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

TY - JOUR

T1 - A high-resolution map of human evolutionary constraint using 29 mammals

AU - Lindblad-Toh, Kerstin

AU - Garber, Manuel

AU - Zuk, Or

AU - Lin, Michael F

AU - Parker, Brian J

AU - Jordan, Gregory

AU - Mauceli, Evan

AU - Ward, Lucas D

AU - Lowe, Craig B

AU - Holloway, Alisha K

AU - Clamp, Michele

AU - Gnerre, Sante

AU - Moltke, Ida

AU - Wen, Jiayu

AU - Pedersen, Jakob Skou

PY - 2011/10/27

Y1 - 2011/10/27

N2 - 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.

AB - 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.

U2 - 10.1038/nature10530

DO - 10.1038/nature10530

M3 - Journal article

C2 - 21993624

SN - 0028-0836

VL - 478

SP - 476

EP - 482

JO - Nature

JF - Nature

IS - 7370

ER -