The Effect of Tandem Substitutions on the Correlation Between Synonymous and Nonsynonymous Rates in Rodents

Corresponding author: Nick G. C. Smith, School of Biological Sciences, University of Sussex, Brighton BN1 9QG, United Kingdom., n.g.c.smith{at}sussex.ac.uk (E-mail)

Communicating editor: G. B. GOLDING

Nonsynonymous substitutions in DNA cause amino acid substitutions while synonymous substitutions in DNA leave amino acids unchanged. The cause of the correlation between the substitution rates at nonsynonymous (K_A) and synonymous (K_S) sites in mammals is a contentious issue, and one that impacts on many aspects of molecular evolution. Here we use a large set of orthologous mammalian genes to investigate the causes of the K_A-K_S correlation in rodents. The strength of the K_A-K_S correlation exceeds the neutral theory expectation when substitution rates are estimated using algorithmic methods, but not when substitution rates are estimated by maximum likelihood. Irrespective of this methodological uncertainty the strength of the K_A-K_S correlation appears mostly due to tandem substitutions, an excess of which is generated by substitutional nonindependence. Doublet mutations cannot explain the excess of tandem synonymous-nonsynonymous substitutions, and substitution patterns indicate that selection on silent sites is the likely cause. We find no evidence for selection on codon usage. The nature of the relationship between synonymous divergence and base composition is unclear because we find a significant correlation if we use maximum-likelihood methods but not if we use algorithmic methods. Finally, we find that K_S is reduced at the start of genes, which suggests that selection for RNA structure may affect silent sites in mammalian protein-coding genes.

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