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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.

SUBMITTER: Soares P

PROVIDER: S-EPMC3606437 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Evaluating purifying selection in the mitochondrial DNA of various mammalian species.

Soares Pedro P Abrantes Diogo D Rito Teresa T Thomson Noel N Radivojac Predrag P Li Biao B Macaulay Vincent V Samuels David C DC Pereira Luísa L

PloS one 20130322 3

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 a ...[more]

PMID: 23533597

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Project description:Study questionDoes selection for mtDNA mutations occur in human oocytes?Summary answerWe provide statistical evidence in favor of the existence of purifying selection for mtDNA mutations in human oocytes acting between the expulsion of the first and second polar bodies (PBs).What is known alreadySeveral lines of evidence in Metazoa, including humans, indicate that variation within the germline of mitochondrial genomes is under purifying selection. The presence of this internal selection filter in the germline has important consequences for the evolutionary trajectory of mtDNA. However, the nature and localization of this internal filter are still unclear while several hypotheses are proposed in the literature.Study design, size, durationIn this study, 60 mitochondrial genomes were sequenced from 17 sets of oocytes, first and second PBs, and peripheral blood taken from nine women between 38 and 43 years of age.Participants/materials, setting, methodsWhole genome amplification was performed only on the single cell samples and Sanger sequencing was performed on amplicons. The comparison of variant profiles between first and second PB sequences showed no difference in substitution rates but displayed instead a sharp difference in pathogenicity scores of protein-coding sequences using three different metrics (MutPred, Polyphen and SNPs&GO).Main results and the role of chanceUnlike the first, second PBs showed no significant differences in pathogenic scores with blood and oocyte sequences. This suggests that a filtering mechanism for disadvantageous variants operates during oocyte development between the expulsion of the first and second PB.Large scale dataN/A.Limitations, reasons for cautionThe sample size is small and further studies are needed before this approach can be used in clinical practice. Studies on a model organism would allow the sample size to be increased.Wider implications of the findingsThis work opens the way to the study of the correlation between mtDNA mutations, mitochondrial capacity and viability of oocytes.Study funding/competing interest(s)This work was supported by a SISMER grant. Laboratory facilities and skills were freely provided by SISMER, and by the Alma Mater Studiorum, University of Bologna. The authors have no conflict of interest to disclose.

Project description:The trajectories of postglacial range expansions, the occurrence of lineage patches and the formation and maintenance of secondary contact between lineages may mostly reflect neutral demographic processes, including density blocking, that may leave long-lasting genetic signatures. However, a few studies have recently shown that climate may also play a role. We used red deer, a large, mobile herbivore that is assumed to be sensitive to climate change, to test hypotheses of possible selection on the mitochondrial DNA cytochrome b gene (mtDNA cytb) and competitive and/or density-blocking (using mtDNA control region). We searched for a possible link between the phylogeographic structure and abiotic climatic variables. Finally, we tested for isolation by distance and isolation by environment and assessed the impact of human-mediated translocations on the genetic structure of red deer. Our analysis of 30 red deer populations in Poland using the mtDNA control region (N = 357) and cytochrome b (N = 50) markers not only confirmed the presence of the Western and South-Eastern lineages of the species but also indicated the presence of a previously unnoticed, rare relic haplotype that grouped together C. e. italicus from Italy (the Mesola deer). No significant signs of positive selection were detected for the mtDNA cytb gene in the studied red deer. However, a significant signal for purifying selection was found in our study that may explain the narrowness of the contact zone because gene flow between the Western and South-Eastern lineages should drive relatively strong mito-nuclear incompatibilities. MtDNA control region differentiation among red deer populations in Poland correlated with different abiotic climatic variables. Strikingly, the southernmost ice sheet limits during the Elsterian was the most important factor, and it explained the largest amount of variation. However, neither isolation by distance (IBD) nor isolation by environment (IBE) were recorded, and a very limited impact of human translocations was evident. The above-mentioned results suggest that in contemporary red deer populations in Poland, the phylogeographic pattern is well preserved, and long-term processes (density and/or competitive blocking) still play a major role.

Dataset Information

Evaluating purifying selection in the mitochondrial DNA of various mammalian species.

Publications

Evaluating purifying selection in the mitochondrial DNA of various mammalian species.

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