed using the following reaction: 5X
Superscript II First Strand Buffer (Invitrogen), 1uL (1pmole/uL) of RT primer (Genisphere), luL.
Superase-In™ Rnase inhibitor, 1uL 10mM ea. DNTP, 2uL. 0.1 M DTT, 1uL Superscript II and
Sug total RNA. The reaction was performed at 42°C for 2hrs. The reaction was stopped by adding 3.5ulL of 0.5 M NaOH/50 mM EDTA and incubating at 65°C for 10 minutes. The reaction was neutralized by adding Sul of IM Tris-HCL, pH 7.5. 101.50L of 10mM Tris, pH 8, 1mM EDTA was added and the cDNA was purified and concentrated by following the Microcon
YM-30 (Millipore) protocol. The concentrated cDNA was brought to a final volume of 10uLL with Nuclease-free water and the following reagents added: 20ul of 2X hybridization buffer (Genisphere), 2uL. dT LNA blocker and 8uL Nuclease-free water for a total of 40ul.. The hybridization mixture was heated at 80°C for 10 minutes and loaded onto the microarray slide at the edge of the lifterSlip. The slide was then placed into a GeneMachines dual hybridization chamber and placed in a 60°C water bath overnight. The following day the slides were processed according to the 3DNA Array 350 (Genisphere) protocol. Briefly, the slides were . washed (2XSSC-.2%SDS, 2X SSC, .2X SSC), spun dry at 1000rpm for 1 min and the 3DNA capture hybridization performed. The slides were washed (2XSSC-.2%SDS, 2X SSC, .2X SSC) spun dry at 1000rpm for 1 min and scanned using a GMS 418 array scanner (Affymetrix).
Microarray analysis
[0108] Scanned images representing RNA transcripts bound to specific clones were
RN quantified and checked for spot quality control using Imagene analysis software (BioDiscovery).
Quantified images were analyzed using Genesight analysis software (BioDiscovery). The analysis represented subtraction of background surrounding the spots, averaging spot replicates, deletion of clone information representing clone hybridization signals not greater than 200 above background on all samples, log (base 2) transformation and global normalization of each slide (values expressed as percent of average spot intensity).
EXAMPLE 4
Expression Analysis Using Microarray
[0109] RNA was extracted from cartilage as described, supra. Microarray analysis (described supra) was performed on 8 osteoarthritic cartilage samples from clinically diagnosed canines undergoing total hip replacement and 8 normal cartilage samples. A standard T-test (two categories) was performed on the final hybridization signals for osteoarthritic characterization of cartilage samples (p<0.05 and p<0.01, results shown in Tables 3 and 4, respectively).
TABLE 3
OA AVG Normal AVG DIF(0A-N) 1028¢ [1542 [080 [085 [006 [056 J074 [167 1548c [549 [041 [479 [046 069 [162 718s [593 [066 [520 [043 |064 [156 [1tb [085 [066 [-146 030 [0.60 [152 [370a [606 [046 [554 [061 |oOS51 [143 1551a [376a |-066 [042 [-101 [024 1036 128 1357a 1090d
60a [0148 1034 oii ~~ T025 [029 ~~ [122 [9e [550 1016 1580 1035 [030 [1.23 [9940 |-182 043 |-144 024 [030 [131
[5232 [136 [028 [093 Jo32 [-043 [134 [58a [009 1022 [034 ~~ lo24 [043 [135 [1282b [-150 [047 [-104 ~~ J035 [046 [137 17392 |-046 027 000 ~~ |015 [046 ]137 1612a |-056 |041 [009 ~~ 028 [-047 ~~ [139 [631b |-223 ~~ 1000 [-175 ~~ ]025 [048 1140 758b [039 ~~ J043 [009 {031 [048 ~~ [140
: ) (1191a [047 1053 1099 ~~ [035 [052 [143 [12542 [-048 1046 [006 [028 [054 [146 4822 [155 [025 [-099 ~~ 039 [056 148 [17852 [219 ~~ 009 [-163 1027 [056 [148
570b 1013 1060 072 1027 |-059 [150 1504 [069° [055 1128 [039 [-059 [151 11033c |-247 1052 [-188 1029 [-059 ~~ [is51 |. 8a 1-051 losi J008 ~~ [030 |-060 [151 [46a [007 [054 [052 [034 [-060 [151 17582 [142 ~~ ]0.63 [200 ~~ 023 ]-060 [151 119852 |-192 [023 [-133 ~~ [050 [-060 [151 326e [012 "025 [048 ~~ Jo24 1-060 [151 851c |-004 1040 [056 [022 |-060 [151 16752 [-175 ~~ |044 |-115 ~~ 1040 |-060 [152 17722 1078 ~~ ]051 [138 [060 |-060 [i152 1707 [2.25 071 ]-164 [030 [060 [152 14742 [238 1036 [178 [042 |-060 [152 1712a [2.61 10.63 [322 060 [061 [153 1382d [171 1009 [-110 [071 [061 [153
