MicroRNA targets in Drosophila

Genome Biology

Volumn 5, Issue 1, 2003, Pages

  Enright, Anton J ^a   John, Bino ^a   Gaul, Ulrike ^b   Tuschl, Thomas ^b   Sander, Chris ^a   Marks, Debora S ^c  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b ROCKEFELLER UNIVERSITY   (United States)

^c Russ Berrie Pavilion ^*  (United States)

Author keywords

Additional Data File; Ecdysone; miRNA Sequence; miRNA Target; Target Site

Indexed keywords

ECDYSONE; HOMEODOMAIN PROTEIN; MICRORNA;

3' UNTRANSLATED REGION; ANIMAL; ARTICLE; BIOLOGY; CHEMISTRY; DROSOPHILA MELANOGASTER; GENE; GENE EXPRESSION REGULATION; GENETICS; HOMEOBOX; METABOLISM; METHODOLOGY; NERVOUS SYSTEM; PREDICTION AND FORECASTING; PRENATAL DEVELOPMENT; SIGNAL TRANSDUCTION;

3' UNTRANSLATED REGIONS; ANIMALS; COMPUTATIONAL BIOLOGY; DROSOPHILA MELANOGASTER; ECDYSONE; GENE EXPRESSION REGULATION, DEVELOPMENTAL; GENES, HOMEOBOX; GENES, INSECT; HOMEODOMAIN PROTEINS; MICRORNAS; NERVOUS SYSTEM; PREDICTIVE VALUE OF TESTS; SIGNAL TRANSDUCTION;

EID: 0842321501     PISSN: 14747596     EISSN: 1474760X     Source Type: Journal    
DOI: 10.1186/gb-2003-5-1-r1     Document Type: Article

References (87)

