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Human Molecular Genetics Advance Access originally published online on June 30, 2005
Human Molecular Genetics 2005 14(15):2221-2229; doi:10.1093/hmg/ddi226
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Small fitness effect of mutations in highly conserved non-coding regions

Gregory V Kryukov1,2, Steffen Schmidt1,2 and Shamil Sunyaev1,2,*

1Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School and 2Harvard-M.I.T. Division of Health Science and Technology, Harvard Medical School New Research Building, 77 Avenue Louis Pasteur, Boston, MA 02115, USA

* To whom correspondence should be addressed. Tel: +1 6175254735; Fax: +1 6175254705; Email: ssunyaev{at}rics.bwh.harvard.edu

Received February 9, 2005; Revised May 20, 2005; Accepted June 22, 2005

Comparison of human and mouse genomes has revealed that many non-coding regions have levels of sequence conservation similar to protein-coding genes. These regions have attracted a lot of attention as potentially functional genomic sequences. However, little is known about the effect mutations in these conserved non-coding regions have on fitness and how many of them are present in the human genome as deleterious polymorphisms. To gain insight into the selective constraints imposed on conserved non-coding and protein-coding regions, we compared substitution rates in primate and rodent lineages and analyzed the density and allele frequencies of human polymorphism. Genomic regions conserved between primate and rodent groups show higher relative conservation within rodents than within primates. Thus, our analysis indicates a genome-wide relaxation of selective constraint in the primate lineage, which most likely resulted from a smaller effective population size. We found that this relaxation is much more profound in conserved non-coding regions than in protein-coding regions, and that mutations at a large proportion of sites in conserved non-coding regions are associated with very small fitness effect. Data on human polymorphism are also consistent with very weak selection in conserved non-coding regions. This staggering enrichment in sites at the borderline of neutrality can be explained by assuming an important role for synergistic epistasis in the evolution of non-coding regions. Our results suggest that most individual mutations in conserved non-coding regions are only slightly deleterious but are numerous and may have a significant cumulative impact on fitness.


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