[81a [177 Toile [-1d4 [025 |-065 [135 : (15572 [179 [028 [45 Tose 064 [136 [1495 [1.30 [0.64 [066 [ods [064 [136 23 [1.60 [045 [086 lox [065 [136 (18001 [067 [066 [039 [065 [157 14155 [0.73 [035 [007 [032 [066 [iss 2074b [1.62 [048 [096 [038 [066 [158 2250s [2.05 [021 [149 [039 [066 [158 [17400 [162 [049 [096 [036 [066 [158
Bla [076 [018 [142 [031 [066 [158 (032d [081 Joss [042 021 [069 [lel (1373 [237 [022 |-168 [ode [0.60 |Lel 20666 [126 [035 [057 027 [060 [161 7952 |-Ll6 [032 [047 [019 [069 [tel 306s [195 [037 [125 [03 [069 [lel 4002 [1.27 [078 [196 [041 [069 [tel 5276-025 [065 [044 [025 [069 [lel 22a [ost Joss [tz [021 [06 liel
(2083e [173 ]039 [-104 [028 [069 ~~ [16l 555 [058 [033 [128 [016 [069 [i162 129 [-222 Jo4r 1-153 © Jo34 06 = [162 2262 [-232 [072 [163 ~~ [044 [069 ~~ 162 272d [217 1022 [148 © 029 [069 [162 17092 [213 ]040 [-143 = Jo034 |070 ~~ [162 [13542 [229 ~~ Jo066 |-159 ~~ [038 [-070 ~~ [162 ) 7942 [098 Joss 1026 ~~ [046 [072 [165 192a |-183 Jodt [107 ~~ Jo79 [076 [1.60 [1651a |-201 Jo24 [124 ~~ 1066 [-077 [171 17a [006 068 108 [032 [080 [174 2161c |-179 044 [-099 ~~ Jo70 [-080 [174
[isTea [238 [086 [1s [045 [08 [178 1503 [207 [066 [23 Tos [0s [179 o79a [101 [060 [278 [052 [08s [184
Sta [061 [076 [028 [060 [089 [185 13056 | 236 [005 [166 [023 [090 [186 4395 [090 [030 [004 [036 [004 [191 43a [099 [oso [to ozs [096 [194
Tid63a [0.08 [021 [oss [017 [096 [194 7666 | 185 [031 [086 [050 [009 [195
T4125 [1.00 [029 [28 [045 [099 [195 [423 [3.55 [077 [4st [020 [099 [195
WQ 2005/075685 PCT/US2005/003375 (2241a [024 TT63 "Tos [048 |-110 [215 (2263b |-1.18 ~~ [052 [008 oda ]-110 [215 (14382 13.02 [039 1417 043 |-115 [222 [2056 |-136 [047 [-013 ~~ J049 |-122 [234 [1646a [135 1079 [258 ~~ J0S1 [123 1235 [851d [-181 ~~ 047 [-058 063 |-123 [235 [465 [-116 [037 foo8 ~~ 068 [125 [237 (900 |262 1067 [387 1096 [125 238 1488> [021 [078 [146 ~~ 1066 |-125 [238 (1452a [200 ~~ J061 [335 ~~ 028 |-126 [240 (1270a |-147 ~~ 1036 [019 054 |-128 [243 [21422 [023 [057 [152 ~~ 118 [120 [245 (1371 [340 122 1-230 = 045 [130 [246 (0452 [076 J068 [206 030 |-130 [247 [2117p [231 [127 [362 [112 [131 [248 [1367a [092 ~~ [083 [225 1065 [-133 [251 [1818s [282 [088 [416 ~~ [123 [-134 253 [21980 [-003 ~~ los4 [132 [121 |-134 [254 (1130a [017 [084 [156 1096 [-139 [261 [851a |-151 j060 [-013 ~~ [040 [139 [262 (1138a [233 Jo75 373 ~~ 088 [141 ~~ |265 [10082 [272 [080 [414 1092 [142 [267 [21132 {270 [123 1413 [111 [143 [269 [5522 [019 Joss [165 ~~ Jod46 |-146 [274 [23742 [073 Jo076 221 ~~ 1060 |-148 [279 [1532a |-057 ~~ Jo070 1094 070 [-151 [285 (21182 [083 [068 1069 038 |-152 [28 [1366a | 160 [090 [314 [082 [-153 [290 [1262p [027 ~~ Jo47 [128 ~~ J113 [155 [293 (1441c [231 ~~ J040 424 [049 [-193 [380 [21a [069 [077 [295 1077 |-226 [480 [1246a [028 ~~ J085 1333 [144 [305 [829 [1253a |-126 |o064 [210 ~~ [184 [336 [1026 [22242 [008 ~~ lo044 1348 ~~ |064 [1-340 [1057 (10154 |-1.04 ~~ J052 [301 [18 [405 [1652 [22520 [-050 fo0s58 [390 ~~ [180 [-439 ~~ ]2100
TABLE 4 [GeneID [OA AVG [STD [Normal AVG [STD [DIF(OA-N) [Fold (1028c [181 Jo75 [024 ~~ Joo4 [157 1296 (7682 [199 ~~ Jo0s54 o88 ~~ J055 JL [216 (141c [394 Jos7 [301 Jo75 093 ~~ |190 (1548c [549 ~~ Jod41 [479 ~~ [046 1069 [162 (1357a [200 oa2 [-173 [007 [028 © |121 [168c [511 [019 }s40 [021 [-029 [122 (383d [-178 018 [-147 ~~ [014 1-030 [124 [2127c Joos ~~ [023 Jo48 ~~ fo31 [-039 [131
[5306 [136 "B31 ~Ti7s To23 1-040 [132 [16a [097 [034 |-056 [025 |-041 [133 (58a |-009 [022 [034 1024 1-043 [135 [7392 |[-046 [027 ooo ~~ Jo15 [-046 [137 [1612 [-056 |o41 [009 ~~ J028 [-047 [139 21472 |-163 041 [111 033 [052 [143 [12542 [-048 |046 [006 [028 [054 [146 [482a |-155 ~~ 1025 [099 1039 [056 |148 [17852 [219 1009 |-163 ~~ 027 [056 [148 oo }
8a [-051 051 1008 1030 [060 [151 [46a [-007 [054 Jos52 034 |-060 [151 [19852 |-192 [023 [-133 ~~ [050 [060 [151 [326e [-012 [025 Jo48 024 060 [151 [85.1c ~ [004 040 Jos56 [022 [060 [151 (16752 |-175 [014 |-115 ~~ [040 [060 [152 [23a [-160 045 ]-096 022 [065 [156 (14150 [073 ~~ J033 [007 ~~ [032 [066 [158 (2074p [-162 048 [096 038 [066 [158 (2250a [215 Jo21 [-140 ~~ 039 [066 [158 [17402 |-162 [049 [-096 1036 [066 [158 (8la__ [076 [018 [142 1031 [-066 [158
