这项比较基因组研究(将完整的人类基因组与包括黑猩猩、小鼠和狗在内的29种胎生哺乳动物的基因组进行对比)识别出4.2%的人类基因组是受演化选择限制的,并且为这些受限制的基因中大约60% 的基因赋予了一个潜在的功能。该研究发现了一系列演化特征,为了解编码和非编码功能基因组元素、RNA结构家族的候选对象以及基因组组织和演化的各个方面提供了线索。它们与跟疾病相关的变体的重叠表明,这些发现对于人类疾病的研究将是有用的。(生物谷 Bioon.com)
doi:10.1038/nature10530
PMC:
PMID:
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 Alfldi, 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,Broad Institute Sequencing Platform and Whole Genome Assembly Team,Kim C. Worley,Christie L. Kovar,Donna M. Muzny,Richard A. Gibbs,Baylor College of Medicine Human Genome Sequencing Center Sequencing Team,Wesley C. Warren,Elaine R. Mardis,George M. Weinstock,, Richard K. Wilson,Genome Institute at Washington University,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& Manolis Kellis, et al.
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.