The dynamics by which mitochondrial DNA (mtDNA) evolves within organisms are still poorly understood, despite the fact that inheritance and proliferation of mutated mtDNA cause fatal and incurable diseases. When two mtDNA haplotypes are present in a cell, it is usually assumed that segregation (the proliferation of one haplotype over another) is negligible. We challenge this assumption by showing that segregation depends on the genetic distance between haplotypes. We provide evidence by creating four mouse models containing mtDNA haplotype pairs of varying diversity. We find tissue-specific segregation in all models over a wide range of tissues. Key findings are segregation in postmitotic tissues (important for disease models) and segregation covering all developmental stages from prenatal to old age. We identify four dynamic regimes of mtDNA segregation. Our findings suggest potential complications for therapies in human populations: we propose "haplotype matching" as an approach to avoid these issues.

Biomodels Austria University of Veterinary Medicine Vienna Veterinärplatz 1 1210 Vienna Austria

Biotechnology in Animal Production Department for Agrobiotechnology IFA Tulln 3430 Tulln Austria

Center for Medical Research Medical University of Graz 8010 Graz Austria

Department for Agrobiotechnology IFA Tulln University of Natural Resources and Applied Life Sciences Tulln 3430 Austria

Department of Mathematics Imperial College London London SW7 2AZ United Kingdom

Department of Statistics University of Vienna 1010 Vienna Austria

Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna Veterinärplatz 1 1210 Vienna Austria

Institute of Laboratory Animal Science University of Veterinary Medicine Vienna Veterinärplatz 1 1210 Vienna Austria

Nuffield Department of Obstetrics and Gynaecology University of Oxford Oxford OX3 9DU United Kingdom

Research Facility Studenec Academy of Sciences of the Czech Republic Květná 8 60365 Brno Czech Republic

VetCore Facility for Research University of Veterinary Medicine Vienna Veterinärplatz 1 1210 Vienna Austria

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Mitochondria on the move: Horizontal mitochondrial transfer in disease and health

Large-scale genetic analysis reveals mammalian mtDNA heteroplasmy dynamics and variance increase through lifetimes and generations

Sperm morphology in two house mouse subspecies: do wild-derived strains and wild mice tell the same story?

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