[2266b [-1.26 [033 |-057 027 |069 [161 [7952 |-116 [032 [-047 ~~ ]019 060 [161 [206 [-1.93 [037 [-125 ~~ ]052 [069 [161 (327 [-025 063 1044 023 [060 [161 [2122 |-181 033 [-142 ~~ ]027 |-069 [161 [2083 |-173 [039 [-1.04 ~~ ]028 0690 [161 [555b [oss [033 J128 J0d6 [069 [1.62 [1296a |-222 ~~ |o041 [-153 ~~ 034 [069 [162 a [272d |-207 [022 [-148 [029 |-060 [162 (1951a [-181 [032 [-105 ~~ 069 |-076 |170 [17a |oo06 [068 J08 [032 [080 174
© [9792 _J191 ~~ fo69 [278 [052 [088 [184 [13090 [256 [0.05 |-166 |023 |090 [186 } [1430b [090 [030 004 036 |-094 ~~ ]191 [4932 [099 ~~ [089 [194 ~~ 1028 [096 [194 (1463 |-008 [021 [088 [017 _ [-096 |194 |] 766b [185 [031 [08 [050 [-099 [199 ‘14126 [190 ~~ [029 [28 [049 [099 [199 1423b [355 ~~ [0.77 [454 ~~ 020 [099 1199 [4650 |-116 |037 |008 ~~ J068 [-125 {237 |} (9902 [262 ~~ |067 [387 1096 [-125 [238 1488b [021 078 [146 [066 |-125 [238 [11392 [017 ~~ |084 [156 1096 [-139 [261
1008a 23742 073 076 221 [060 |-148 279 15322 (21182 [0.83 [068 l069 [038 [-152 12386 1366a [160 [090 [314 ~~ ]08 [-153 [290 1262b. 21a Jo69 ~~ [o77 [295 ~~ Jo77 [226 [480 1246a 2224a 10.57 1015d 16.52 2252b 21.00
[0110] The use of differential display to isolate gene transcripts has enabled the present inventors to develop a microarray chip enriched in transcripts involved in osteoarthritis. The use of this chip to analyze samples from canines with osteoarthritis (1) confirms the results from differential display and (2) enables further characterization of canine osteoarthritis at the molecular level. Transcripts analyzed by gPCR (discussed infra) have validated the differential expression analysis from the microarray.
EXAMPLE 5
Quantitative Polymerase Chain Reaction (QPCR) {
[0111] Confirmation of changes in RNA transcripts was performed using quantitative
PCR. Reverse transcriptase reactions were performed using Super Script™ II Reverse
Transcriptase for RT-PCR (Invitrogen) according to the manufacture’s directions. 1pg of RNA was added to 1.5pL.10 mM dNTP’s, 1.5pL random hexamers and 0.6pL Oligo dT primers and brought to a final volume of 15 uL.. Samples were incubated at 68°C for 10 minutes and then brought down to 4°C for at least 1 minute using a GeneAmp PCR System 9700 (Applied
Biosystems). A portion (0.25X) of the above reaction was removed and used as a minus RT reaction (Negative Control containing No Super Script™ II Reverse Transcriptase). Using the same Super Script™ II Reverse Transcriptase kit, a master mix containing 3uL of 10X RT buffer, 6pL of 25mM MgCl,, 3uL 0.1M DTT and 1.5pL. RNAse Inhibitor was made. A portion (0.25X) was removed and 0.375uL. H,O was added for the minus RT samples. To the remainder of the Master Mix, 1.125uL Super Script™ II Reverse Transcriptase was added for the positive
RT reactions. All reactions were then incubated at 42°C for lhour, boiled at 95°C for Sminutes, and the brought down to 4°C using a GeneAmp PCR System 9700. The samples were then diluted 1 part RT reaction to 29 Parts H,O to create a stock of cDNA for experimentation.
[0112] Primers and 5° nuclease assay probes were designed based on selected . sequences from the differential display using Primer Express™ v1.5 (Applied Biosystems Primer
Express® Tutorial for Real Time Quantitative PCR Primer and Probe Design Tutorial). Minor groove Binding probes (ABI Custom Oligo Synthesis Factory) were ordered from ABI. All oligos were reconstituted with TE buffer pH=8.0 (Ambion) to 100uM stock concentration, and then diluted with TE buffer to a 5uM working stock concentration. TagMan® Universal PCR - Master Mix (Applied Biosystems) was used for quantitative PCR reactions according to the manufacture’s directions. Primer concentration was 300M each and Probe concentration was 200pM (determined optimal from earlier experiments). 4p of RT and minus RT reactions were used for quantitative PCR reactions. All positive reactions were done in triplicate, and negative controls were performed singly. Standard qPCR conditions were used as described in the
TagMan® Universal Master Mix (Applied Biosystems, 50.0°C for 2 minutes, 95.0°C for 10 minutes, and 40-50 cycles of 95°C for 15 seconds then 60°C for 1 minute) at 0.5 volumes.
