University of Birmingham > Talks@bham > Applied Mathematics Seminar Series > Physical modelling and Bayesian inference elucidates the debated mechanism of the mtDNA bottleneck

Physical modelling and Bayesian inference elucidates the debated mechanism of the mtDNA bottleneck

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Organisms ameliorate dangerous damage to mitochondrial DNA (mtDNA) between generations through a developmental process called the mtDNA bottleneck. The mechanism by which this process occurs is debated mechanistically and lacks a quantitative theory, limiting our ability to plan clinical approaches to prevent or address the inheritance of mtDNA disease. We address this problem by producing a physically motivated, general model for the bottleneck, which is predictive and analytically tractable. This model for the first time allows a statistical comparison of the different proposed mechanisms given experimental data. We resolve the mechanistic question of the bottleneck, and show that the debated magnitude of mtDNA copy number reduction is relatively unimportant. In addition, our model yields analytic results for mtDNA and heteroplasmy statistics at arbitrary times during development, allowing us to explore the effects of mtDNA turnover, mitophagy and selective pressure on the dynamics of the bottleneck, and the power of sampling strategies to yield clinically important predictions. We find that upregulating mitophagy during the bottleneck increases cell-to-cell variability of mutant load, potentially increasing the ability to remove damaged mtDNA.

This talk is part of the Applied Mathematics Seminar Series series.

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