Strong Purifying Selection in Transmission of Mammalian Mitochondrial DNA

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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. Mammalian mitochondrial DNA (mtDNA) is maternally transmitted and does not undergo bi-parental recombination in the germ line. This asexual mode of transmission, together with a high rate of mutation, should eventually lead to the accumulation of numerous deleterious mtDNA mutations and a “mutational meltdown” (a phenomenon know as Muller's Ratchet). In this study, we utilized a genetic mouse model, the mtDNA mutator mouse, to introduce random mtDNA mutations, and followed transmission of these mutations. 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. As a consequence of this phenomenon, the established maternal mouse lines carried high levels of a few mtDNA mutations. We sequenced the entire mtDNA to characterize the maternally transmitted mutations in the established mouse lines. Surprisingly, mutations causing amino acid changes were strongly underrepresented in comparison with “silent” changes in the protein-coding genes. These results show that mtDNA is subject to strong purifying selection in the maternal germ line. Such selection of functional mtDNA genomes likely involves a mechanism for functional testing to prevent transmission of mutated genomes to the offspring.