Samples were run on an ABI Prism 7700 Sequence Detector using ABI Sequence Detector
Program v1.7a.
[0113] All samples were run singularly against each primer/probe set to determine what standard curve should be used. Standard curves were generated using serial dilutions of liver
RNA or RNA from experimental samples. Alternately, if the samples did not fall within either of the curve ranges, the sample with the lowest Cr (cycle threshold) would be re-reverse transcribed and a 1:10 serial dilution would be used as the standard curve for that primer/probe set. Values were normalized to G3PDH (glyceraldehyde-3-phoshate dehydrogenase) levels as determined by quantitative PCR. Inductions were calculated from each of the lowest sample’s normalized value.
Error bars represent standard error of the means.
[0114] Table 5 shows the primers and probes used for the qPCR analysis.
TABLE 5
I. Clone Target SEQ | Primers and Probes (5° - 3°)
ID
NO:
K9 G3PDH - Fwd | 1567 | GTC ATC ATC TCT GCT CCT TCT GC 1568 | TGA CAA TCT TGA GGG AGT TGT CA - Probe 1569 | 6FAM - CTT CTC ATG GTT CAC GCC CAT CAC AAA -
MGBNFQ
11B - Fwd 1570 | TTG ATA CTC CTA GTC TTG TCT ATT CAC TGA
TCG AGT TTT TGC TCT TTG GAG AA
- Probe 1572 | 6FAM - TCA TTC AAC CCA GCA TTG AAC AAG GCT -
MGBNFQ
59A -Fwd 1573 | AGC AGG TGT TCA TCC CAG AATG
MGBNFQ
MGBNFQ 3 :
TTT T - MGBNFQ [159A -Fwd 11582 [CAGGCTGCCAACGAATGG
MGBNFQ
MGBNFQ
CTC A - MGBNFQ
MGBNFQ
AGC - MGBNFQ
MGBNFQ
CAA - MGBNFQ
CAA - MGBNFQ
T
B WO 2005/075685 PCT/US2005/003375
CAA ATG AGG - MGBNFQ
EXAMPLE 6 qPCR analysis of Canine OA Cartilage
[0115] qPCR was performed as described, supra, on 6 osteoarthritic cartilage samples from clinically diagnosed canines undergoing total hip replacement and 8 normal cartilage samples. Results are shown in Figure 2 (A-E).
EXAMPLE 7
Microarray Analysis of Treated OA Samples
A. In Vitro Chondrocyte Cell Culture
[0116] Canine cartilage was digested in a 37°C shaking water bath using the following enzymes: trypsin (0.25%) for 25 minutes, hyaluronidase (150U/ml) for 1 hour, and collagenase (0.78%) overnight. Digested cartilage was filtered to obtain chondrocytes. Dulbecco’s Modified
Eagle Medium (DMEM) + 2.4% alginate (low melting) + cells were dropped from a 10cc syringe into calcium chloride (102 mM) to form “beads.” Chondrocyte beads were cultured in
DMEM/F12 + P/S (100 U/mL penicillin and 100 pg/mL streptomycin) + 10% Fetal Bovine
Serum (FBS). Media was changed every other day. At the end of the treatment (see below), the chondrocyte beads were dissolved in sodium citrate (55mM) and EDTA (30mM). Suspensions were centrifuged at 1800 rpm for 10minutes. Cells were washed with phosphate buffer and centrifuged again at 1800 rpm for 5 minutes. One mL lysis binding solution (Ambion®
RNAqueous™) was added to the isolated canine chondrocyte pellet, mixed thoroughly and stored at —20°C until RNA isolation could be performed.
B. RNA Isolation from Cell Culture
[0117] Samples were vortexed and homogenized using a Quiashredder (Qiagen) column according to manufacture’s directions. The homogenized lysate was collected and 1 equal volume of 64% ethanol was added to it. This mixture was then applied to an RNAqueous™ filter cartridge, 700 uL at a time, and centrifuged for 1 minute at 10,000 rpm. The cartridge was washed using 700uL wash solution #1 and 500 uL wash solution #2/3 with centrifugation at 10,000 rpm for 1 minute for each wash. The filter cartridge was dried by centrifugation (10,000 rpm) for 1 minute. RNA was eluted 3 times by centrifugation (as above) using 30 uL. aliquots of 95-100°C elution solution. The resulting RNA was DNAse-treated and quantitated as stated previously. Following RNA isolation, the RNA was prepared for microarray hybridization as . stated previously.
C. Statistical Analysis of Cell Culture Microarray
[0118] Data were transformed to logarithm, base 2. Data were normalized using quantile normalization. After normalization, a concordance correlation was computed.
[6119] Differentially expressed genes were determined using a paired t test (0=0.05) for the EPA vs. AA; EPAstim' vs. AAstim; chondroitin sulfate and glucosamine 100pg vs. control, 100pg vs. 10ug and 10pg vs. control.
[0120] Differentially expressed genes were determined by first using ratios of AAstim vs. AA and EPAstim vs. EPA followed by a paired t test (0=0.05) for the ratios of AAstim/AA and EPAstim/EPA.
[0121] Differentially expressed genes following a unidirectional trend for all glucosamine and chondroitin sulfate analyses were determined for each treatment pair where responses to the treatment resulted in increases or decreases, in the same direction, in all three samples.
