What fraction of the human genome is functional?

Genome Research

Volumn 21, Issue 11, 2011, Pages 1769-1776

  Ponting, Chris P ^a   Hardison, Ross C ^b  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b PENNSYLVANIA STATE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

NUCLEOTIDE DERIVATIVE;

ACCURACY; DNA SEQUENCE; GENE SEQUENCE; GENETIC CONSERVATION; HUMAN; HUMAN GENOME; MAMMAL; MOLECULAR EVOLUTION; NONHUMAN; PHYLOGENY; PRIORITY JOURNAL; REVIEW; STEADY STATE;

ANIMALS; CONSERVED SEQUENCE; EVOLUTION, MOLECULAR; GENOME, HUMAN; HUMANS; MODELS, GENETIC; SEQUENCE HOMOLOGY;

EUTHERIA; MAMMALIA; RATTUS; RODENTIA;

EID: 80555142991     PISSN: 10889051     EISSN: 15495469     Source Type: Journal    
DOI: 10.1101/gr.116814.110     Document Type: Review

References (58)

1. Aparicio S, Morrison A, Gould A, Gilthorpe J, Chaudhuri C, Rigby P, Krumlauf R, Brenner S. 1995. Detecting conserved regulatory elements with the model genome of the Japanese puffer fish, Fugu rubripes. Proc Natl Acad Sci 92: 1684-1688.
2. Asthana S, Roytberg M, Stamatoyannopoulos J, Sunyaev S. 2007. Analysis of sequence conservation at nucleotide resolution. PLoS Comput Biol 3: e254. doi: 10.1371/journal.pcbi.0030254.
3. Blow MJ, McCulley DJ, Li Z, Zhang T, Akiyama JA, Holt A, Plajzer-Frick I, Shoukry M, Wright C, Chen F, et al. 2010. ChIP-Seq identification of weakly conserved heart enhancers. Nat Genet 42: 806-810.
4. Bodine DM, Ley TJ. 1987. An enhancer element lies 3′ to the human A l globin gene. EMBO J 6: 2997-3004.
5. Bourque G, Leong B, Vega VB, Chen X, Lee YL, Srinivasan KG, Chew JL, Ruan Y, Wei CL, Ng HH, et al. 2008. Evolution of the mammalian transcription factor binding repertoire via transposable elements. Genome Res 18: 1752-1762.
6. Chan YF, Marks ME, Jones FC, Villarreal G Jr, Shapiro MD, Brady SD, Southwick AM, Absher DM, Grimwood J, Schmutz J, et al. 2010. Adaptive evolution of pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer. Science 327: 302-305.
7. Cheng Y, Wu W, Kumar SA, Yu D, Deng W, Tripic T, King DC, Chen KB, Zhang Y, Drautz D, et al. 2009. Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expression. Genome Res 19: 2172-2184.
8. Chiaromonte F, Weber RJ, Roskin KM, Diekhans M, Kent WJ, Haussler D. 2003. The share of human genomic DNA under selection estimated from human-mouse genomic alignments. Cold Spring Harb Symp Quant Biol 68: 245-254. (Pubitemid 38955573)
9. Church DM, Goodstadt L, Hillier LW, Zody MC, Goldstein S, She X, Bult CJ, Agarwala R, Cherry JL, DiCuccio M, et al. 2009. Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol 7: e1000112. doi: 10.1371/journal.pbio.1000112.
10. Cooper GM, Stone EA, Asimenos G, Green ED, Batzoglou S, Sidow A. 2005. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res 15: 901-913. (Pubitemid 40994210)
11. Davydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S. 2010. Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol 6: e1001025. doi: 10.1371/journal.pcbi.1001025.
12. Dermitzakis ET, Clark AG. 2002. Evolution of transcription factor binding sites in mammalian gene regulatory regions: conservation and turnover. Mol Biol Evol 19: 1114-1121. (Pubitemid 34743235)
13. Durrett R, Schmidt D. 2008.Waiting for two mutations: with applications to regulatory sequence evolution and the limits of Darwinian evolution. Genetics 180: 1501-1509.
14. Emorine L, Kuehl M, Weir L, Leder P, Max EE. 1983. A conserved sequence in the immunoglobulin Jk-Ck intron: possible enhancer element. Nature 304: 447-449. (Pubitemid 13077945)
15. The ENCODE Project Consortium. 2007. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447: 799-816.
16. The ENCODE Project Consortium. 2011. A user's guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol 9: e1001046. doi: 10.1371/journal.pbio. 1001046.
17. Eory L, Halligan DL, Keightley PD. 2010. Distributions of selectively constrained sites and deleterious mutation rates in the hominid and murid genomes. Mol Biol Evol 27: 177-192.