1. Pasquinelli AE: MicroRNAs: deviants no longer. Trends Genet. 2002, 18: 171-173. 10.1016/S0168-9525(01)02624-5. DOI: 10.1016/S0168-9525(01)02624-5
2. Ambros V: MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell. 2003, 113: 673-676. 10.1016/S0092-8674(03)00428-8. DOI: 10.1016/S0092-8674(03)00428-8
3. Carrington JC, Ambros V: Role of microRNAs in plant and animal development. Science. 2003, 301: 336-338. 10.1126/science.1085242. DOI: 10.1126/science.1085242
4. Lin SY, Johnson SM, Abraham M, Vella MC, Pasquinelli A, Gamberi C, Gottlieb E, Slack FJ: The C. elegans hunchback Homolog, hbl-1, controls temporal patterning and is a probable MicroRNA target. Dev Cell. 2003, 4: 639-650. 10.1016/S1534-5807(03)00124-2. DOI: 10.1016/S1534-5807(03)00124-2
5. The miRNA registry. [http://www.sanger.ac.uk/Software/Rfam/mirna/]
6. Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen X, Dreyfuss G, Eddy SR, Griffiths-Jones S, Marshall M, et al: A uniform system for microRNA annotation. RNA. 2003, 9: 277-279. 10.1261/rna.2183803. DOI: 10.1261/rna.2183803
7. Slack F, Ruvkun G: Temporal pattern formation by heterochronic genes. Annu Rev Genet. 1997, 31: 611-634. 10.1146/annurev.genet.31.1.611. DOI: 10.1146/annurev.genet.31.1.611
8. Pasquinelli AE, Ruvkun G: Control of developmental timing by microRNAs and their targets. Annu Rev Cell Dev Biol. 2002, 18: 495-513. 10.1146/annurev.cellbio.18.012502.105832. DOI: 10.1146/annurev.cellbio.18.012502.105832
9. Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Muller P, et al: Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000, 408: 86-89. 10.1038/35040556. DOI: 10.1038/35040556
10. Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T: Identification of tissue-specific microRNAs from mouse. Curr Biol. 2002, 12: 735-739. 10.1016/S0960-9822(02)00809-6. DOI: 10.1016/S0960-9822(02)00809-6
11. Moss EG, Tang L: Conservation of the heterochronic regulator Lin-28, its developmental expression and microRNA complementary sites. Dev Biol. 2003, 258: 432-442. 10.1016/S0012-1606(03)00126-X. DOI: 10.1016/S0012-1606(03)00126-X
12. Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM: bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell. 2003, 113: 25-36. 10.1016/S0092-8674(03)00231-9. DOI: 10.1016/S0092-8674(03)00231-9
13. Xu P, Vernooy SY, Guo M, Hay BA: The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism. Curr Biol. 2003, 13: 790-795. 10.1016/S0960-9822(03)00250-1. DOI: 10.1016/S0960-9822(03)00250-1
14. Rhoades MW, Reinhart BJ, Lim LP, Burge CB, Bartel B, Bartel DP: Prediction of plant microRNA targets. Cell. 2002, 110: 513-520. 10.1016/S0092-8674(02)00863-2. DOI: 10.1016/S0092-8674(02)00863-2
15. Llave C, Xie Z, Kasschau KD, Carrington JC: Cleavage of scarecrow-like mRNA targets directed by a class of Arabidopsis miRNA. Science. 2002, 297: 2053-2056. 10.1126/science.1076311. DOI: 10.1126/science.1076311
16. Palatnik JF, Allen E, Wu X, Schommer C, Schwab R, Carrington JC, Weigel D: Control of leaf morphogenesis by microRNAs. Nature. 2003, 425: 257-263. 10.1038/nature01958. DOI: 10.1038/nature01958
17. Chen X: A microRNA as a translational repressor of APETALA2 in Arabidopsis flower development. Science. 11 September 2003 (10.1126/science.1088060)
18. Tang G, Reinhart BJ, Bartel DP, Zamore PD: A biochemical framework for RNA silencing in plants. Genes Dev. 2003, 17: 49-63. 10.1101/gad.1048103. DOI: 10.1101/gad.1048103
