Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos
Nature Cell Biology
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Chinnery, P. (2018). Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos. Nature Cell Biology https://doi.org/10.1038/s41556-017-0017-8
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.
P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z), and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2), the Medical Research Council (UK) Centre for Translational Muscle Disease research (G0601943) and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. W.W.C.T. is supported by a Croucher Foundation studentship, and M.A.S. by a Wellcome Investigator Award.
WELLCOME TRUST (101876/Z/13/Z)
WELLCOME TRUST (101876/B/13/A)
Wellcome Trust (096738/Z/11/Z)
External DOI: https://doi.org/10.1038/s41556-017-0017-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/270236