Stochastic modelling, Bayesian inference, and new in vivomeasurements elucidate the debated mtDNA bottleneck mechanism
- Imperial College London, United Kingdom
- IFA Tulln, Austria
- University of Veterinary Medicine, Austria
- University of Veterinary Medicine Vienna, Austria
- University of Oxford, United Kingdom
Abstract
Dangerous damage to mitochondrial DNA (mtDNA) can be ameliorated during mammalian development through a highly debated mechanism called the mtDNA bottleneck. Uncertaintysurrounding 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 mtDNAturnover, meaning that the debated exact magnitude of mtDNAcopy number depletion is flexible. New experimental measurements from a wild-derived mtDNA pairing in mice confirm the theoretical predictions of this model. Weanalytically solve a mathematical description of thismechanism, computing probabilities of mtDNA disease onset,efficacy of clinical sampling strategies, and effects of potential dynamic interventions, thus developing aquantitative and experimentally-supported stochastic theoryof the bottleneck.
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Ethics
Animal experimentation: The study was discussed and approved by the institutional ethics committee in accordance with Good Scientific Practice (GSP) guidelines and national legislation. FELASA recommendations for the health monitoring of SPF mice were followed. Approved by the institutional ethics committee and the national authority according to Section 26 of the Law for Animal Experiments, Tierversuchsgesetz 2012 - TVG 2012.
Copyright
© 2015, Johnston et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Stochastic modelling, Bayesian inference, and new in vivomeasurements elucidate the debated mtDNA bottleneck mechanism
eLife 4:e07464.
https://doi.org/10.7554/eLife.07464
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