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

Lookup NU author(s): Dr Vasileios Floros, Dr Angela Pyle, Dr Wei Wei, Dr Brendan PayneORCiD, Dr Jonathan Coxhead, Professor Gavin Hudson, Moira Crosier, Dr Henrik Strahl von SchultenORCiD, Professor Patrick Chinnery



This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature Publishing Group, 2018.

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© 2018 © The Authors 2017, under exclusive licence to Macmillan Publishers Limited, part of Springer Nature Mitochondrial DNA (mtDNA) mutations cause inherited diseases and are implicated in the pathogenesis of common late-onset disorders, but how they arise is not clear1,2. 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.

Publication metadata

Author(s): Floros VI, Pyle A, Dietmann S, Wei W, Tang WWC, Irie N, Payne B, Capalbo A, Noli L, Coxhead J, Hudson G, Crosier M, Strahl H, Khalaf Y, Saitou M, Ilic D, Surani MA, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Nature Cell Biology

Year: 2018

Volume: 20

Pages: 144-151

Online publication date: 15/01/2018

Acceptance date: 27/11/2017

Date deposited: 22/02/2018

ISSN (print): 1465-7392

ISSN (electronic): 1476-4679

Publisher: Nature Publishing Group


DOI: 10.1038/s41556-017-0017-8


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