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Cell Rep. 2014 Jun 26;7(6):2031-2041. doi: 10.1016/j.celrep.2014.05.020. Epub 2014 Jun 6.

MtDNA segregation in heteroplasmic tissues is common in vivo and modulated by haplotype differences and developmental stage.

Author information

1
Biotechnology in Animal Production, Department for Agrobiotechnology, IFA Tulln, 3430 Tulln, Austria.
2
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
3
Department of Mathematics, Imperial College London, London SW7 2AZ, United Kingdom.
4
Research Facility Studenec, Academy of Sciences of the Czech Republic, Květná 8, 60365 Brno, Czech Republic.
5
Biomodels Austria, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
6
Department for Agrobiotechnology, IFA Tulln, University of Natural Resources and Applied Life Sciences, Tulln 3430, Austria.
7
Department of Statistics, University of Vienna, 1010 Vienna, Austria.
8
VetCore Facility for Research, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
9
Center for Medical Research, Medical University of Graz, 8010 Graz, Austria.
10
Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford OX3 9DU, United Kingdom.
11
Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
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Contributed equally

Abstract

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.

PMID:
24910436
PMCID:
PMC4570183
DOI:
10.1016/j.celrep.2014.05.020
[Indexed for MEDLINE]
Free PMC Article

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