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- Title
Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission.
- Authors
Freyer, Christoph; Cree, Lynsey M; Mourier, Arnaud; Stewart, James B; Koolmeister, Camilla; Milenkovic, Dusanka; Wai, Timothy; Floros, Vasileios I; Hagström, Erik; Chatzidaki, Emmanouella E; Wiesner, Rudolf J; Samuels, David C; Larsson, Nils-Göran; Chinnery, Patrick F
- Abstract
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 tRNAMet 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 tRNAMet mutation were linked to a compensatory increase in overall mitochondrial RNA levels, ameliorating the biochemical phenotype and explaining why fecundity is not compromised.
- Subjects
MITOCHONDRIAL DNA; GERM cells; POPULATION bottleneck; GENETIC mutation; PREVENTIVE medicine; LABORATORY mice
- Publication
Nature Genetics, 2012, Vol 44, Issue 11, p1282
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.2427