Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission.

TitleVariation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission.
Publication TypeJournal Article
Year of Publication2012
AuthorsFreyer, C, Cree, LM, Mourier, A, Stewart, JB, Koolmeister, C, Milenkovic, D, Wai, T, Floros, VI, Hagström, E, Chatzidaki, EE, Wiesner, RJ, Samuels, DC, Larsson, N-G, Chinnery, PF
JournalNat Genet
Date Published2012 Nov
KeywordsAnimals, DNA, Mitochondrial, DNA-Directed DNA Polymerase, Female, Fertility, Genetic Heterogeneity, Genome, Mitochondrial, Germ-Line Mutation, Mice, Mice, Inbred C57BL, Oocytes, RNA, RNA, Transfer, Met

A genetic bottleneck explains the marked changes in mitochondrial DNA (mtDNA) heteroplasmy that are observed during the transmission of pathogenic mutations, but the precise timing of these changes remains controversial, and it is not clear whether selection has a role. These issues are important for the genetic counseling of prospective mothers and for the development of treatments aimed at disease prevention. By studying mice transmitting a heteroplasmic single-base-pair deletion in the mitochondrial tRNA(Met) gene, we show that the extent of mammalian mtDNA heteroplasmy is principally determined prenatally within the developing female germline. Although we saw no evidence of mtDNA selection prenatally, skewed heteroplasmy levels were observed in the offspring of the next generation, consistent with purifying selection. High percentages of mtDNA genomes with the tRNA(Met) mutation were linked to a compensatory increase in overall mitochondrial RNA levels, ameliorating the biochemical phenotype and explaining why fecundity is not compromised.

Alternate JournalNat. Genet.
Citation Key10.1038/ng.2427
PubMed ID23042113
PubMed Central IDPMC3492742
Grant List071095 / / Wellcome Trust / United Kingdom
084980 / / Wellcome Trust / United Kingdom
096919 / / Wellcome Trust / United Kingdom
newbrc-2007-1 / / Department of Health / United Kingdom
/ / Medical Research Council / United Kingdom