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

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Title: Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism
Authors: Johnston, IG
Burgstaller, JP
Havlicek, V
Kolbe, T
Ruelicke, T
Brem, G
Poulton, J
Jones, NS
Item Type: Journal Article
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.
Issue Date: 2-Jun-2015
Date of Acceptance: 29-May-2015
URI: http://hdl.handle.net/10044/1/40179
DOI: http://dx.doi.org/10.7554/eLife.07464
ISSN: 2050-084X
Publisher: eLife Sciences Publications
Journal / Book Title: eLife
Volume: 4
Copyright Statement: © 2015 Johnston et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: MR/J013617/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Biology
Life Sciences & Biomedicine - Other Topics
RANDOM GENETIC DRIFT
MITOCHONDRIAL-DNA HETEROPLASMY
RAPID SEGREGATION
HUMAN OOCYTES
COPY NUMBER
MONTE-CARLO
DISEASE
GENOMES
MOUSE
REPLICATION
bottleneck
chromosomes
computational biology
developmental biology
genes
mouse
mtDNA
statistics
stochastic modelling
systems biology
Animals
Biostatistics
DNA, Mitochondrial
Mice
Models, Biological
Models, Statistical
Wills
q-bio.QM
q-bio.SC
stat.AP
Publication Status: Published
Open Access location: https://elifesciences.org/content/4/e07464v2
Article Number: e07464
Appears in Collections:Mathematics
Applied Mathematics and Mathematical Physics