[0122] Differentially expressed genes were determined using a Welch modified two- sample t test for both 1,25 D3 vs. control and 24,25 D3 vs. control (0=0.05). 1. Chondroitin Sulfate Treatment
[0123] Chondrocytes were treated with chondroitin sulfate based on the recognition of chondroitin sulfate as a joint nutrient. Chondrocyte beads were treated with 100 pg/mL, 10 ng/mL or O ug/mL (control) chondroitin sulfate (n=3) for 1 week in DMEM/F12 + P/S + 10%
FBS. Media was changed every other day. After one week, the chondrocytes beads were dissolved in sodium citrate (55mM) and EDTA (30mM). Suspensions were centrifuged at 1800 rpm for 10minutes. Cells were washed with phosphate buffer and centrifuged again at 1800 rpm for 5 minutes. One mL lysis binding solution (Ambion® RNAqueous™) was added to the isolated canine chondrocyte pellet, mixed thoroughly and stored at "20°C until RNA isolation could be performed. One sample from the chondroitin sulfate treatment was removed due to poor correlation with the rest of the array data. This reduced this analysis to an n=3. The results are shown in Tables 7-12. with Chondroitin Sulfate Treatment Comparing the Effect of 100 pg/mL and 10 pg/mL Chondroitin Sulfate on
:
TABLE 8: Differential Expression of OA-Associated Genes of 100 pg/mL and 0 pg/mL Chondroitin Sulfate (Control) on Chondrocytes (p<0.5)
[1304a ~ [035 T7280 |,
BEE YT I § VS as (010 ior [73a 1-029 ~~ J122 (995a |-060 [152 with Chondroitin Sulfate Treatment Comparing the Effect of 10 pg/mL and 0 pg/mL Chondroitin Sulfate (Control) on
Chondrocytes (p<0.5)
TABLE 10: Differential Expression of OA-Associated
Effect of 100 pg/mL and 10 pg/mL Chondroitin Sulfate on
Chondrocytes; Dataset shows a Unidirectional Trend in
Fold Change Across All Samples (1b [oed [161 soa Joa [isd] soa oso list
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Tee [ow [tor ooze [016 uz o102a [064 [156
CE SR FY
F7S ES RS FN US om oar Jin
ECTS YE a [od [im os oer J1s6
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EN EY SS FA CA
TABLE 11: Differential Expression of OA-Associated
Effect of 100 ng/mL and 0 pg/mL (Control) Chondroitin
Sulfate on Chondrocytes; Dataset shows a Unidirectional
Trend in Fold Change Across All Samples [1456b 1-009 [106
BS [A FW VR
BES FY S Fv BA
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Genes with Chondroitin Sulfate Treatment Comparing the
Effect of 10 pg/mL and 0 pg/mL (Control) Chondroitin
Sulfate on Chondrocytes; Dataset shows a Unidirectional
Trend in Fold Change Across All Samples
FER TS 7 SE
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EC UT FY A
2. Glucosamine Treatment
[0124] Glucosamine treatment was used to determine the effect of this joint health nutrient on the differential expression of OA-associated genes. Chondrocyte beads were treated with 100 pg/mL, 10 pg/mL or O pg/mL (control) glucosamine (n=3) for 1 week in DMEM/F12 + - P/S + 10% FBS. Media was changed every other day. After one week, the chondrocytes beads were dissolved in sodium citrate (55mM) and EDTA (30mM). Suspensions were centrifuged at 1800 rpm for 10minutes. Cells were washed with phosphate buffer and centrifuged again at 1800 rpm for 5 minutes. One mL lysis binding solution (Ambion® RNAqueous™) was added to the isolated canine chondrocyte pellet, mixed thoroughly and stored at "20°C until RNA isolation could be performed. The results are shown in Tables 13-18.
TABLE 13: Differential Expression of OA-Associated
Genes with Glucosamine Treatment Comparing the Effect of 100 pg/mL and 10 pg/mL Glucosamine on Chondrocytes (p<0.5)
DIF (100-10) 1044c 1131b 1257b 147% 1532a 16562 1896b 2085c 2137b 841b
TABLE 14: Differential Expression of OA-Associated
Genes with Glucosamine Treatment Comparing the Effect of 100 pg/mL and 0 pg/mL (Control) Glucosamine on
Chondrocytes (p<0.5)
DIF (100-C)
ae [ims (3a [mesa Jose Tie
TABLE 15: Differential Expression of OA-Associated
Genes with Glucosamine Treatment Comparing the Effect of 10 pg/mL and 0 pg/mL (Control) Glucosamine on
Chondrocytes (p<0.5) }
TABLE 16: Differential Expression of OA-Associated of 100 pg/mL and 10 pg/mL Glucosamine on
Chondrocytes; Dataset shows a Unidirectional Trend in
Fold Change Across All Samples (1099c ~~ [066 [158
16562 [073 ~~ |166 [16604 [060 ~~ ier
Genes with Glucosamine Treatment Comparing the Effect of 100 ng/mL and 0 pg/mL (Control) Glucosamine on
Chondrocytes; Dataset shows a Unidirectional Trend in
Fold Change Across All Samples
(283% |-069 [162
TABLE 18: Differential Expression of OA-Associated
Genes with Glucosamine Treatment Comparing the Effect
Chondrocytes; Dataset shows a Unidirectional Trend in
Fold Change Across All Samples (14002 [-066 ~~ ]158 [1405 Joe6 ~~ J158
(643 __ Joas [isa 1670d 094 13 1683a 136 (251 1712a os tia 1948b 02s lio a es ao7 2095a 094 Juez 2117b 114 220 45.1b 468f 50.2d 530b 553b 557b 3. 10,25-dihydroxyvitamin D3 (1,25 D3) and 24R,25-dihydroxyvitamin D3 (24,25
D3) Treatment
[0125] 1,25 D3 and 24R,25D3 treatment was applied to chondrocytes based on their known effects on prostaglandin production and differential responses to the vitamin D3 metabolites in chondrocytes to determine the effect of these compounds on OA-associated gene expression. Chondrocyte beads were treated with 107M 1,25 D3 or 10M 24,25 D3 for 24 hours or without Vitamin D (equivalent ethanol was added to control), (n=3) in DMEM/F12 + P/S + 10% FBS. After 24 hours, the chondrocyte beads were dissolved in sodium citrate (55mM) and
EDTA (30mM). Suspensions were centrifuged at 1800 rpm for 10 minutes. Cells were washed with phosphate buffer and centrifuged again at 1800 rpm for 5 minutes. One mL lysis binding solution (Ambion® RNAqueous™) was added to the isolated canine chondrocyte pellet, mixed thoroughly and stored at -20°C until RNA isolation could be performed. The results are shown in Tables 19 and 20.