19. Xie Z, Kasschau KD, Carrington JC: Negative feedback regulation of dicer-like1 in Arabidopsis by microRNA-guided mRNA degradation. Curr Biol. 2003, 13: 784-789. 10.1016/S0960-9822(03)00281-1. DOI: 10.1016/S0960-9822(03)00281-1
20. Lee RC, Feinbaum RL, Ambros V: The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993, 75: 843-854. 10.1016/0092-8674(93)90529-Y. DOI: 10.1016/0092-8674(93)90529-Y
21. Wightman B, Ha I, Ruvkun G: Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993, 75: 855-862. 10.1016/0092-8674(93)90530-4. DOI: 10.1016/0092-8674(93)90530-4
22. Moss EG, Lee RC, Ambros V: The cold shock domain protein LIN-28 controls developmental timing in C. elegans and is regulated by the lin-4 RNA. Cell. 1997, 88: 637-646. 10.1016/S0092-8674(00)81906-6. DOI: 10.1016/S0092-8674(00)81906-6
23. Slack FJ, Basson M, Liu Z, Ambros V, Horvitz HR, Ruvkun G: The lin-41 RBCC gene acts in the C. elegans heterochronic pathway between the let-7 regulatory RNA and the LIN-29 transcription factor. Mol Cell. 2000, 5: 659-669. DOI: 10.1016/S1097-2765(00)80245-2
24. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G: The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000, 403: 901-906. 10.1038/35002607. DOI: 10.1038/35002607
25. Abrahante JE, Daul AL, Li M, Volk ML, Tennessen JM, Miller EA, Rougvie AE: The Caenorhabditis elegans hunchback-like Gene lin-57/hbl-1 controls developmental time and is regulated by microRNAs. Dev Cell. 2003, 4: 625-637. 10.1016/S1534-5807(03)00127-8. DOI: 10.1016/S1534-5807(03)00127-8
26. Bernstein E, Caudy AA, Hammond SM, Hannon GJ: Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature. 2001, 409: 363-366. 10.1038/35053110. DOI: 10.1038/35053110
27. Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD: A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science. 2001, 293: 834-838. 10.1126/science.1062961. DOI: 10.1126/science.1062961
28. Park W, Li J, Song R, Messing J, Chen X: CARPEL FACTORY, a Dicer homolog, and HEN1, a novel protein, act in microRNA metabolism in Arabidopsis thaliana. Curr Biol. 2002, 12: 1484-1495. 10.1016/S0960-9822(02)01017-5. DOI: 10.1016/S0960-9822(02)01017-5
29. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S, Kim VN: The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003, 425: 415-419. 10.1038/nature01957. DOI: 10.1038/nature01957
30. Lee Y, Jeon K, Lee JT, Kim S, Kim VN: MicroRNA maturation: stepwise processing and subcellular localization. EMBO J. 2002, 21: 4663-4670. 10.1093/emboj/cdf476. DOI: 10.1093/emboj/cdf476
31. Hammond SM, Bernstein E, Beach D, Hannon GJ: An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature. 2000, 404: 293-296. 10.1038/35005107. DOI: 10.1038/35005107
32. Martinez LA, Naguibneva I, Lehrmann H, Vervisch A, Tchenio T, Lozano G, Harel-Bellan A: Synthetic small inhibiting RNAs: efficient tools to inactivate oncogenic mutations and restore p53 pathways. Proc Natl Acad Sci USA. 2002, 99: 14849-14854. 10.1073/pnas.222406899. DOI: 10.1073/pnas.222406899
33. Hutvagner G, Zamore PD: A microRNA in a multiple-turnover RNAi enzyme complex. Science. 2002, 297: 2056-2060. 10.1126/science.1073827. DOI: 10.1126/science.1073827
34. Zeng Y, Yi R, Cullen BR: MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc Natl Acad Sci USA. 2003, 100: 9779-9784. 10.1073/pnas.1630797100. DOI: 10.1073/pnas.1630797100
35. Doench JG, Petersen CP, Sharp PA: siRNAs can function as miRNAs. Genes Dev. 2003, 17: 438-442. 10.1101/gad.1064703. DOI: 10.1101/gad.1064703
