Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism
Iain G Johnston,
Joerg P Burgstaller,
Vitezslav Havlicek,
Thomas Kolbe,
Thomas Rülicke,
Gottfried Brem,
Jo Poulton,
Nick S Jones
Affiliations
Iain G Johnston
Department of Mathematics, Imperial College London, London, United Kingdom
Joerg P Burgstaller
Biotechnology in Animal Production, Department for Agrobiotechnology, IFA Tulln, IFA Tulln, Tulln, Austria; Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
Vitezslav Havlicek
Reproduction Centre Wieselburg, Department for Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria
Thomas Kolbe
Biomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria; IFA-Tulln, University of Natural Resources and Life Sciences, Tulln, Austria
Thomas Rülicke
Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria
Gottfried Brem
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; Biotechnology in Animal Production, Department for Agrobiotechnology, IFA Tulln, Tulln, Austria
Jo Poulton
Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, United Kingdom
Nick S Jones
Department of Mathematics, Imperial College London, London, United Kingdom
Dangerous damage to mitochondrial DNA (mtDNA) can be ameliorated during mammalian development through a highly debated mechanism called the mtDNA bottleneck. Uncertainty surrounding this process limits our ability to address inherited mtDNA diseases. We produce a new, physically motivated, generalisable theoretical model for mtDNA populations during development, allowing the first statistical comparison of proposed bottleneck mechanisms. Using approximate Bayesian computation and mouse data, we find most statistical support for a combination of binomial partitioning of mtDNAs at cell divisions and random mtDNA turnover, meaning that the debated exact magnitude of mtDNA copy number depletion is flexible. New experimental measurements from a wild-derived mtDNA pairing in mice confirm the theoretical predictions of this model. We analytically solve a mathematical description of this mechanism, computing probabilities of mtDNA disease onset, efficacy of clinical sampling strategies, and effects of potential dynamic interventions, thus developing a quantitative and experimentally-supported stochastic theory of the bottleneck.
