Evaluating Purifying Selection in the Mitochondrial DNA of Various Mammalian Species

Abstract

Mitochondrial DNA (mtDNA), the circular DNA molecule inside the mitochondria of all eukaryotic cells, has been shown to be under the effect of purifying selection in several species. Traditional testing of purifying selection has been based simply on ratios of nonsynonymous to synonymous mutations, without considering the relative age of each mutation, which can be determined by phylogenetic analysis of this non-recombining molecule. The incorporation of a mutation time-ordering from phylogeny and of predicted pathogenicity scores for nonsynonymous mutations allow a quantitative evaluation of the effects of purifying selection in human mtDNA. Here, by using this additional information, we show that purifying selection undoubtedly acts upon the mtDNA of other mammalian species/genera, namely Bos sp., Canis lupus, Mus musculus, Orcinus orca, Pan sp. and Sus scrofa. The effects of purifying selection were comparable in all species, leading to a significant major proportion of nonsynonymous variants with higher pathogenicity scores in the younger branches of the tree. We also derive recalibrated mutation rates for age estimates of ancestors of these various species and proposed a correction curve in order to take into account the effects of selection. Understanding this selection is fundamental to evolutionary studies and to the identification of deleterious mutations.

A genetic chronology for the Indian Subcontinent points to heavily sex-biased dispersals

“…The values indicated throughout the text are therefore ML estimates (corrected for purifying selection). This is not observed in the global mtDNA tree [30, 64] and seems peculiar to the haplogroups in South Asia, due to demographic effects, as we argue below.…”

Meta-Analysis of Mitochondrial DNA Reveals Several Population Bottlenecks during Worldwide Migrations of Cattle

“…Purifying selection acting on mtDNA has been demonstrated for both bovine and other mammals [41], although it may be weaker for domestic livestock than for wild species [42]. Positive selection may improve the adaptation of cattle to different environments.…”

Mitochondrial maintenance failure in aging and role of sexual dimorphism

“…Heteroplasmy has significant implications for aging, as studies in mouse show that the presence of more than one mitochondrial genotype can cause tissue-specific conflicts in metabolic regulation that result in deleterious phenotypes [98]. The female germ line has been confirmed to be acting as a selective sieve that reduces the transmission of non-optimal mitochondrial genomes in both Drosophila [108–110] and vertebrates, including mammals [11, 111, 112]. The data from Drosophila suggest that the mitochondria are being selected for their relative replication ability within the female germ line cells [108, 113].…”

“…While there are some conflicting reports and technical issues associated with measurement of mitochondrial DNA, the data suggest that mitochondrial DNA copy number is mis-regulated in human metabolic disease and cancer, involving increases or decreases in abundance of intact genomes, as well as accumulation of damaged and deleted molecules [176]. In addition to promoting inflammation [111], mitochondrial DNA fragments are emerging as potential mediators of nuclear DNA damage during aging [155, 177, 178]. …”