36. Saxena S, Jonsson ZO, Dutta A: Small RNAs with imperfect match to endogenous mRNA repress translation: implications for off-target activity of siRNA in mammalian cells. J Biol Chem. 2003, 278: 44312-44319. 10.1074/jbc.M307089200. DOI: 10.1074/jbc.M307089200
37. Elbashir SM, Martinez J, Patkaniowska A, Lendeckel W, Tuschl T: Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate. EMBO J. 2001, 20: 6877-6888. 10.1093/emboj/20.23.6877. DOI: 10.1093/emboj/20.23.6877
38. Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, Li B, Cavet G, Linsley PS: Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol. 2003, 21: 635-637. 10.1038/nbt831. DOI: 10.1038/nbt831
39. Supplementary Material for: 'MicroRNA targets in Drosophila. [http://www.microrna.org/]
40. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T: Identification of novel genes coding for small expressed RNAs. Science. 2001, 294: 853-858. 10.1126/science.1064921. DOI: 10.1126/science.1064921
41. Sempere LF, Sokol NS, Dubrovsky EB, Berger EM, Ambros V: Temporal regulation of microRNA expression in Drosophila melanogaster mediated by hormonal signals and broad-Complex gene activity. Dev Biol. 2003, 259: 9-18. 10.1016/S0012-1606(03)00208-2. DOI: 10.1016/S0012-1606(03)00208-2
42. Aravin AA, Lagos-Quintana M, Yalcin A, Zavolan M, Marks D, Snyder B, Gaasterland T, Meyer J, Tuschl T: The small RNA profile during Drosophila melanogaster development. Dev Cell. 2003, 5: 337-350. 10.1016/S1534-5807(03)00228-4. DOI: 10.1016/S1534-5807(03)00228-4
43. Lai EC, Tomancak P, Williams RW, Rubin GM: Computational identification of Drosophila microRNA genes. Genome Biol. 2003, 4: R42-10.1186/gb-2003-4-7-r42. DOI: 10.1186/gb-2003-4-7-r42
44. Wuchty S, Fontana W, Hofacker IL, Schuster P: Complete suboptimal folding of RNA and the stability of secondary structures. Biopolymers. 1999, 49: 145-165. 10.1002/(SICI)1097-0282(199902)49:2<145::AID-BIP4>3.3.CO;2-7. DOI: 10.1002/(SICI)1097-0282(199902)49:2<145::AID-BIP4>3.0.CO;2-G
45. Griffiths-Jones S, Bateman A, Marshall M, Khanna A, Eddy SR: Rfam: an RNA family database. Nucleic Acids Res. 2003, 31: 439-441. 10.1093/nar/gkg006. DOI: 10.1093/nar/gkg006
46. Bray N, Dubchak I, Pachter L: AVID: A global alignment program. Genome Res. 2003, 13: 97-102. 10.1101/gr.789803. DOI: 10.1101/gr.789803
47. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al: Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000, 25: 25-29. 10.1038/75556. DOI: 10.1038/75556
48. Hubbard T, Barker D, Birney E, Cameron G, Chen Y, Clark L, Cox T, Cuff J, Curwen V, Down T, et al: The Ensembl genome database project. Nucleic Acids Res. 2002, 30: 38-41. 10.1093/nar/30.1.38. DOI: 10.1093/nar/30.1.38
49. FlyBase Consortium: The FlyBase database of the Drosophila genome projects and community literature. Nucleic Acids Res. 2002, 30: 106-108. 10.1093/nar/30.1.106. DOI: 10.1093/nar/30.1.106
50. Gelbart WM, Crosby M, Matthews B, Rindone WP, Chillemi J, Russo Twombly S, Emmert D, Ashburner M, Drysdale RA, Whitfield E, et al: FlyBase: a Drosophila database. The FlyBase consortium. Nucleic Acids Res. 1997, 25: 63-66. 10.1093/nar/25.1.63. DOI: 10.1093/nar/25.1.63
51. Minakhina S, Steward R: Several small RNAs, one precursor and two genes - a complex locus essential for viability. A Dros Res Conf. 2003, 44: 403A-
52. Minakhina S, Yang J, Steward R: Tamo selectively modulates nuclear import in Drosophila. Genes Cells. 2003, 8: 299-310. DOI: 10.1046/j.1365-2443.2002.00634.x
53. Akam M: Hox genes: from master genes to micromanagers. Curr Biol. 1998, 8: R676-678. DOI: 10.1016/S0960-9822(98)70433-6
