Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism
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, generalis...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2015-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/07464 |
| _version_ | 1828375546658029568 |
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| author | Iain G Johnston Joerg P Burgstaller Vitezslav Havlicek Thomas Kolbe Thomas Rülicke Gottfried Brem Jo Poulton Nick S Jones |
| author_facet | Iain G Johnston Joerg P Burgstaller Vitezslav Havlicek Thomas Kolbe Thomas Rülicke Gottfried Brem Jo Poulton Nick S Jones |
| author_sort | Iain G Johnston |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:48:53Z |
| format | Article |
| id | doaj.art-8019d712523d4708afa02fd46cc2e356 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:48:53Z |
| publishDate | 2015-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8019d712523d4708afa02fd46cc2e3562022-12-22T02:05:15ZengeLife Sciences Publications LtdeLife2050-084X2015-06-01410.7554/eLife.07464Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanismIain G Johnston0Joerg P Burgstaller1Vitezslav Havlicek2Thomas Kolbe3Thomas Rülicke4Gottfried Brem5Jo Poulton6Nick S Jones7Department of Mathematics, Imperial College London, London, United KingdomBiotechnology in Animal Production, Department for Agrobiotechnology, IFA Tulln, IFA Tulln, Tulln, Austria; Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, AustriaReproduction Centre Wieselburg, Department for Biomedical Sciences, University of Veterinary Medicine, Vienna, AustriaBiomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria; IFA-Tulln, University of Natural Resources and Life Sciences, Tulln, AustriaInstitute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, AustriaInstitute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; Biotechnology in Animal Production, Department for Agrobiotechnology, IFA Tulln, Tulln, AustriaNuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, United KingdomDepartment of Mathematics, Imperial College London, London, United KingdomDangerous 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.https://elifesciences.org/articles/07464mtDNAbottleneckstochastic modellingdevelopmental biologystatistic |
| spellingShingle | Iain G Johnston Joerg P Burgstaller Vitezslav Havlicek Thomas Kolbe Thomas Rülicke Gottfried Brem Jo Poulton Nick S Jones Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism eLife mtDNA bottleneck stochastic modelling developmental biology statistic |
| title | Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism |
| title_full | Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism |
| title_fullStr | Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism |
| title_full_unstemmed | Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism |
| title_short | Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism |
| title_sort | stochastic modelling bayesian inference and new in vivo measurements elucidate the debated mtdna bottleneck mechanism |
| topic | mtDNA bottleneck stochastic modelling developmental biology statistic |
| url | https://elifesciences.org/articles/07464 |
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