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Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission

Lookup NU author(s): Dr Jim StewartORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Zhang H, Esposito MG, Pezet M, Aryaman J, Wei W, Klimm F, Calabrese C, Burr SP, Macabelli CH, Viscomi C, Saitou M, Chiaratti M, Stewart JB, Jones N, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Science Advances

Year: 2021

Volume: 7

Issue: 50

Print publication date: 10/12/2021

Online publication date: 08/12/2021

Acceptance date: 15/10/2021

Date deposited: 08/12/2021

ISSN (electronic): 2375-2548

Publisher: American Association for the Advancement of Science (AAAS)


DOI: 10.1126/sciadv.abi5657


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Funder referenceFunder name
MR/S005021/1Medical Research Council (MRC)
the Academy of Medical Sciences-Newton Advanced Fellowship
the National Institute for Health Research (NIHR) Biomedical Research Centre