dihvdroxyvitamin D; Treatment on Chondrocytes (p<0.5) oz [1095 [ioa2 - [os [L771
Jom [ila [ws [oa [136
C068 962 [sss [073 [166 10%a [968 Jos |o3 ~~ [125 : i101a [776 |716 oe [151 1120s 817 |777 [040 ~~ [132 1147s [804 |743 _ |06L 1152 117d [860 [sie [oa [135 174d [066 [830 [136 [257 1178s [812 [75s [os7 [149 1275 |s72 sor 064 [156 d6la [789 |696 (002 [190 1503 [886 |s47 [040 ~~ ]132 iss4c [000 so [061 ~~ ]152 u7b [927 [106 |179 [346 2163 [869 749 120 ~~ [230 22666 [860 792 077 [171 [23372 [1357 1262 [095 ~~ [193
[2342 [795 [761 © [033 1126 (235% [843 [79 ~~ [-047 [138 dihydroxyvitamin D; Treatment on Chondrocytes (p<0.5) (1023 |1iar (048 [064 0 [156 (3402 {771 [841 1069 [162 [371a 933 960 026 [1.20 131 1.23 4. Eicosapentaenoic acid (EPA) and Arachidonic Acid (AA) Treatment
[0126] Chondrocytes were treated with eicosapentaenoic acid (EPA) and arachidonic acid (AA) based on the recognition in the literature that EPA acts as an anti-inflammatory. AA was used as a control to represent a typical western diet. Chondrocytes were enriched with 50uM
EPA or 50uM AA (using albumin as a carrier) for two weeks in DMEM/HAMS + P/S + 10%
FBS. Media was changed every other day. Each set (n=3) was split and half were treated with stimulated monocyte neutrophil conditioned media (SMNCM) for one week with media changed every other day. SMNCM was made by isolating monocytes and neutrophils from canine whole blood using NycoPrep™ according to the manufacture’s directions. Monocytes and neutrophils were stimulated with lipopolysaccharide (20ng/mL) for 72 hours. The resulting supernatant was used as SMNCM in cell culture experimentation (SMNCM made up 10% of media used during experimentation). Chondrocyte beads were dissolved in sodium citrate (55mM) and EDTA (30mM). Suspensions were centrifuged at 1800 rpm for 10minutes. Cells were washed with phosphate buffer and centrifuged again at 1800 rpm for 5 minutes. One mL lysis binding solution (Ambion® RNAqueous™) was added to the isolated canine chondrocyte pellet, mixed thoroughly and stored at -20°C until RNA isolation could be performed. One sample from the
EPA/AA stim treatment was removed due to poor correlation with the rest of the array data.
This reduced these analyses to an n=3. The results are shown in Tables 21-23.
TABLE 21: Differential Expression of OA-Associated
Genes Comparing AA Treatment with EPA ! Treatment of Chondrocytes (p<0.05) : DIF (AA-EPA) 1190b 1381a 1391a ' | 1450a 1451a 1466b 16782 1730a 20952 [oop J-017 [113 ' {
TABLE 22: Differential Expression of OA-
Associated Genes with Inflammatory Stimulation
Comparing AA Treatment with EPA Treatment of
Chondrocytes (p<0.05)
DIF (AAs-EPAs) 1099¢ 1104b 1106a 1184a 1190b 1323b-r 133%
ota Joss Tie (14252 068 161 [164c [060 — Ji61 ] [21132 [090 18
TABLE 23: Differential Expression of OA-Associated Genes with Inflammatory (p<0.05) [1091 [120 __Joso fo30 [123 [13395 [1901 [009 _ |-200 ~~ [400 (1340 (083 [016 066 ~~ |158 (1406a [046 [009 [037 ~~ |129 (15982 1019 [009 Jo27 [121 [1741a___ |002 [064 |o66 1158
1981a 2255a 253b 350b 079 Jooo l-087 0 [18 465b [4% [045 Joos ~~ [-054 0 [145 |- - 706b [7092 [053 lo09 load 0 [136 758b
[0127] The experiments demonstrated that various treatments can affect the expression of OA-associated genes. In some cases, the effect on gene expression was statistically significant (p<0.05). In other cases, although the change could not be demonstrated to be statistically significant due to the variability of expression, there was a definite trend for expression to be changed in one direction only (either increased expression or decreased expression). This unidirectional change is considered to be both biologically relevant and significant. In some cases, it is believed that down-regulation of expression of certain genes will have a beneficial biological effect on OA. For other genes, increased expression will have a beneficial biological effect. The invention allows the identification of genes that correlate with beneficial effects as demonstrated by regulation of compounds known to be involved in anti- inflammatory processes, for example. The invention also permits the identification of new compounds which should have beneficial effects based on their regulation of gene expression of the OA-associated genes described in this invention.
