Abstract
There is an intense debate concerning whether selection or demographics has been most important in shaping the sequence variation observed in modern human mitochondrial DNA (mtDNA). Purifying selection is thought to be important in shaping mtDNA sequence evolution, but the strength of this selection has been debated, mainly due to the threshold effect of pathogenic mtDNA mutations and an observed excess of new mtDNA mutations in human population data. We experimentally addressed this issue by studying the maternal transmission of random mtDNA mutations in mtDNA mutator mice expressing a proofreading-deficient mitochondrial DNA polymerase. We report a rapid and strong elimination of nonsynonymous changes in protein-coding genes; the hallmark of purifying selection. There are striking similarities between the mutational patterns in our experimental mouse system and human mtDNA polymorphisms. These data show strong purifying selection against mutations within mtDNA protein-coding genes. To our knowledge, our study presents the first direct experimental observations of the fate of random mtDNA mutations in the mammalian germ line and demonstrates the importance of purifying selection in shaping mitochondrial sequence diversity.
Highlights
Mammalian mitochondrial DNA has a high mutation rate and is inherited in a non-Mendelian manner only from the mother [1,2]
The bottleneck phenomenon, which was first proposed after observation of rapid fixation of mitochondrial DNA variants in Holstein cows [7,8], allows for rapid exposure of variant mtDNAs to selection at the level of the individual [9], and may thereby, at the level of the population, protect against mutational meltdown
Maternal transmission of mtDNA is typically subjected to a bottleneck phenomenon whereby only a fraction of the mtDNA copies in the germ-cell precursor are amplified to generate the approximately 105 mtDNA copies present in the mature oocyte
Summary
Mammalian mitochondrial DNA (mtDNA) has a high mutation rate and is inherited in a non-Mendelian manner only from the mother [1,2]. Though there are reports of mitochondrial recombination in mammals, it is thought to be quite rare, and it is currently not known whether this phenomenon would be at a sufficient frequency to leave a signature in the population [3,4,5,6]. This asexual mode of transmission should leave the mitochondrial genome vulnerable to mutational meltdown by Muller’s Ratchet, a process leading to deleterious mutation accumulation in asexual, nonrecombining lineages. The mtDNA bottleneck appears to result from the replication of only a small subset of the mtDNA molecules as the primordial germ cells differentiate to generate oocytes [10]
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