A high-resolution map of human evolutionary constraint using 29 mammals.

TitleA high-resolution map of human evolutionary constraint using 29 mammals.
Publication TypeJournal Article
Year of Publication2011
AuthorsLindblad-Toh, K, Garber, M, Zuk, O, Lin, MF, Parker, BJ, Washietl, S, Kheradpour, P, Ernst, J, Jordan, G, Mauceli, E, Ward, LD, Lowe, CB, Holloway, AK, Clamp, M, Gnerre, S, Alföldi, J, Beal, K, Chang, J, Clawson, H, Cuff, J, Di Palma, F, Fitzgerald, S, Flicek, P, Guttman, M, Hubisz, MJ, Jaffe, DB, Jungreis, I, W Kent, J, Kostka, D, Lara, M, Martins, AL, Massingham, T, Moltke, I, Raney, BJ, Rasmussen, MD, Robinson, J, Stark, A, Vilella, AJ, Wen, J, Xie, X, Zody, MC, Baldwin, J, Bloom, T, Chin, CWhye, Heiman, D, Nicol, R, Nusbaum, C, Young, S, Wilkinson, J, Worley, KC, Kovar, CL, Muzny, DM, Gibbs, RA, Cree, A, Dihn, HH, Fowler, G, Jhangiani, S, Joshi, V, Lee, S, Lewis, LR, Nazareth, LV, Okwuonu, G, Santibanez, J, Warren, WC, Mardis, ER, Weinstock, GM, Wilson, RK, Delehaunty, K, Dooling, D, Fronik, C, Fulton, L, Fulton, B, Graves, T, Minx, P, Sodergren, E, Birney, E, Margulies, EH, Herrero, J, Green, ED, Haussler, D, Siepel, A, Goldman, N, Pollard, KS, Pedersen, JS, Lander, ES, Kellis, M
Corporate AuthorsBroad Institute Sequencing Platform and Whole Genome Assembly Team, Baylor College of Medicine Human Genome Sequencing Center Sequencing Team, Genome Institute at Washington University
Date Published2011 Oct 12
KeywordsAnimals, Disease, Evolution, Molecular, Exons, Genome, Genome, Human, Genomics, Health, Humans, Mammals, Molecular Sequence Annotation, Phylogeny, RNA, Selection, Genetic, Sequence Alignment, Sequence Analysis, DNA

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.

Alternate JournalNature
PubMed ID21993624
PubMed Central IDPMC3207357
Grant ListR01 HG004037 / HG / NHGRI NIH HHS / United States
R01 HG003474 / HG / NHGRI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
GM82901 / GM / NIGMS NIH HHS / United States
095908 / / Wellcome Trust / United Kingdom
U54 HG003067-09 / HG / NHGRI NIH HHS / United States
R01 GM082901 / GM / NIGMS NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States

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