Strong Purifying Selection in Transmission of Mammalian Mitochondrial DNA

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.

Increased mitochondrial mutation frequency after an island colonization: positive selection or accumulation of slightly deleterious mutations?

“…Still, one should nonetheless expect that there should be selection against strongly deleterious non-synonymous mutations in the germline, as found in mitochondrial mutator lines [8]. Indeed in the Kerguelen mice, we find only one non-conservative amino acid change (as judged by the Blossum64 matrix score-table 1), namely the D .…”

“…We found a total of seven additional single-step point mutations, four in coding regions leading to amino acid changes, two synonymous ones and one in tRNA Val (table 1). In addition, tRNA Arg shows a variable number of As within a stretch of As in two animals, representing a known polymorphic region [8]. The ND6 mutation in one individual showed signs of heteroplasmy (table 1) with about 40 per cent of the peak size representing the original C at this position.…”

“…Mitochondrial genomes were sequenced from 16 mice using primers described in Stewart et al [8] and in electronic supplementary material, table S1 (sequences are deposited under GenBank accession nos JX945964 to JX945979). Mice were collected as described in Chapuis et al [9] (locations are depicted in electronic supplementary material, figure S1).…”

“…Mitochondrial genomes from inbred laboratory lines were retrieved from GenBank (accession nos in electronic supplementary material, table S2). Since both the island mice and the laboratory mice are derived from a single, albeit different, mitochondrial haplotype [7,10], we estimated mutation frequencies with respect to the total number of nucleotides sequenced by counting the mutations in comparison to the consensus sequence, in a procedure analogous to the estimation of mutation frequencies from mutation-accumulation lines [8].…”

Molecular clock debate: Time dependency of molecular rate estimates for mtDNA: this is not the time for wishful thinking

“…Instead, here, we focus on purifying (negative) selection and its consequences for the rate of sequence evolution. While purifying selection operates at the level of the germline (Stewart et al, 2008), it does not act instantaneously, and, instead, a substantial proportion of slightly deleterious mutations are lost continuously from the mtDNA gene pool over a prolonged period of time (Elson et al, 2004;Kivisild et al, 2006;Howell et al, 2007;Elson et al, submitted for publication). As a result of this selection acting throughout the human mtDNA phylogenetic tree, relatively more mutations have been lost in older branches (for example, mtDNAs from Africans) than in younger branches (for example, mtDNAs from Europeans).…”