DNA mismatch repair and synonymous codon evolution in mammals.

It has been suggested that the differences in synonymous codon use between mammalian genes within a genome are due to differences in the efficiency of DNA mismatch repair. This hypothesis was tested by developing a model of mismatch repair, which was used to predict the expected relationship between the rate of substitution and G+C content at silent sites. It was found that the silent-substitution rate should decline with increasing G+C content over most of the G+C-content range, if it is assumed that mismatch repair is G+C biased, an assumption which is supported by data. This prediction was then tested on a set of 58 primate and artiodactyl genes. There was no evidence of a direct decline in substitution rate with increasing G+C content, for either twofold- or fourfold-degenerate sites. It was therefore concluded that variation in the efficiency of mismatch repair is not responsible for the differences in synonymous codon use between mammalian genes. In support of this conclusion, analysis of the model also showed that the parameter range over which mismatch repair can explain the differences in synonymous codon use between genes is very small.