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


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.

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Figure 1: Levels of heteroplasmy in 9 different tissues from 3 control and 17 mutant adult mice after at least 7 generations of backcrossing.
Figure 2: Measurements of the proportion of mtDNA with the m.3875delC mutation in mothers, PGCs, oocytes and offspring.
Figure 3: The average shift in the mutation level between the next generation and the mothers for PGCs, oocytes and offspring.
Figure 4: Analysis of steady-state levels of mitochondrial tRNAs in 16-week-old animals with different levels of the m.3875delC mutation of tRNAMet.


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We would like to thank C. Göttlinger and G. Rappl for help with the fluorescence-activated cell sorting (FACS) analysis. T.W. is supported by a long-term Human Frontier Science Program (HFSP) fellowship. P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science and a National Institute for Health Research (NIHR) Senior Investigator, who also receives funding from the Wellcome Centre for Mitochondrial Research, the Medical Research Council (UK) Translational Muscle Centre, the UK NIHR Biomedical Research Centre for Ageing and Age-Related Disease and NIHR Dementia Biomedical Research Unit awards to the Newcastle upon Tyne Foundation Hospitals National Health Service (NHS) Trust. N.-G.L. is supported by the Swedish Research Council, the Leducq foundation and a European Research Council Advanced Investigator grant.

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Authors and Affiliations



P.F.C., C.F., L.M.C. and N.-G.L. conceived the study and supervised the laboratory work, which was carried out by C.F., L.M.C., A.M., J.B.S., C.K., V.I.F., D.M., T.W., E.H., R.J.W. and E.E.C. D.C.S. performed the statistical analysis. P.F.C. wrote the manuscript with C.F., which was modified after critical appraisal from the other authors.

Corresponding authors

Correspondence to Nils-Göran Larsson or Patrick F Chinnery.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Tables 1–3 and 5 (PDF 25942 kb)

Supplementary Table 4

Raw heteroplasmy data from the mothers, oogonia, oocytes and offspring. See excel file. (XLSX 26 kb)

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Freyer, C., Cree, L., Mourier, A. et al. Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission. Nat Genet 44, 1282–1285 (2012).

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