Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission.
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Authors
Zhang, Haixin
Esposito, Marco
Pezet, Mikael G
Calabrese, Claudia
Viscomi, Carlo
Publication Date
2021-12-10Journal Title
Sci Adv
ISSN
2375-2548
Publisher
American Association for the Advancement of Science (AAAS)
Volume
7
Issue
50
Language
eng
Type
Article
This Version
VoR
Metadata
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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
Abstract
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.
Sponsorship
Wellcome Trust (101876/Z/13/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Wellcome Trust (212219/Z/18/Z)
MRC (MR/S035699/1)
Identifiers
34878831, PMC8654302
External DOI: https://doi.org/10.1126/sciadv.abi5657
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333089
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