54. McGinnis W, Krumlauf R: Homeobox genes and axial patterning. Cell. 1992, 68: 283-302. 10.1016/0092-8674(92)90471-N. DOI: 10.1016/0092-8674(92)90471-N
55. Mann RS: Why are Hox genes clustered?. Bioessays. 1997, 19: 661-664. DOI: 10.1002/bies.950190804
56. Lagos-Quintana M, Rauhut R, Meyer J, Borkhardt A, Tuschl T: New microRNAs from mouse and human. RNA. 2003, 9: 175-179. 10.1261/rna.2146903. DOI: 10.1261/rna.2146903
57. Simon JA, Tamkun JW: Programming off and on states in chromatin: mechanisms of Polycomb and trithorax group complexes. Curr Opin Genet Dev. 2002, 12: 210-218. 10.1016/S0959-437X(02)00288-5. DOI: 10.1016/S0959-437X(02)00288-5
58. Rieckhof GE, Casares F, Ryoo HD, Abu-Shaar M, Mann RS: Nuclear translocation of extradenticle requires homothorax, which encodes an extradenticle-related homeodomain protein. Cell. 1997, 91: 171-183. 10.1016/S0092-8674(00)80400-6. DOI: 10.1016/S0092-8674(00)80400-6
59. Riddiford M: Hormones and Drosophila Development. In The Development of Drosophila melanogaster. Edited by: Martinez Arias M, Bate A. 1993, Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 899-940.
60. Baehrecke EH: Steroid regulation of programmed cell death during Drosophila development. Cell Death Differ. 2000, 7: 1057-1062. 10.1038/sj.cdd.4400753. DOI: 10.1038/sj.cdd.4400753
61. Thummel CS: Molecular mechanisms of developmental timing in C. elegans and Drosophila. Dev Cell. 2001, 1: 453-465. 10.1016/S1534-5807(01)00060-0. DOI: 10.1016/S1534-5807(01)00060-0
62. Thummel CS, Chory J: Steroid signaling in plants and insects - common themes, different pathways. Genes Dev. 2002, 16: 3113-3129. 10.1101/gad.1042102. DOI: 10.1101/gad.1042102
63. Simon AF, Shih C, Mack A, Benzer S: Steroid control of longevity in Drosophila melanogaster. Science. 2003, 299: 1407-1410. 10.1126/science.1080539. DOI: 10.1126/science.1080539
64. Broadus J, McCabe JR, Endrizzi B, Thummel CS, Woodard CT: The Drosophila beta FTZ-F1 orphan nuclear receptor provides competence for stage-specific responses to the steroid hormone ecdysone. Mol Cell. 1999, 3: 143-149. 10.1016/S1097-2765(00)80305-6. DOI: 10.1016/S1097-2765(00)80305-6
65. D'Avino PP, Thummel CS: crooked legs encodes a family of zinc finger proteins required for leg morphogenesis and ecdysone-regulated gene expression during Drosophila metamorphosis. Development. 1998, 125: 1733-1745.
66. Beckstead R, Ortiz JA, Sanchez C, Prokopenko SN, Chambon P, Losson R, Bellen HJ: Bonus, a Drosophila homolog of TIF1 proteins, interacts with nuclear receptors and can inhibit betaFTZ-F1-dependent transcription. Mol Cell. 2001, 7: 753-765. 10.1016/S1097-2765(01)00220-9. DOI: 10.1016/S1097-2765(01)00220-9
67. Dunne JC, Kondylis V, Rabouille C: Ecdysone triggers the expression of Golgi genes in Drosophila imaginal discs via broad-complex. Dev Biol. 2002, 245: 172-186. 10.1006/dbio.2002.0632. DOI: 10.1006/dbio.2002.0632
68. Jiang C, Lamblin AF, Steller H, Thummel CS: A steroid-triggered transcriptional hierarchy controls salivary gland cell death during Drosophila metamorphosis. Mol Cell. 2000, 5: 445-455. DOI: 10.1016/S1097-2765(00)80439-6
69. Jiang C, Baehrecke EH, Thummel CS: Steroid regulated programmed cell death during Drosophila metamorphosis. Development. 1997, 124: 4673-4683.
70. Wismar J, Habtemichael N, Warren JT, Dai JD, Gilbert LI, Gateff E: The mutation without children(rgl) causes ecdysteroid deficiency in third-instar larvae of Drosophila melanogaster. Dev Biol. 2000, 226: 1-17. 10.1006/dbio.2000.9811. DOI: 10.1006/dbio.2000.9811
