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

Kerstin Lindblad-Toh (), Manuel Garber, Or Zuk, Michael F. Lin, Brian J. Parker, Stefan Washietl, Pouya Kheradpour, Jason Ernst, Gregory Jordan, Evan Mauceli, Lucas D. Ward, Craig B. Lowe, Alisha K. Holloway, Michele Clamp, Sante Gnerre, Jessica Alföldi, Kathryn Beal, Jean Chang, Hiram Clawson, James Cuff, Federica Di Palma, Stephen Fitzgerald, Paul Flicek, Mitchell Guttman, Melissa J. Hubisz, David B. Jaffe, Irwin Jungreis, W. James Kent, Dennis Kostka, Marcia Lara, Andre L. Martins, Tim Massingham, Ida Moltke, Brian J. Raney, Matthew D. Rasmussen, Jim Robinson, Alexander Stark, Albert J. Vilella, Jiayu Wen, Xiaohui Xie, Michael C. Zody, Kim C. Worley, Christie L. Kovar, Donna M. Muzny, Richard A. Gibbs, Wesley C. Warren, Elaine R. Mardis, George M. Weinstock, Richard K. Wilson, Ewan Birney, Elliott H. Margulies, Javier Herrero, Eric D. Green, David Haussler, Adam Siepel, Nick Goldman, Katherine S. Pollard, Jakob S. Pedersen, Eric S. Lander () and Manolis Kellis ()
Additional contact information
Kerstin Lindblad-Toh: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Manuel Garber: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Or Zuk: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Michael F. Lin: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Brian J. Parker: The Bioinformatics Centre, University of Copenhagen
Stefan Washietl: MIT Computer Science and Artificial Intelligence Laboratory
Pouya Kheradpour: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Jason Ernst: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Gregory Jordan: EMBL-EBI, Wellcome Trust Genome Campus
Evan Mauceli: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Lucas D. Ward: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Craig B. Lowe: Center for Biomolecular Science and Engineering, University of California
Alisha K. Holloway: Gladstone Institutes, University of California
Michele Clamp: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Sante Gnerre: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Jessica Alföldi: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Kathryn Beal: EMBL-EBI, Wellcome Trust Genome Campus
Jean Chang: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Hiram Clawson: Center for Biomolecular Science and Engineering, University of California
James Cuff: Research Computing, Faculty of Arts and Sciences, Harvard University
Federica Di Palma: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Stephen Fitzgerald: EMBL-EBI, Wellcome Trust Genome Campus
Paul Flicek: EMBL-EBI, Wellcome Trust Genome Campus
Mitchell Guttman: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Melissa J. Hubisz: Cornell University
David B. Jaffe: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Irwin Jungreis: MIT Computer Science and Artificial Intelligence Laboratory
W. James Kent: Gladstone Institutes, University of California
Dennis Kostka: Gladstone Institutes, University of California
Marcia Lara: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Andre L. Martins: Cornell University
Tim Massingham: EMBL-EBI, Wellcome Trust Genome Campus
Ida Moltke: The Bioinformatics Centre, University of Copenhagen
Brian J. Raney: Center for Biomolecular Science and Engineering, University of California
Matthew D. Rasmussen: MIT Computer Science and Artificial Intelligence Laboratory
Jim Robinson: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Alexander Stark: Research Institute of Molecular Pathology (IMP)
Albert J. Vilella: EMBL-EBI, Wellcome Trust Genome Campus
Jiayu Wen: The Bioinformatics Centre, University of Copenhagen
Xiaohui Xie: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Michael C. Zody: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Kim C. Worley: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza
Christie L. Kovar: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza
Donna M. Muzny: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza
Richard A. Gibbs: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza
Wesley C. Warren: Genome Institute at Washington University, Washington University School of Medicine
Elaine R. Mardis: Genome Institute at Washington University, Washington University School of Medicine
George M. Weinstock: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza
Richard K. Wilson: Genome Institute at Washington University, Washington University School of Medicine
Ewan Birney: EMBL-EBI, Wellcome Trust Genome Campus
Elliott H. Margulies: Genome Informatics Section, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health
Javier Herrero: EMBL-EBI, Wellcome Trust Genome Campus
Eric D. Green: NISC Comparative Sequencing Program, Genome Technology Branch and NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health
David Haussler: Center for Biomolecular Science and Engineering, University of California
Adam Siepel: Cornell University
Nick Goldman: EMBL-EBI, Wellcome Trust Genome Campus
Katherine S. Pollard: Gladstone Institutes, University of California
Jakob S. Pedersen: The Bioinformatics Centre, University of Copenhagen
Eric S. Lander: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
Manolis Kellis: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center

Nature, 2011, vol. 478, issue 7370, 476-482

Abstract: Abstract 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.

Date: 2011
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DOI: 10.1038/nature10530

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