18. Flint J, Tufarelli C, Peden J, Clark K, Daniels RJ, Hardison R, Miller W, Philipsen S, Tan-Un KC, McMorrow T, et al. 2001. Comparative genome analysis delimits a chromosomal domain and identifies key regulatory elements in the a globin cluster. Hum Mol Genet 10: 371-382. (Pubitemid 32166548)
19. Gaffney DJ, Keightley PD. 2005. The scale of mutational variation in the murid genome. Genome Res 15: 1086-1094. (Pubitemid 41126864)
20. Garber M, Guttman M, Clamp M, Zody MC, Friedman N, Xie X. 2009. Identifying novel constrained elements by exploiting biased substitution patterns. Bioinformatics 25: i54-i62.
21. Gottgens B, Barton LM, Gilbert JG, Bench AJ, Sanchez MJ, Bahn S, Mistry S, Grafham D, McMurray A, Vaudin M, et al. 2000. Analysis of vertebrate SCL loci identifies conserved enhancers. Nat Biotechnol 18: 181-186. (Pubitemid 30091179)
22. Hardison RC, Roskin KM, Yang S, Diekhans M, Kent WJ, Weber R, Elnitski L, Li J, O'Connor M, Kolbe D, et al. 2003. Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolution. Genome Res 13: 13-26.
23. Jordan IK, Rogozin IB, Glazko GV, Koonin EV. 2003. Origin of a substantial fraction of human regulatory sequences from transposable elements. Trends Genet 19: 68-72. (Pubitemid 36120660)
24. Kasowski M, Grubert F, Heffelfinger C, Hariharan M, Asabere A, Waszak SM, Habegger L, Rozowsky J, Shi M, Urban AE, et al. 2010. Variation in transcription factor binding among humans. Science 328: 232-235.
25. King DC, Taylor J, Zhang Y, Cheng Y, Lawson HA, Martin J, Chiaromonte F, Miller W, Hardison RC. 2007. Finding cis-regulatory elements using comparative genomics: some lessons from ENCODE data. Genome Res 17: 775-786. (Pubitemid 46919713)
26. Kunarso G, Chia NY, Jeyakani J, Hwang C, Lu X, Chan YS, Ng HH, Bourque G. 2010. Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nat Genet 42: 631-634.
27. Li J, Miller W. 2003. Significance of interspecies matches when evolutionary rate varies. J Comput Biol 10: 537-554. (Pubitemid 37372165)
28. Lindblad-Toh K, Wade CM, Mikkelsen TS, Karlsson EK, Jaffe DB, Kamal M, Clamp M, Chang JL, Kulbokas EJ III, Zody MC, et al. 2005. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438: 803-819. (Pubitemid 41753059)
29. Lindblad-Toh K, Garber M, Zuk O, Lin MF, Parker BJ, Washietl S, Kheradpour P, Ernst J, Jordan G, Mauceli E, et al. 2011. Evolutionary constraint in the human genome based on 29 eutherian mammals. Nature 477. doi: 10.1038/nature10530.
30. Lowe CB, Bejerano G, Haussler D. 2007. Thousands of human mobile element fragments undergo strong purifying selection near developmental genes. Proc Natl Acad Sci 104: 8005-8010. (Pubitemid 47185866)
31. Lunter G, Ponting CP, Hein J. 2006. Genome-wide identification of human functional DNA using a neutral indel model. PLoS Comput Biol 2: e5. doi: 10.1371/journal.pcbi.0020005.
32. Lunter G, Rocco A, Mimouni N, Heger A, Caldeira A, Hein J. 2008. Uncertainty in homology inferences: assessing and improving genomic sequence alignment. Genome Res 18: 298-309. (Pubitemid 351240740)
33. Margulies EH, Blanchette M, Haussler D, Green ED. 2003. Identification and characterization of multi-species conserved sequences. Genome Res 13: 2507-2518. (Pubitemid 37541140)
34. Margulies EH, Cooper GM, Asimenos G, Thomas DJ, Dewey CN, Siepel A, Birney E, Keefe D, Schwartz AS, Hou M, et al. 2007. Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome. Genome Res 17: 760-774. (Pubitemid 46919712)
35. Meader S, Ponting CP, Lunter G. 2010. Massive turnover of functional sequence in human and other mammalian genomes. Genome Res 20: 1335-1343.
36. Miller W, Rosenbloom K, Hardison RC, Hou M, Taylor J, Raney B, Burhans R, King DC, Baertsch R, Blankenberg D, et al. 2007. 28-way vertebrate alignment and conservation track in the UCSC Genome Browser. Genome Res 17: 1797-1808. (Pubitemid 351360004)
37. Mouse Genome Sequencing Consortium. 2002. Initial sequencing and comparative analysis of the mouse genome. Nature 420: 520-562.
38. Nobrega MA, Zhu Y, Plajzer-Frick I, Afzal V, Rubin EM. 2004. Megabase deletions of gene deserts result in viable mice. Nature 431: 988-993. (Pubitemid 39434420)
