MBE Advance Access originally published online on January 3, 2008
Molecular Biology and Evolution 2008 25(3):568-579; doi:10.1093/molbev/msm284
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Research Articles |
Mutation-Selection Models of Codon Substitution and Their Use to Estimate Selective Strengths on Codon Usage
* Department of Biology, Galton Laboratory, University College London, London, United Kingdom
Department of Biology, University of Copenhagen, Copenhagen, Denmark
E-mail: z.yang{at}ucl.ac.uk.
Accepted for publication December 19, 2007.
Current models of codon substitution are formulated at the levels of nucleotide substitution and do not explicitly consider the separate effects of mutation and selection. They are thus incapable of inferring whether mutation or selection is responsible for evolution at silent sites. Here we implement a few population genetics models of codon substitution that explicitly consider mutation bias and natural selection at the DNA level. Selection on codon usage is modeled by introducing codon-fitness parameters, which together with mutation-bias parameters, predict optimal codon frequencies for the gene. The selective pressure may be for translational efficiency and accuracy or for fine-tuning translational kinetics to produce correct protein folding. We apply the models to compare mitochondrial and nuclear genes from several mammalian species. Model assumptions concerning codon usage are found to affect the estimation of sequence distances (such as the synonymous rate dS, the nonsynonymous rate dN, and the rate at the 4-fold degenerate sites d4), as found in previous studies, but the new models produced very similar estimates to some old ones. We also develop a likelihood ratio test to examine the null hypothesis that codon usage is due to mutation bias alone, not influenced by natural selection. Application of the test to the mammalian data led to rejection of the null hypothesis in most genes, suggesting that natural selection may be a driving force in the evolution of synonymous codon usage in mammals. Estimates of selection coefficients nevertheless suggest that selection on codon usage is weak and most mutations are nearly neutral. The sensitivity of the analysis on the assumed mutation model is discussed.
Key Words: codon substitution model • codon usage • mutation • selection • synonymous substitution
Jeffrey Thorne, Associate Editor