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

JP. Burgstaller, IG. Johnston, NS. Jones, J. Albrechtová, T. Kolbe, C. Vogl, A. Futschik, C. Mayrhofer, D. Klein, S. Sabitzer, M. Blattner, C. Gülly, J. Poulton, T. Rülicke, J. Piálek, R. Steinborn, G. Brem,

. 2014 ; 7 (6) : 2031-41.

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc15023347

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.

Citace poskytuje Crossref.org

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$a Burgstaller, Joerg Patrick $u Biotechnology in Animal Production, Department for Agrobiotechnology, IFA Tulln, 3430 Tulln, Austria; Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Veterinärplatz 1, 1210 Vienna, Austria. Electronic address: joerg.burgstaller@vetmeduni.ac.at.
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$a 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.
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$a Johnston, Iain G $u Department of Mathematics, Imperial College, London, London SW7 2AZ, UK.
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$a Vogl, Claus $u Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
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$a Futschik, Andreas $u Department of Statistics, University of Vienna, 1010 Vienna, Austria.
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