[0128] The results demonstrate that one can affect the biology of the cells with various treatments and have a direct impact on gene expression of OA-associated genes. The invention permits the rapid and powerful screening of compounds to identify candidate treatments and preventatives of OA in animals, particularly humans.
[0129] The disclosures of each patent, patent application, publication and accession number to database sequences cited or described in this document are hereby incorporated herein by reference, in their entirety.
[0130] Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications
Claims (33)
1. A combination comprising a plurality of polynucleotide molecules wherein the polynucleotide molecules are differentially expressed in an osteoarthritic subject or in a pre- osteoarthritic subject compared to expression in subjects which are not osteoarthritic or pre- osteoarthritic.
2. The combination of claim 1, wherein the plurality of polynucleotide molecules comprises two or more molecules selected from SEQ ID NOs:1-1558 or fragments thereof.
3. A method for the detection of differential expression of nucleic acids in a sample, comprising the steps of: a) hybridizing a combination comprising a plurality of polynucleotide molecules wherein the polynucleotide molecules are differentially expressed in an osteoarthritic subject or in a pre- osteoarthritic subject compared to expression in subjects which are not osteoarthritic or pre- osteoarthritic with nucleic acids of the sample, thereby forming one or more hybridization complexes; b) detecting the hybridization complexes; and c) comparing the hybridization complexes with those of a standard, wherein differences between the standard and sample hybridization complexes indicate differential expression of nucleic acids in the sample.
4. The method of claim 3, wherein the polynucleotide molecules hybridize with nucleic acid sequences selected from SEQ ID NOs:1-1558 or fragments thereof.
5. The method of claim 3, wherein the polynucleotide molecules hybridize with nucleic acid sequences selected from gene sequences identified in Table 2 or fragments thereof.
6. A method for the detection of differential expression of polypeptides in a sample, comprising the steps of: a) reacting a combination comprising a plurality of protein binding molecules with polypeptides of the sample, thereby allowing specific binding to occur, wherein the proteins bound by the protein-binding molecules are differentially expressed in an osteoarthritic subject or in a pre- osteoarthritic subject compared to expression in subjects which are not osteoarthritic or pre- osteoarthritic; b) detecting specific binding; and ¢) comparing the specific binding in the sample with that of a standard, wherein differences between the standard and sample specific binding indicate differential expression of polypeptides - in the sample.
7. The method of claim 3 or 6, further comprising the step of treating the sample with a test compound, wherein comparison to a standard is indicative of whether treatment with the test compound altered the differential expression of nucleic acids or polypeptides in the sample.
8. A composition of matter comprising a collection of two or more probes for detecting expression of genes differentially expressed in osteoarthritic or pre-osteoarthritic subjects compared to subjects that are not osteoarthritic or pre-osteoarthritic, wherein the probes comprise two or more of: a) nucleic acid molecules that specifically hybridize to two or more of the genes or gene fragments identified in Tables 1 and 2, or fragments thereof; or b) polypeptide binding agents that specifically bind to polypeptides produced by expression of two or more nucleic acid molecules comprising sequences selected from one or more of genes or gene fragments identified in Tables 1 and 2, or fragments thereof.
9. The composition of claim 8 wherein the genes or gene fragments comprise SEQ ID NOs:1- 1558 or fragments thereof.
10. The composition of claim 8 wherein the gene or gene fragments comprise genes or gene fragments identified in Table 2.
11. A device for detecting expression of a plurality of genes differentially expressed in osteoarthritis, comprising a substrate to which is affixed, at known locations, a plurality of probes, wherein the probes comprise:
a) a plurality of oligonucleotides or polynucleotides, each of which specifically hybridizes to a different sequence selected from any of SEQ ID NOS: 1-1558 or fragments thereof; or b) a plurality of polypeptide binding agents, each of which specifically binds to a different polypeptide or fragment thereof produced by expression of a nucleic acid molecule comprising a sequence selected from the genes or gene fragments comprising any of SEQ ID NOS: 1-1558 or fragments thereof. -
12. A method for measuring the effect of a test compound on the expression of one or more genes differentially expressed in osteoarthritis, comprising the steps of: : a) measuring standard expression by measuring transcription or translation products of one or more of the genes or gene fragments comprising any of SEQ ID NOS: 1-1558, or fragments thereof, in a standard sample in the absence of the test compound, : b) measuring test expression by measuring the transcription or translation products of one or more of the genes or gene fragments comprising any of SEQ ID N 0S: 1-1558, or fragments thereof, in a test sample in the presence of the test compound; ¢) comparing the standard expression to the test expression, wherein a change in the test expression compared to the standard expression is indicative of an effect of the test compound on the expression of genes differentially expressed in osteoarthritis compared to a non-osteoarthritic condition.
13. The method of claim 12, wherein said measuring utilizes a composition of matter comprising a plurality of probes, wherein the probes comprise two or more of two or more of the genes or gene fragments comprising any of SEQ ID NOS: 1-1558, or fragments thereof.
14. The method of claim 12, wherein the standard and test samples are obtained from at least one mammalian subject.
15. A method for measuring the effect of a test compound on expression of an OA-associated gene, wherein the gene is selected from the group consisting of the genes identified in Table 6, the method comprising measuring production of transcription or translation products produced by expression of the gene in the presence or absence of the test compound, wherein a change in the production of transcription or translation products in the presence of the test compound is . indicative of an effect of the test compound on expression of the gene.
