Large-scale Genetic Analysis Reveals Mammalian MtDNA Heteroplasmy Dynamics and Variance Increase Through Lifetimes and Generations

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Jun 29

PMID 29950599

Citations 38

Authors

Joerg P Burgstaller

Thomas Kolbe

Vitezslav Havlicek

Stephanie Hembach

Joanna Poulton

Jaroslav Pialek

Ralf Steinborn

Thomas Rulicke

Gottfried Brem

Nick S Jones

Iain G Johnston

Affiliations

Soon will be listed here.

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.

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