71. Rayburn LY, Gooding HC, Choksi SP, Maloney D, Kidd AR, Siekhaus DE, Bender M: amontillado, the Drosophila homolog of the prohormone processing protease PC2, is required during embryogenesis and early larval development. Genetics. 2003, 163: 227-237.
72. Kadesch T: Notch signaling: a dance of proteins changing partners. Exp Cell Res. 2000, 260: 1-8. 10.1006/excr.2000.4921. DOI: 10.1006/excr.2000.4921
73. Baker KD, Warren JT, Thummel CS, Gilbert LI, Mangelsdorf DJ: Transcriptional activation of the Drosophila ecdysone receptor by insect and plant ecdysteroids. Insect Biochem Mol Biol. 2000, 30: 1037-1043. 10.1016/S0965-1748(00)00075-8. DOI: 10.1016/S0965-1748(00)00075-8
74. Lai EC, Burks C, Posakony JW: The K box, a conserved 3' UTR sequence motif, negatively regulates accumulation of enhancer of split complex transcripts. Development. 1998, 125: 4077-4088.
75. Lai EC, Rubin GM: Neuralized is essential for a subset of Notch pathway-dependent cell fate decisions during Drosophila eye development. Proc Natl Acad Sci USA. 2001, 98: 5637-5642. 10.1073/pnas.101135498. DOI: 10.1073/pnas.101135498
76. Chisholm A, Tessier-Lavigne M: Conservation and divergence of axon guidance mechanisms. Curr Opin Neurobiol. 1999, 9: 603-615. 10.1016/S0959-4388(99)00021-5. DOI: 10.1016/S0959-4388(99)00021-5
77. Mueller BK: Growth cone guidance: first steps towards a deeper understanding. Annu Rev Neurosci. 1999, 22: 351-388. 10.1146/annurev.neuro.22.1.351. DOI: 10.1146/annurev.neuro.22.1.351
78. Giniger E: How do Rho family GTPases direct axon growth and guidance? A proposal relating signaling pathways to growth cone mechanics. Differentiation. 2002, 70: 385-396. 10.1046/j.1432-0436.2002.700801.x. DOI: 10.1046/j.1432-0436.2002.700801.x
79. Littleton JT, Ganetzky B: Ion channels and synaptic organization: analysis of the Drosophila genome. Neuron. 2000, 26: 35-43. DOI: 10.1016/S0896-6273(00)81135-6
80. Ambros V, Moss EG: Heterochronic genes and the temporal control of C. elegans development. Trends Genet. 1994, 10: 123-127. 10.1016/0168-9525(94)90213-5. DOI: 10.1016/0168-9525(94)90213-5
81. Waterman MS, Eggert M: A new algorithm for best subsequence alignments with application to tRNA-rRNA comparisons. J Mol Biol. 1987, 197: 723-728. DOI: 10.1016/0022-2836(87)90478-5
82. Smith TF, Waterman MS: Identification of common molecular subsequences. J Mol Biol. 1981, 147: 195-197. DOI: 10.1016/0022-2836(81)90087-5
83. Schneider R, Sander C: The HSSP database of protein structure-sequence alignments. Nucleic Acids Res. 1996, 24: 201-205. 10.1093/nar/24.1.201. DOI: 10.1093/nar/24.1.201
84. Pesole G, Liuni S, Grillo G, Licciulli F, Mignone F, Gissi C, Saccone C: UTRdb and UTRsite: specialized databases of sequences and functional elements of 5' and 3' untranslated regions of eukaryotic mRNAs. Update 2002. Nucleic Acids Res. 2002, 30: 335-340. 10.1093/nar/30.1.335. DOI: 10.1093/nar/30.1.335
85. Stark A, Brennecke J, Russell RB, Cohen SM: Identification of Drosophila microRNA targets. PLoS Biology. October 13 2003 (DOI: 10.1371/journal.pbio.0000060)
86. Rajewsky N, Socci ND: Computational identification of microRNA targets. Dev Biol.
87. Ashburner M, Lewis S: On ontologies for biologists: the Gene Ontology - untangling the web. Novartis Found Symp. 2002, 247: 66-80. 10.1002/0470857897.ch6. [discussion 80-63, 84-90, 244-252] DOI: 10.1002/0470857897.ch6