Journal
ELIFE
Volume 4, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.07464
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Funding
- Medical Research Council (MRC) [MR/J013617/1, MR/J010448/1]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/D020190/1]
- Wellcome Trust [0948685/Z/10/Z]
- BBSRC [BB/D020190/1] Funding Source: UKRI
- MRC [MR/J013617/1, MR/J010448/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D020190/1] Funding Source: researchfish
- Medical Research Council [MR/J013617/1, MR/J010448/1] Funding Source: researchfish
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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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