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Large-scale genetic analysis reveals mammalian mtDNA heteroplasmy dynamics and variance increase through lifetimes and generations

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Title: Large-scale genetic analysis reveals mammalian mtDNA heteroplasmy dynamics and variance increase through lifetimes and generations
Authors: Burgstaller, J
Kolbe, T
Havlicek, V
Hembach, S
Poulton, J
Piálek, J
Steinborn, R
Rülicke, T
Brem, G
Jones, NS
Johnston, I
Item Type: Journal Article
Abstract: Vital mitochondrial DNA (mtDNA) populations exist in cells and may consist of heteroplasmic mixtures of mtDNA types. The evolution of these heteroplasmic populations through development, ageing, and generations is central to genetic diseases, but is poorly understood in mammals. Here we dissect these population dynamics using a dataset of unprecedented size and temporal span, comprising 1947 single-cell oocyte and 899 somatic measurements of heteroplasmy change throughout lifetimes and generations in two genetically distinct mouse models. We provide a novel and detailed quantitative characterisation of the linear increase in heteroplasmy variance throughout mammalian life courses in oocytes and pups. We find that differences in mean heteroplasmy are induced between generations, and the heteroplasmy of germline and somatic precursors diverge early in development, with a haplotype-specific direction of segregation. We develop stochastic theory predicting the implications of these dynamics for ageing and disease manifestation and discuss its application to human mtDNA dynamics.
Issue Date: 27-Jun-2018
Date of Acceptance: 22-May-2018
URI: http://hdl.handle.net/10044/1/60255
DOI: https://dx.doi.org/10.1038/s41467-018-04797-2
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 9
Copyright Statement: © The Author(s) 2018. This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly fromthe copyright holder. To view a copy of this license, visithttp://creativecommons.org/licenses/by/4.0/
Sponsor/Funder: Medical Research Council (MRC)
Engineering & Physical Science Research Council (EPSRC)
Funder's Grant Number: MR/J013617/1
EP/N014529/1
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MITOCHONDRIAL-DNA HETEROPLASMY
RAPID SEGREGATION
GERM-LINE
BOTTLENECK
SELECTION
DRIFT
EVOLUTION
EXPLAINS
DISEASE
TRANSMISSION
Age Factors
Animals
DNA Copy Number Variations
DNA, Mitochondrial
Datasets as Topic
Female
Genome, Mitochondrial
Haplotypes
Mice
Mice, Inbred C57BL
Mitochondria
Models, Animal
Oocytes
Oocytes
Mitochondria
Animals
Mice, Inbred C57BL
Mice
DNA, Mitochondrial
Models, Animal
Age Factors
Haplotypes
Female
Genome, Mitochondrial
DNA Copy Number Variations
Datasets as Topic
MD Multidisciplinary
Publication Status: Published
Article Number: ARTN 2488
Appears in Collections:Mathematics
Applied Mathematics and Mathematical Physics
Faculty of Natural Sciences