Are Nonsynonymous Transversions Generally More Deleterious than Nonsynonymous Transitions?

It has been suggested that, due to the structure of the genetic code, nonsynonymous transitions are less likely than transversions to cause radical changes in amino acid physicochemical properties so are on average less deleterious. This view was supported by some but not all mutagenesis experiments. Because laboratory measures of fitness effects have limited sensitivities and relative frequencies of different mutations in mutagenesis studies may not match those in nature, we here revisit this issue using comparative genomics. We extend the standard codon model of sequence evolution by adding the parameter [Formula: see text] that quantifies the ratio of the fixation probability of transitional nonsynonymous mutations to that of transversional nonsynonymous mutations. We then estimate [Formula: see text] from the concatenated alignment of all protein-coding DNA sequences of two closely related genomes. Surprisingly, [Formula: see text] ranges from 0.13 to 2.0 across 90 species pairs sampled from the tree of life, with 51 incidences of [Formula: see text] < 1 and 30 incidences of [Formula: see text] >1 that are statistically significant. Hence, whether nonsynonymous transversions are overall more deleterious than nonsynonymous transitions is species-dependent. Because the corresponding groups of amino acid replacements differ between nonsynonymous transitions and transversions, [Formula: see text] is influenced by the relative exchangeabilities of amino acid pairs. Indeed, an extensive search reveals that the large variation in [Formula: see text] is primarily explainable by the recently reported among-species disparity in amino acid exchangeabilities. These findings demonstrate that genome-wide nucleotide substitution patterns in coding sequences have species-specific features and are more variable among evolutionary lineages than are currently thought.