Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission.
Pezet, Mikael G
American Association for the Advancement of Science (AAAS)
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Zhang, H., Esposito, M., Pezet, M. G., Aryaman, J., Wei, W., Klimm, F., Calabrese, C., et al. (2021). Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission.. Sci Adv, 7 (50) https://doi.org/10.1126/sciadv.abi5657
Heteroplasmic mitochondrial DNA (mtDNA) mutations are a common cause of inherited disease, but a few recurrent mutations account for the vast majority of new families. The reasons for this are not known. We studied heteroplasmic mice transmitting m.5024C>T corresponding to a human pathogenic mutation. Analyzing 1167 mother-pup pairs, we show that m.5024C>T is preferentially transmitted from low to higher levels but does not reach homoplasmy. Single-cell analysis of the developing mouse oocytes showed the preferential increase in mutant over wild-type mtDNA in the absence of cell division. A similar inheritance pattern is seen in human pedigrees transmitting several pathogenic mtDNA mutations. In m.5024C>T mice, this can be explained by the preferential propagation of mtDNA during oocyte maturation, counterbalanced by purifying selection against high heteroplasmy levels. This could explain how a disadvantageous mutation in a carrier increases to levels that cause disease but fails to fixate, causing multigenerational heteroplasmic mtDNA disorders.
Wellcome Trust (101876/Z/13/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Wellcome Trust (212219/Z/18/Z)
External DOI: https://doi.org/10.1126/sciadv.abi5657
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333089
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/