Mutation hot spots in mammalian mitochondrial DNA

Abstract

Animal mitochondrial DNA is characterized by a remarkably high level of within-species homoplasy, that is, phylogenetic incongruence between sites of the molecule. Several investigators have invoked recombination to explain it, challenging the dogma of maternal, clonal mitochondrial inheritance in animals. Alternatively, a high level of homoplasy could be explained by the existence of mutation hot spots. By using an exhaustive mammalian data set, we test the hot spot hypothesis by comparing patterns of site-specific polymorphism and divergence in several groups of closely related species, including hominids. We detect significant co-occurrence of synonymous polymorphisms among closely related species in various mammalian groups, and a correlation between the site-specific levels of variability within humans (on one hand) and between Hominoidea species (on the other hand), indicating that mutation hot spots actually exist in mammalian mitochondrial coding regions. The whole data, however, cannot be explained by a simple mutation hot spots model. Rather, we show that the site-specific mutation rate quickly varies in time, so that the same sites are not hypermutable in distinct lineages. This study provides a plausible mutation model that potentially accounts for the peculiar distribution of mitochondrial sequence variation in mammals without the need for invoking recombination. It also gives hints about the proximal causes of mitochondrial site-specific hypermutability in humans. ©2006 by Cold Spring Harbor Laboratory Press.