TISSUE-SPECIFIC SELECTION FOR DIFFERENT MTDNA GENOTYPES IN HETEROPLASMIC MICE

Mammalian mitochondrial DNA (mtDNA) is a highly polymorphic, high-copy -number genome that is maternally inherited. New mutations in mtDNA se gregate rapidly in the female germline due to a genetic bottleneck in early oogenesis(1-3) and as a result most individuals are homoplasmic for a single species of mtDNA. Sequence variants thus accumulate along maternal lineages without genetic recombination. Most of the extant v ariation in mtDNA in mammalian populations has been assumed to be neut ral with respect to selection(4); however, comparisons of the ratio of replacement to silent nucleotide substitutions between species sugges t that the evolution of mammalian mtDNA is not strictly neutral(5). To test directly whether polymorphic mtDNAs behave as neutral variants, we examined the segregation of two different mtDNA genotypes in the ti ssues of heteroplasmic mice. We find evidence for random genetic drift in some tissues, but in others strong, tissue-specific and age-relate d, directional selection for different mtDNA genotypes in the same ani mal. These surprising data suggest that the coding sequence of mtDNA m ay represent a compromise between the competing demands of different t issues and point to the existence of unknown, tissue-specific nuclear genes important in the interaction between the nuclear and mitochondri al genomes.