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

被引：792

作者：

Lindblad-Toh, Kerstin ^{[1
,2
]}

Garber, Manuel ^{[1
]}

Zuk, Or ^{[1
]}

Lin, Michael F. ^{[1
,3
]}

Parker, Brian J. ^{[4
]}

Washietl, Stefan ^{[3
]}

Kheradpour, Pouya ^{[1
,3
]}

Ernst, Jason ^{[1
,3
]}

Jordan, Gregory ^{[5
]}

Mauceli, Evan ^{[1
]}

Ward, Lucas D. ^{[1
,3
]}

Lowe, Craig B. ^{[6
,7
,8
]}

Holloway, Alisha K. ^{[9
]}

Clamp, Michele ^{[1
,10
]}

Gnerre, Sante ^{[1
]}

Alfoeldi, Jessica ^{[1
]}

Beal, Kathryn ^{[5
]}

Chang, Jean ^{[1
]}

Clawson, Hiram ^{[6
]}

Cuff, James ^{[11
]}

Di Palma, Federica ^{[1
]}

Fitzgerald, Stephen ^{[5
]}

Flicek, Paul ^{[5
]}

Guttman, Mitchell ^{[1
]}

Hubisz, Melissa J. ^{[12
]}

Jaffe, David B. ^{[1
]}

Jungreis, Irwin ^{[3
]}

Kent, W. James ^{[9
]}

Kostka, Dennis ^{[9
]}

Lara, Marcia ^{[1
]}

Martins, Andre L. ^{[12
]}

Massingham, Tim ^{[5
]}

Moltke, Ida ^{[4
]}

Raney, Brian J. ^{[6
]}

Rasmussen, Matthew D. ^{[3
]}

Robinson, Jim ^{[1
]}

Stark, Alexander ^{[13
]}

Vilella, Albert J. ^{[5
]}

Wen, Jiayu ^{[4
]}

Xie, Xiaohui ^{[1
]}

Zody, Michael C. ^{[1
]}

Worley, Kim C. ^{[14
]}

Kovar, Christie L. ^{[14
]}

Muzny, Donna M. ^{[14
]}

Gibbs, Richard A. ^{[14
]}

Warren, Wesley C. ^{[15
]}

Mardis, Elaine R. ^{[15
]}

Weinstock, George M. ^{[14
,15
]}

Wilson, Richard K. ^{[15
]}

Birney, Ewan ^{[5
]}

机构：

[1] Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge Ctr 7, Cambridge, MA 02142 USA

[2] Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab, SE-75123 Uppsala, Sweden

[3] MIT Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA

[4] Univ Copenhagen, Dept Biol, Bioinformat Ctr, DK-2200 Copenhagen, Denmark

[5] EMBL EBI, Hinxton CB10 1SD, England

[6] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA

[7] Stanford Univ, Dept Dev Biol, Stanford, CA 94305 USA

[8] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[9] Univ Calif San Francisco, Gladstone Inst, San Francisco, CA 94158 USA

[10] BioTeam Inc, Middleton, MA 01949 USA

[11] Harvard Univ, Fac Arts & Sci, Div Sci, Cambridge, MA 02138 USA

[12] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY 14853 USA

[13] Res Inst Mol Pathol IMP, A-1030 Vienna, Austria

[14] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[15] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA

[16] NHGRI, Genome Informat Sect, Genome Technol Branch, NIH, Bethesda, MD 20892 USA

[17] NHGRI, NISC Comparat Sequencing Program, Genome Technol Branch, NIH, Bethesda, MD 20892 USA

[18] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA

[19] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94158 USA

[20] Univ Calif San Francisco, Div Biostat, San Francisco, CA 94158 USA

[21] Aarhus Univ Hosp, Dept Mol Med MOMA, DK-8200 Aarhus N, Denmark

来源：

NATURE | 2011年 / 478卷 / 7370期

基金：

美国国家科学基金会; 奥地利科学基金会;

关键词：

RELIABLE PREDICTION; GENOME SEQUENCE; CODING SEQUENCE; DISCOVERY; ELEMENTS; REVEALS; GENE; EXPRESSION; SELECTION; DYNAMICS;

D O I：

10.1038/nature10530

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 similar to 4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for similar to 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.

引用

页码：476 / 482

页数：7

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