Likelihood analysis of asymmetrical mutation bias gradients in vertebrate mitochondrial genomes.

Protein-coding genes in mitochondrial genomes have varying degrees of asymmetric skew in base frequencies at the third codon position. The variation in skew among genes appears to be caused by varying durations of time that the heavy strand spends in the mutagenic single-strand state during replication (D(ssH)). The primary data used to study skew have been the gene-by-gene base frequencies in individual taxa, which provide little information on exactly what kinds of mutations are responsible for the base frequency skew. To assess the contribution of individual mutation components to the ancestral vertebrate substitution pattern, here we analyze a large data set of complete vertebrate mitochondrial genomes in a phylogeny-based likelihood context. This also allows us to evaluate the change in skew continuously along the mitochondrial genome and to directly estimate relative substitution rates. Our results indicate that different types of mutation respond differently to the D(ssH) gradient. A primary role for hydrolytic deamination of cytosines in creating variance in skew among genes was not supported, but rather linearly increasing rates of mutation from adenine to hypoxanthine with D(ssH) appear to drive regional differences in skew. Substitutions due to hydrolytic deamination of cytosines, although common, appear to quickly saturate, possibly due to stabilization by the mitochondrial DNA single-strand-binding protein. These results should form the basis of more realistic models of DNA and protein evolution in mitochondria.