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MBE Advance Access published online on October 12, 2005
Molecular Biology and Evolution, doi:10.1093/molbev/msj035
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© The Author 2005. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Accepted October 10, 2005

Research Article

Evidence for Purifying Selection Against Synonymous Mutations in Mammalian Exonic Splicing Enhancers

Joanna L. Parmley 1, J. V. Chamary 1, and Laurence D. Hurst 1*

1 Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, United Kingdom

* To whom correspondence should be addressed.
Laurence D. Hurst, E-mail: l.d.hurst{at}bath.ac.uk


  Abstract

Silent sites in mammals have classically been assumed to be free from selective pressures. Consequently, the synonymous substitution rate (Ks) is often used as a proxy for the mutation rate. Although accumulating evidence demonstrates that the assumption is not valid, the mechanism(s) by which selection acts remain unclear. Recent work has revealed that the presence of exonic splicing enhancers (ESEs) in coding sequence might influence synonymous evolution. ESEs are predominantly located near intron-exon junctions, which may explain the reduced SNP density in these regions. Here we show that synonymous sites in putative ESEs evolve more slowly than the remaining exonic sequence. Differential mutabilities of ESEs do not appear to explain this difference. We observe that substitution frequency at four-fold synonymous sites decreases as one approaches the ends of exons, consistent with the existing SNP data. This gradient is at least in part explained by ESEs being more abundant near junctions. Between-gene variation in Ks is hence partly explained by the proportion of the gene that acts as an ESE. Given the relative abundance of ESEs and the reduced rates of synonymous divergence within them, we estimate that constraints on synonymous evolution within ESEs causes the true mutation rate to be underestimated by not more than ~8%. We also find that Ks outside of ESEs is much lower in alternatively spliced exons than in constitutive exons, implying that other causes of selection on synonymous mutations exist. Additionally, selection on ESEs appears to affect non-synonymous sites and may explain why amino acid usage near intron-exon junctions is non-random.

Keywords: codon usage bias; mutation rate; purifying selection; splicing; synonymous sites.
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