Molecular evolution of cytochrome c oxidase: rate variation among subunit VIa isoforms

Cytochrome c oxidase (COX) consists of 13 subunits, 3 encoded in themitochondrial genome and 10 in the nucleus. Little is known of the role ofthe nuclear-encoded subunits, some of which exhibit tissue-specificisoforms. Subunit VIa is unique in having tissue-specific isoforms in allmammalian species examined. We examined relative evolutionary rates for theCOX6A heart (H) and liver (L) isoform genes along the length of themolecule, specifically in relation to the tissue-specific function(s) ofthe two isoforms. Nonsynonymous (amino acid replacement) substitutions inthe COX6AH gene occurred more frequently than in the ubiquitously expressedCOX6AL gene. Maximum-parsimony analysis and sequence divergences fromreconstructed ancestral sequences revealed that after the ancestral COX6Agene duplicated to yield the genes for the H and L isoforms, the sequencesencoding the mitochondrial matrix region of the COX VIa protein experiencedan elevated rate of nonsynonymous substitutions relative to synonymoussubstitutions. This is expected for relaxed selective constraints aftergene duplication followed by purifying selection to preserve thereplacements with tissue-specific functions.