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

  • Author(s): Lindblad-Toh, Kerstin
  • Garber, Manuel
  • Zuk, Or
  • Lin, Michael F
  • Parker, Brian J
  • Washietl, Stefan
  • Kheradpour, Pouya
  • Ernst, Jason
  • Jordan, Gregory
  • Mauceli, Evan
  • Ward, Lucas D
  • Lowe, Craig B
  • Holloway, Alisha K
  • Clamp, Michele
  • Gnerre, Sante
  • Alföldi, Jessica
  • Beal, Kathryn
  • Chang, Jean
  • Clawson, Hiram
  • Cuff, James
  • Di Palma, Federica
  • Fitzgerald, Stephen
  • Flicek, Paul
  • Guttman, Mitchell
  • Hubisz, Melissa J
  • Jaffe, David B
  • Jungreis, Irwin
  • Kent, W James
  • Kostka, Dennis
  • Lara, Marcia
  • Martins, Andre L
  • Massingham, Tim
  • Moltke, Ida
  • Raney, Brian J
  • Rasmussen, Matthew D
  • Robinson, Jim
  • Stark, Alexander
  • Vilella, Albert J
  • Wen, Jiayu
  • Xie, Xiaohui
  • Zody, Michael C
  • Broad Institute Sequencing Platform and Whole Genome Assembly Team
  • Baldwin, Jen
  • Bloom, Toby
  • Chin, Chee Whye
  • Heiman, Dave
  • Nicol, Robert
  • Nusbaum, Chad
  • Young, Sarah
  • Wilkinson, Jane
  • Worley, Kim C
  • Kovar, Christie L
  • Muzny, Donna M
  • Gibbs, Richard A
  • Baylor College of Medicine Human Genome Sequencing Center Sequencing Team
  • Cree, Andrew
  • Dihn, Huyen H
  • Fowler, Gerald
  • Jhangiani, Shalili
  • Joshi, Vandita
  • Lee, Sandra
  • Lewis, Lora R
  • Nazareth, Lynne V
  • Okwuonu, Geoffrey
  • Santibanez, Jireh
  • Warren, Wesley C
  • Mardis, Elaine R
  • Weinstock, George M
  • Wilson, Richard K
  • Genome Institute at Washington University
  • Delehaunty, Kim
  • Dooling, David
  • Fronik, Catrina
  • Fulton, Lucinda
  • Fulton, Bob
  • Graves, Tina
  • Minx, Patrick
  • Sodergren, Erica
  • Birney, Ewan
  • Margulies, Elliott H
  • Herrero, Javier
  • Green, Eric D
  • Haussler, David
  • Siepel, Adam
  • Goldman, Nick
  • Pollard, Katherine S
  • Pedersen, Jakob S
  • Lander, Eric S
  • Kellis, Manolis
  • et al.
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.

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