Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission.

Change log
Zhang, Haixin 
Esposito, Marco 
Pezet, Mikael G 

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.

31 Biological Sciences, 32 Biomedical and Clinical Sciences, 3105 Genetics, Genetics, Clinical Research, Neurodegenerative, 2 Aetiology, 2.1 Biological and endogenous factors
Journal Title
Sci Adv
Conference Name
Journal ISSN
Volume Title
American Association for the Advancement of Science (AAAS)
Wellcome Trust (101876/Z/13/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Wellcome Trust (212219/Z/18/Z)
MRC (MR/S035699/1)