Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos

Vasileios I. Floros, Angela Pyle, Sabine DIetmann, Wei Wei, Walfred W.C. Tang, Naoko Irie, Brendan Payne, Antonio Capalbo, Laila Noli, Jonathan Coxhead, Gavin Hudson, Moira Crosier, Henrik Strahl, Yacoub Khalaf, Mitinori Saitou, Dusko Ilic, M. Azim Surani, Patrick F. Chinnery

Research output: Contribution to journalArticlepeer-review

96 Citations (Scopus)

Abstract

Mitochondrial DNA (mtDNA) mutations cause inherited diseases and are implicated in the pathogenesis of common late-onset disorders, but how they arise is not clear 1,2 . Here we show that mtDNA mutations are present in primordial germ cells (PGCs) within healthy female human embryos. Isolated PGCs have a profound reduction in mtDNA content, with discrete mitochondria containing ~5 mtDNA molecules. Single-cell deep mtDNA sequencing of in vivo human female PGCs showed rare variants reaching higher heteroplasmy levels in late PGCs, consistent with the observed genetic bottleneck. We also saw the signature of selection against non-synonymous protein-coding, tRNA gene and D-loop variants, concomitant with a progressive upregulation of genes involving mtDNA replication and transcription, and linked to a transition from glycolytic to oxidative metabolism. The associated metabolic shift would expose deleterious mutations to selection during early germ cell development, preventing the relentless accumulation of mtDNA mutations in the human population predicted by Muller's ratchet. Mutations escaping this mechanism will show shifts in heteroplasmy levels within one human generation, explaining the extreme phenotypic variation seen in human pedigrees with inherited mtDNA disorders.

Original languageEnglish
Pages (from-to)144-151
Number of pages8
JournalNature Cell Biology
Volume20
Issue number2
DOIs
Publication statusPublished - 2018 Feb 1
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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