Extreme-Depth Re-sequencing of Mitochondrial DNA Finds No Evidence of Paternal Transmission in Humans

摘要

Recent reports have questioned the accepted dogma that mammalian mitochondrial DNA (mtDNA) is strictly maternally inherited. In humans, the argument hinges on detecting a signature of inter-molecular recombination in mtDNA sequences sampled at the population level, inferring a paternal source for the mixed haplotypes. However, interpreting these data is fraught with difficulty, and direct experimental evidence is lacking. Using extreme-high depth mtDNA re-sequencing up to ~1.2 million-fold coverage, we find no evidence that paternal mtDNA haplotypes are transmitted to offspring in humans, thus excluding a simple dilution mechanism for uniparental transmission of mtDNA present in all healthy individuals. Our findings indicate that an active mechanism eliminates paternal mtDNA which likely acts at the molecular level. Author Summary Emerging evidence raises the possibility that human mitochondrial DNA (mtDNA) is not strictly maternally inherited, but it has not been technically possible to test this hypothesis directly. We identified trios with discordant mtDNA haplotypes, parent-offspring trios were validated using polymorphic microsatellites, and then used extreme-high depth mtDNA re-sequencing to look for paternally transmitted mtDNA. Despite having up to ~1.2 million-fold coverage of mtDNA, we find no evidence that paternal mtDNA haplotypes are transmitted to offspring in humans. Our findings exclude a simple dilution mechanism for uniparental transmission of mtDNA present in all healthy individuals.