39. Odom DT, Dowell RD, Jacobsen ES, Gordon W, Danford TW, MacIsaac KD, Rolfe PA, Conboy CM, Gifford DK, Fraenkel E. 2007. Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nat Genet 39: 730-732. (Pubitemid 46848594)
40. Parker SC, Hansen L, Abaan HO, Tullius TD, Margulies EH. 2009. Local DNA topography correlates with functional noncoding regions of the human genome. Science 324: 389-392.
41. Pennacchio LA, Ahituv N, Moses AM, Prabhakar S, Nobrega MA, Shoukry M, Minovitsky S, Dubchak I, Holt A, Lewis KD, et al. 2006. In vivo enhancer analysis of human conserved non-coding sequences. Nature 444: 499-502. (Pubitemid 44809068)
42. Pheasant M, Mattick JS. 2007. Raising the estimate of functional human sequences. Genome Res 17: 1245-1253. (Pubitemid 47360899)
43. Picard D, Schaffner W. 1984. A lymphocyte-specific enhancer in the mouse immunoglobulin k gene. Nature 307: 80-82. (Pubitemid 14132939)
44. Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A. 2010. Detection ofnonneutral substitution rates on mammalian phylogenies. Genome Res 20: 110-121.
45. Ponting CP, Goodstadt L. 2009. Separating derived from ancestral features of mouse and human genomes. Biochem Soc Trans 37: 734-739.
46. Ponting CP, Nellaker C, Meader S. 2011. Rapid turnover of functional sequence in human and other genomes. Annu Rev Genomics Hum Genet (in press). doi: 10.1146/annurev-genom-090810-183115.
47. Rat Genome Sequencing Project Consortium. 2004. Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428: 493-521.
48. Sagai T, Masuya H, Tamura M, Shimizu K, Yada Y, Wakana S, Gondo Y, Noda T, Shiroishi T. 2004. Phylogenetic conservation of a limb-specific, cisacting regulator of Sonic hedgehog (Shh). Mamm Genome 15: 23-34. (Pubitemid 38096207)
49. Schmidt D, Wilson MD, Ballester B, Schwalie PC, Brown GD, Marshall A, Kutter C, Watt S, Martinez-Jimenez CP, Mackay S, et al. 2010. Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding. Science 328: 1036-1040.
50. Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, Clawson H, Spieth J, Hillier LW, Richards S, et al. 2005. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res 15: 1034-1050. (Pubitemid 41126859)
51. Smith NG, Brandstrom M, Ellegren H. 2004. Evidence for turnover of functional noncoding DNA inmammalian genome evolution. Genomics 84: 806-813. (Pubitemid 39314440)
52. Thomas JW, Touchman JW, Blakesley RW, Bouffard GG, Beckstrom- Sternberg SM, Margulies EH, Blanchette M, Siepel AC, Thomas PJ, McDowell JC, et al. 2003. Comparative analyses of multi-species sequences from targeted genomic regions. Nature 424: 788-793. (Pubitemid 37021709)
53. Valverde-Garduno V, Guyot B, Anguita E, Hamlett I, Porcher C, Vyas P. 2004. Differences in the chromatin structure and cis-element organization of the human and mouse GATA1 loci: implications for cis-element identification. Blood 104: 3106-3116. (Pubitemid 39507125)
54. Visel A, Prabhakar S, Akiyama JA, Shoukry M, Lewis KD, Holt A, Plajzer-Frick I, Afzal V, Rubin EM, Pennacchio LA. 2008. Ultraconservation identifies a small subset of extremely constrained developmental enhancers. Nat Genet 40: 158-160. (Pubitemid 351171389)
55. Wang H, Zhang Y, Cheng Y, Zhou Y, King DC, Taylor J, Chiaromonte F, Kasturi J, Petrykowska H, Gibb B, et al. 2006. Experimental validation of predicted mammalian erythroid cis-regulatory modules. Genome Res 16: 1480-1492. (Pubitemid 44878487)
56. Wang T, Zeng J, Lowe CB, Sellers RG, Salama SR, Yang M, Burgess SM, Brachmann RK, Haussler D. 2007. Species-specific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53. Proc Natl Acad Sci 104: 18613-18618. (Pubitemid 350210745)
57. Wold B, Myers RM. 2008. Sequence census methods for functional genomics. Nat Methods 5: 19-21.
58. Woolfe A, Goodson M, Goode DK, Snell P, McEwen GK, Vavouri T, Smith SF, North P, Callaway H, Kelly K, et al. 2005. Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol 3: e7. doi: 10.1371/journal.pbio.0030007.