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

Creators: Lindblad-Toh, Kerstin; Guttman, Mitchell

Abstract

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.

Additional Information

© 2011 Macmillan Publishers Limited. This article is distributed under the terms of the Creative Commons Attribution-Non-Commercial-Share Alike licence (http://creativecommons.org/licenses/by-nc-sa/3.0/), which permits distribution, and reproduction in any medium, provided the original author and source are credited. This licence does not permit commercial exploitation, and derivative works must be licensed under the same or similar licence. Received 25 January 2011; Accepted 05 September 2011 Published online 12 October 2011. 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 organismal material. We thank L. Gaffney for help with figures. This work 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.). Author Contributions: K.L-.T., E.S.L. and M.K. led the project and oversaw the analysis. K.L.-T. M.C., J.Ch., E.H.M., E.D.G. and E.S.L. planned the project. K.L.-T., F.D.P., M.L., E.S.L., K.C.W., C.L.K., D.M.M., R.A.G., W.C.W., E.R.M., G.M.W. and R.K.W. oversaw or significantly contributed to data generation. S.G. assembled the 2× genomes. Major contributions to analysis were made by M.Ga., O.Z. and M.C. to evaluate measures and patterns of evolutionary selection, M.F.L. to evaluate protein-coding potential and translational readthrough, B.J.P., S.W. to analyse RNA structures and families, P.K. on regulatory motifs and motif instances, J.E. on chromatin states, G.J. on codon-specific positive selection, E.M. on promoter motif, L.D.W. on GWAS overlap with conserved elements, C.B.L. on exaptation and A.K.H., K.S.P. on HARs and PARs. J.A., K.B., H.C., J.Cu., S.F., P.F., M.Gu., M.J.H., D.B.J., I.J., W.J.K., D.K., A.L.M., T.M., I.M., B.J.R., M.D.R., J.R., A.St., A.J.V., J.W., X.X., M.C.Z., E.B., E.H.M., J.H., D.H., A.Si., N.G. and J.S.P. performed or oversaw various analyses. K.L.-T., E.S.L. and M.K. wrote the paper with input from the other authors. The authors declare no competing financial interests.

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