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Pubmed ID :21993624
Publication Date : //

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.

Authors : 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 , , 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 , , 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 , , 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 ,

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