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A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes

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Abstract

Mammalian mitochondrial DNA (mtDNA) is inherited principally down the maternal line, but the mechanisms involved are not fully understood. Females harboring a mixture of mutant and wild-type mtDNA (heteroplasmy) transmit a varying proportion of mutant mtDNA to their offspring. In humans with mtDNA disorders, the proportion of mutated mtDNA inherited from the mother correlates with disease severity1,2,3,4. Rapid changes in allele frequency can occur in a single generation5,6. This could be due to a marked reduction in the number of mtDNA molecules being transmitted from mother to offspring (the mitochondrial genetic bottleneck), to the partitioning of mtDNA into homoplasmic segregating units, or to the selection of a group of mtDNA molecules to re-populate the next generation. Here we show that the partitioning of mtDNA molecules into different cells before and after implantation, followed by the segregation of replicating mtDNA between proliferating primordial germ cells, is responsible for the different levels of heteroplasmy seen in the offspring of heteroplasmic female mice.

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Figure 1: The amount of mtDNA in mature mouse oocytes and preimplantation mouse embryos.
Figure 2: Models of the mitochondrial genetic bottleneck.
Figure 3: Modeling the inheritance of mtDNA heteroplasmy in mice.

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Acknowledgements

P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science and also receives funding from the United Mitochondrial Diseases Foundation and from the EU FP6 program EUmitocombat and MITOCIRCLE. H.-H.M.D. is a National Health and Medical Research Council (Australia) Principal Research Fellow, and his affiliations are with The Murdoch Children's Research Institute and the Department of Paediatrics (University of Melbourne), Royal Children's Hospital, Melbourne, Australia. We thank I. Dimmick for his assistance with the flow cytometry, D. Turnbull and B. Lightowlers for discussions, A. McLaren for her expertise on the cell dynamics of mouse development, and M. Azim Surani for providing the Stella-GFP mice. We also thank D. Thorburn for discussions and advice while studying the heteroplasmic mice, and both W. Hutchinson and S. White for experimental work on the heteroplasmic mice.

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Author notes

  1. Jeffrey R Mann

    Present address: Present address: Department of Zoology, The University of Melbourne, Victoria 3010, Australia.,

Authors and Affiliations

  1. Mitochondrial Research Group, Newcastle University, Newcastle, NE2 4HH, UK

    Lynsey M Cree & Patrick F Chinnery

  2. Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, 24061, Virginia, USA

    David C Samuels, Harsha Karur Rajasimha & Passorn Wonnapinij

  3. Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK

    Susana Chuva de Sousa Lopes

  4. Division of Biology, City of Hope, 1500 E. Duarte Rd., Duarte, 91010, California, USA

    Jeffrey R Mann

  5. The Murdoch Children's Research Institute & Department of Paediatrics (University of Melbourne), Royal Children's Hospital, Parkville, Melbourne, 3052, Victoria, Australia

    Hans-Henrik M Dahl

  6. Institute of Human Genetics, Newcastle University, Newcastle, NE2 4HH, UK

    Patrick F Chinnery

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  1. Lynsey M Cree
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Contributions

This laboratory study was designed by P.F.C. and L.M.C. and carried out by L.M.C. The in silico modeling was designed by D.C.S., programmed by H.K.R. and carried out by D.C.S., H.K.R. and P.W. GFP-Stella mice were produced in the laboratory of M. Azim Surani by S.C.d.S.L. H.-H.M.D. designed and supervised the heteroplasmic mouse work. J.R.M. generated the heteroplasmic mice.

Corresponding author

Correspondence to Patrick F Chinnery.

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Cree, L., Samuels, D., de Sousa Lopes, S. et al. A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat Genet 40, 249–254 (2008). https://doi.org/10.1038/ng.2007.63

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  • DOI: https://doi.org/10.1038/ng.2007.63

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