The Roles of Mutation, Selection, and Expression in Determining Relative Rates of Evolution in Mitochondrial versus Nuclear Genomes

Eukaryotes rely on proteins encoded by the nuclear and mitochondrial (mt) genomes, which interact within multisubunit complexes such as oxidative-phosphorylation enzymes. Although selection is thought to be less efficient on the asexual mt genome, in bilaterian animals the ratio of nonsynonymous to synonymous substitutions (omega) is lower in mt-compared with nuclear-encoded OXPHOS subunits, suggesting stronger effects of purifying selection in the mt genome. Because high levels of gene expression constrain protein sequence evolution, one proposed resolution to this paradox is that mt genes are expressed more highly than nuclear genes. To test this hypothesis, we investigated expression and sequence evolution of mt and nuclear genes from 84 diverse eukaryotes that vary in mt gene content and mutation rate. We found that the relationship between mt and nuclear omega values varied dramatically across eukaryotes. In contrast, transcript abundance is consistently higher for mt genes than nuclear genes, regardless of which genes happen to be in the mt genome. Consequently, expression levels cannot be responsible for the differences in omega. Rather, 84% of the variance in the ratio of omega values between mt and nuclear genes could be explained by differences in mutation rate between the two genomes. We relate these findings to the hypothesis that high rates of mt mutation select for compensatory changes in the nuclear genome. We also propose an explanation for why mt transcripts consistently outnumber their nuclear counterparts, with implications for mitonuclear protein imbalance and aging.