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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Acknowledgements We thank O. Ryder, E. Fuchs, D. Haring, A. Walsh, D. Duffield, S. Wong, T. Alvarado, J. Boylan, S. Combes, P. deJong, J. Allman, J. Patton, D. McMullen, D. Hafner, D. Miller, T. Kunz, G. Hewitt, J. Searle, H. Künzle and D. Williams for providing organismalmaterial. Wethank L.Gaffneyfor help withfigures.Thiswork was supported by the National Human Genome Research Institute (NHGRI), including grant U54 HG003273 (R.A.G.), National Institute for General Medicine (NIGMS) grant no.
GM82901 (Pollard laboratory) and the European Science Foundation (EURYI award to K.L.-T.), NSF National Science Foundation (NSF) postdoctoral fellowship award 0905968 (J.E.), National Science Foundation CAREER 0644282 and NIH R01 HG004037 and the Sloan Foundation (M.K.), and an Erwin Schrödinger Fellowship of the Austrian Fonds zur Förderung der Wissenschaftlichen Forschung (S.W.), the Gates Cambridge Trust (G.J.), Novo Nordisk Foundation (B.J.P. and J.W.); a Statistics Network Fellowship, Department of Mathematical Sciences, University of Copenhagen (B.J.P.); the David and Lucile Packard Foundation (A.S.); the Danish Council for Independent Research Medical Sciences (J.S.P.); The Lundbeck Foundation (J.S.P.).