Journal Article

Selection for Translation Efficiency on Synonymous Polymorphisms in Recent Human Evolution

Yedael Y. Waldman, Tamir Tuller, Alon Keinan and Eytan Ruppin

in Genome Biology and Evolution

Published on behalf of Society for Molecular Biology and Evolution

Volume 3, issue , pages 749-761
Published in print January 2011 |
Published online July 2011 | e-ISSN: 1759-6653 | DOI: http://dx.doi.org/10.1093/gbe/evr076

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Synonymous mutations are considered to be “silent” as they do not affect protein sequence. However, different silent codons have different translation efficiency (TE), which raises the question to what extent such mutations are really neutral. We perform the first genome-wide study of natural selection operating on TE in recent human evolution, surveying 13,798 synonymous single nucleotide polymorphisms (SNPs) in 1,198 unrelated individuals from 11 populations. We find evidence for both negative and positive selection on TE, as measured based on differentiation in allele frequencies between populations. Notably, the likelihood of an SNP to be targeted by positive or negative selection is correlated with the magnitude of its effect on the TE of the corresponding protein. Furthermore, negative selection acting against changes in TE is more marked in highly expressed genes, highly interacting proteins, complex members, and regulatory genes. It is also more common in functional regions and in the initial segments of highly expressed genes. Positive selection targeting sites with a large effect on TE is stronger in lowly interacting proteins and in regulatory genes. Similarly, essential genes are enriched for negative TE selection while underrepresented for positive TE selection. Taken together, these results point to the significant role of TE as a selective force operating in humans and hence underscore the importance of considering silent SNPs in interpreting associations with complex human diseases. Testifying to this potential, we describe two synonymous SNPs that may have clinical implications in phenylketonuria and in Best's macular dystrophy due to TE differences between alleles.

Keywords: translation efficiency; SNP; synonymous mutations; population genetics; causal variants; allele frequency differentiation

Journal Article.  7777 words.  Illustrated.

Subjects: Bioinformatics and Computational Biology ; Evolutionary Biology ; Genetics and Genomics

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