A high-resolution map of human evolutionary constraint using 29 mammals.
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.
Lindblad-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; Kent, WJ; 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; Broad Institute Sequencing Platform and Whole Genome Assembly Team, ; Baldwin, J; Bloom, T; Chin, CW; Heiman, D; Nicol, R; Nusbaum, C; Young, S; Wilkinson, J; Worley, KC; Kovar, CL; Muzny, DM; Gibbs, RA; Baylor College of Medicine Human Genome Sequencing Center Sequencing Team, ; 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; Genome Institute at Washington University, ; 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
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