%0 Journal Article %J Nature %D 2011 %T A high-resolution map of human evolutionary constraint using 29 mammals. %A Lindblad-Toh, Kerstin %A Garber, Manuel %A Zuk, Or %A Lin, Michael F %A Parker, Brian J %A Washietl, Stefan %A Kheradpour, Pouya %A Ernst, Jason %A Jordan, Gregory %A Mauceli, Evan %A Ward, Lucas D %A Lowe, Craig B %A Holloway, Alisha K %A Clamp, Michele %A Gnerre, Sante %A Alföldi, Jessica %A Beal, Kathryn %A Chang, Jean %A Clawson, Hiram %A Cuff, James %A Di Palma, Federica %A Fitzgerald, Stephen %A Flicek, Paul %A Guttman, Mitchell %A Hubisz, Melissa J %A Jaffe, David B %A Jungreis, Irwin %A Kent, W James %A Kostka, Dennis %A Lara, Marcia %A Martins, André L %A Massingham, Tim %A Moltke, Ida %A Raney, Brian J %A Rasmussen, Matthew D %A Robinson, Jim %A Stark, Alexander %A Vilella, Albert J %A Wen, Jiayu %A Xie, Xiaohui %A Zody, Michael C %A Baldwin, Jen %A Bloom, Toby %A Chin, Chee Whye %A Heiman, Dave %A Nicol, Robert %A Nusbaum, Chad %A Young, Sarah %A Wilkinson, Jane %A Worley, Kim C %A Kovar, Christie L %A Muzny, Donna M %A Gibbs, Richard A %A Cree, Andrew %A Dihn, Huyen H %A Fowler, Gerald %A Jhangiani, Shalili %A Joshi, Vandita %A Lee, Sandra %A Lewis, Lora R %A Nazareth, Lynne V %A Okwuonu, Geoffrey %A Santibanez, Jireh %A Warren, Wesley C %A Mardis, Elaine R %A Weinstock, George M %A Wilson, Richard K %A Delehaunty, Kim %A Dooling, David %A Fronik, Catrina %A Fulton, Lucinda %A Fulton, Bob %A Graves, Tina %A Minx, Patrick %A Sodergren, Erica %A Birney, Ewan %A Margulies, Elliott H %A Herrero, Javier %A Green, Eric D %A Haussler, David %A Siepel, Adam %A Goldman, Nick %A Pollard, Katherine S %A Pedersen, Jakob S %A Lander, Eric S %A Kellis, Manolis %K Animals %K Disease %K Evolution, Molecular %K Exons %K Genome %K Genome, Human %K Genomics %K Health %K Humans %K Mammals %K Molecular Sequence Annotation %K Phylogeny %K RNA %K Selection, Genetic %K Sequence Alignment %K Sequence Analysis, DNA %X

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.

%B Nature %V 478 %P 476-82 %8 2011 Oct 12 %G eng %N 7370 %1 https://www.ncbi.nlm.nih.gov/pubmed/21993624?dopt=Abstract %R 10.1038/nature10530