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
Author(s): 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.
Publication Date: 27-Jun-2018
Date of Acceptance: 22-May-2018
URI: http://hdl.handle.net/10044/1/60255
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Copyright Statement: This paper is embargoed until publication. Once published it will be available fully open access.
Sponsor/Funder: Medical Research Council (MRC)
Engineering & Physical Science Research Council (EPSRC)
Funder's Grant Number: MR/J013617/1
EP/N014529/1
Keywords: MD Multidisciplinary
Publication Status: Accepted
Embargo Date: publication subject to indefinite embargo
Appears in Collections:Mathematics
Applied Mathematics and Mathematical Physics
Faculty of Natural Sciences



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