Intra-individual purifying selection on mitochondrial DNA variants during human oogenesis

Abstract

STUDY QUESTION: Does selection for mtDNA mutations occur in human oocytes?SUMMARY ANSWER: We 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 ALREADY: Several 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, DURATION: In 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, METHODS: Whole 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 CHANCE: Unlike 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. LIMITATIONS, REASONS FOR CAUTION:The 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.

The Mitochondrial Genome–on Selective Constraints and Signatures at the Organism, Cell, and Single Mitochondrion Levels

“…The differential accumulation pattern of mtDNA deleterious mutations in Drosophila males as compared to females, termed the "mother's curse", also supports the impact of natural selection on mtDNA sequences at the organism level (Innocenti et al, 2011), since in general, the mtDNA is maternally inherited. The signature of negative selection is also evident at the very early stages of embryo development, i.e., during oogenesis, as discussed above (De Fanti et al, 2017). Although bottleneck of mitochondrial transmission has been suggested to occur during the development of female germ cells in mice (Cree et al, 2008;Floros et al, 2018) and humans (Rebolledo-Jaramillo et al, 2014), divergence between mtDNA mutational patterns between tissues support the impact of natural selection (Latorre-Pellicer et al, 2016).…”

Assessing the fitness consequences of mitonuclear interactions in natural populations

“…Selection for efficient mitochondrial function, and hence mitonuclear compatibility, is expected to be intense, and it might well begin as early as oogenesis, with massive selection on cells in the germ line (Krakauer & Mira, ; Fan et al ., ; Stewart et al ., ; Dowling, ; Radzvilavicius et al ., ; De Fanti et al ., ). When there are multiple mitochondrial genotypes per cell, natural selection becomes inefficient in either eliminating deleterious genotypes or promoting highly functional genotypes (Radzvilavicius et al ., ).…”

Mitochondrial DNA Heteroplasmy and Purifying Selection in the Mammalian Female Germ Line

“…Furthermore, in vivo data from recent analysis of oocytes from nine healthy women found evidence of selection against potentially pathogenic mtDNA variants during oogenesis, occurring between the expulsion of the first and second polar bodies (De Fanti et al . ). Finally, very recent data from Floros et al .…”