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Published online on December 11, 2007, 10.1073/pnas.0705658104
PNAS | December 18, 2007 | vol. 104 | no. 51 | 20443-20448


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BIOLOGICAL SCIENCES / EVOLUTION
Life-history traits drive the evolutionary rates of mammalian coding and noncoding genomic elements

Sergey I. Nikolaev*,{dagger}, Juan I. Montoya-Burgos{ddagger}, Konstantin Popadin§, Leila Parand*, Elliott H. Margulies, National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program,||,**, and Stylianos E. Antonarakis*

*Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet, 1211 Geneva, Switzerland; {ddagger}Department of Animal Biology, University of Geneva, 30 Quai Ansermet, 1211 Geneva, Switzerland; §Institute for Information Transmission Problems RAS, Bolshoi Karetny Pereulok 19, Moscow 127994, Russia; and Genome Technology Branch and ||Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892

Edited by Morris Goodman, Wayne State University School of Medicine, Detroit, MI, and approved October 23, 2007 (received for review June 19, 2007)

A comprehensive phylogenetic framework is indispensable for investigating the evolution of genomic features in mammals as a whole, and particularly in humans. Using the ENCODE sequence data, we estimated mammalian neutral evolutionary rates and selective pressures acting on conserved coding and noncoding elements. We show that neutral evolutionary rates can be explained by the generation time (GT) hypothesis. Accordingly, primates (especially humans), having longer GTs than other mammals, display slower rates of neutral evolution. The evolution of constrained elements, particularly of nonsynonymous sites, is in agreement with the expectations of the nearly neutral theory of molecular evolution. We show that rates of nonsynonymous substitutions (dN) depend on the population size of a species. The results are robust to the exclusion of hypermutable CpG prone sites. The average rate of evolution in conserved noncoding sequences (CNCs) is 1.7 times higher than in nonsynonymous sites. Despite this, CNCs evolve at similar or even lower rates than nonsynonymous sites in the majority of basal branches of the eutherian tree. This observation could be the result of an overall gradual or, alternatively, lineage-specific relaxation of CNCs. The latter hypothesis was supported by the finding that 3 of the 20 longest CNCs displayed significant relaxation of individual branches. This observation may explain why the evolution of CNCs fits the expectations of the nearly neutral theory less well than the evolution of nonsynonymous sites.

constrains | generation time | genome | population size

Author contributions: S.I.N. and J.I.M.-B. contributed equally to this work; S.I.N., J.I.M.-B., and S.E.A. designed research; S.I.N. performed research; E.H.M. and N.I.H.I.S.C.C.S.P. contributed new reagents/analytic tools; S.I.N., K.P., and L.P. analyzed data; and S.I.N., J.I.M.-B., K.P., and S.E.A. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

**National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program: Gerard G. Bouffard, Jacquelyn R. Idol, Valerie V. B. Maduro, and Robert W. Blakesley, Genome Technology Branch; Gerard G. Bouffard, Xiaobin Guan, Nancy F. Hansen, Baishali Maskeri, Jennifer C. McDowell, Morgan Park, Pamela J. Thomas, Alice C. Young, and Robert W. Blakesley, Intramural Sequencing Center.

This article contains supporting information online at www.pnas.org/cgi/content/full/0705658104/DC1.

{dagger}To whom correspondence should be addressed. E-mail: sergey.nikolaev{at}medecine.unige.ch

© 2007 by The National Academy of Sciences of the USA


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