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

Lookup NU author(s): Christoph Freyer, Dr Lynsey Cree, Dr Jim StewartORCiD, Dr Vasileios Floros, Dr David Samuels, Professor Patrick Chinnery


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A genetic bottleneck explains the marked changes in mitochondria! 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 tRNAMet mutation were linked to a compensatory increase in overall mitochondrial RNA levels, ameliorating the biochemical phenotype and explaining why fecundity is not compromised.

Publication metadata

Author(s): Freyer C, Cree LM, Mourier A, Stewart JB, Koolmeister C, Milenkovic D, Wai T, Floros VI, Hagstrom E, Chatzidaki EE, Wiesner RJ, Samuels DC, Larsson NG, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2012

Volume: 44

Issue: 11

Pages: 1282-1285

Print publication date: 07/10/2012

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group


DOI: 10.1038/ng.2427


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