Citation
Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission. Science Advances doi.org/10.17863/CAM.76113
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 of 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 replication 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 which cause disease, but fails to fixate, causing multi-generational heteroplasmic mtDNA disorders.
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