Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism

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Abstract

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.

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Iain G Johnston

Department of Mathematics, Imperial College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Joerg P Burgstaller

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

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The authors declare that no competing interests exist.
Vitezslav Havlicek

Reproduction Centre Wieselburg, Department for Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

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The authors declare that no competing interests exist.
Thomas Kolbe

Biomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria

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The authors declare that no competing interests exist.
Thomas Rülicke

Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria

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The authors declare that no competing interests exist.
Gottfried Brem

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

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The authors declare that no competing interests exist.
Jo Poulton

Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, United Kingdom

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The authors declare that no competing interests exist.
Nick S Jones

Department of Mathematics, Imperial College London, London, United Kingdom

For correspondence
nick.jones@imperial.ac.uk

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The authors declare that no competing interests exist.

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.

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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.