16. The method of claim 15, wherein the gene expression is measured by providing a DNA construct comprising a reporter gene coding sequence operably linked to transcription regulatory sequences of the OA-associated gene, and measuring formation of a reporter gene product in the presence or absence of the test compound. -
17. A method to diagnose or develop a prognosis for a subject who exhibits signs of osteoarthritis, the method comprising: a) obtaining a sample from the subject; b) measuring in the sample the production of transcription or translation products produced by the expression of one or more OA-associated genes or gene fragments comprising any of SEQ ID NOS: 1-1558, or fragments thereof; ¢) comparing the transcription or translation products of the sample with that of a standard, wherein a difference in the expression of any of the OA-associated genes or gene fragments is indicative of osteoarthritis.
18. A kit for detecting the presence of osteoarthritis or predisposition for osteoarthritis in a subject comprising one or more oligonucleotides of at least about 10 consecutive nucleotides of a sequence selected from sequences hybridizing to two or more genes or gene fragments comprising any of SEQ ID NOS: 1-1558, or fragments thereof, wherein the oligonucleotides specifically bind to nucleic acids differentially expressed in an osteoarthritic subject or ina subject predisposed to osteoarthritis compared to expression in subjects which are not osteoarthritic or predisposed to osteoarthritis.
19. A kit for assaying the expression of genes differentially expressed in osteoarthritis, comprising a container containing a collection of two or more probes, wherein the probes comprise one or:more of: a) oligonucleotides or polynucleotides that specifically hybridize to two or more genes or gene fragments comprising any of SEQ ID NOS: 1-1558, or fragments thereof; or
PCT/US2005/003375 ® b) polypeptide binding agents that specifically bind to polypeptides produced by expression of two or more genes or gene fragments comprising any of SEQ ID NOS: 1-1558, or fragments thereof; and instructions for performing an assay of gene expression.
20. Use of a compound that affects the expression of at least one gene associated with osteoarthritis having a sequence selected from SEQ ID NOS: 1-1588, or fragments thereof, in the manufacture of a medicament for modulating osteoarthritis-associated gene expression in a cell.
21. Use of a compound that affects the expression of at least one gene associated with osteoarthritis having a gene product identified in Table 6, in the manufacture of a medicament for modulating osteoarthritis-associated gene expression in a cell.
22. Use of claim 20 or 21, wherein the compound is a vitamin, mineral, neutriceutical, small molecule pharmaceutical, protein, polypeptide, nucleic acid, fatty acid or polysaccharide.
23. Use of claim 22, wherein the compound is eicosopentaenoic acid, arachidonic acid, glucosamine, chondroitin sulfate, 1a,25-dihydroxyvitamin D3, or 24R,25-dihydroxyvitamin
D3.
24. A method for identifying compounds that modulate osteoarthritis-associated genes comprising: a) measuring standard expression by measuring transcription or translation products of one or more of the genes or gene fragments comprising any of SEQ ID NOS: 1-1558, or fragments thereof], in a standard sample in the absence of a test compound; b) measuring test expression by measuring the transcription or translation products of one or more of the genes or gene fragments comprising any of SEQ ID NOS: 1-1558, or fragments thereof, in a test sample in the presence of the test compound; and ¢) comparing the standard expression to the test expression, wherein a change in the test expression compared to the standard expression is indicative of an effect of the test compound on the expression of genes differentially expressed in osteoarthritis compared to a non-osteoarthritic condition. 155 AMENDED SHEET
PCT/US2005/003375 ® 25. A combination of claim 1 or claim 2, substantially as herein described with reference to and as illustrated in any of the examples and accompanying figures.
26. A method of any one of claims 3 to 7, substantially as herein described with reference to and as illustrated in any of the examples and accompanying figures.
27. A composition of any one of claims 8 to 10, substantially as herein described with reference to and as illustrated in any of the examples and accompanying figures.
28. A device of claim 11, substantially as herein described with reference to and as illustrated in any of the examples and accompanying figures.
29. A method of any one of claims 12 to 16, substantially as herein described with reference to and as illustrated in any of the examples and accompanying figures.
30. A method of claim 17, substantially as herein described with reference to and as illustrated in any of the examples and accompanying figures.
31. A kit of claim 18 or claim 19, substantially as herein described with reference to and as illustrated in any of the examples and accompanying figures.
32. Use of any one of claims 20 to 23, substantially as herein described with reference to and as illustrated in any of the examples and accompanying figures.
33. A method of claim 24, substantially as herein described with reference to and as illustrated in any of the examples and accompanying figures. 156 AMENDED SHEET
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| CA2739011A1 (en) * | 2007-10-29 | 2009-05-07 | The Regents Of The University Of California | Osteoarthritis gene therapy |
| EP2123775A1 (en) * | 2008-05-20 | 2009-11-25 | Stiftung Tierärztliche Hochschule Hannover | Analysis for the genetic disposition for hip dysplasia in Canidae |
| US9464330B2 (en) | 2012-12-21 | 2016-10-11 | Pioneer Hi-Bred International, Inc. | Genetic loci associated with soybean cyst nematode resistance and methods of use |
| CN105803085B (en) * | 2016-04-27 | 2019-07-19 | 范彧 | A kind of molecular marked compound and application thereof detecting osteoarthritis |
| TWI827321B (en) * | 2020-03-20 | 2023-12-21 | 台灣粒線體應用技術股份有限公司 | Composition containing mitochondria and its use as a collagen proliferation promoter |
| CN113249464B (en) * | 2021-04-13 | 2022-09-27 | 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） | Use of circular RNA as osteoarthritis marker |
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| CA2555083A1 (en) | 2005-08-18 |
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