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dc.contributor.authorZhang, Haixin
dc.contributor.authorEsposito, Marco
dc.contributor.authorPezet, Mikael G
dc.contributor.authorAryaman, Juvid
dc.contributor.authorWei, Wei
dc.contributor.authorKlimm, Florian
dc.contributor.authorCalabrese, Claudia
dc.contributor.authorBurr, Stephen P
dc.contributor.authorMacabelli, Carolina H
dc.contributor.authorViscomi, Carlo
dc.contributor.authorSaitou, Mitinori
dc.contributor.authorChiaratti, Marcos R
dc.contributor.authorStewart, James B
dc.contributor.authorJones, Nick
dc.contributor.authorChinnery, Patrick F
dc.date.accessioned2022-01-28T14:45:37Z
dc.date.available2022-01-28T14:45:37Z
dc.date.issued2021-12-10
dc.identifier.issn2375-2548
dc.identifier.other34878831
dc.identifier.otherPMC8654302
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/333089
dc.description.abstractHeteroplasmic mitochondrial DNA (mtDNA) mutations are a common cause of inherited disease, but a few recurrent mutations account for the vast majority of new families. The reasons for this are not known. We studied heteroplasmic mice transmitting m.5024C>T corresponding to a human pathogenic mutation. Analyzing 1167 mother-pup pairs, we show that m.5024C>T is preferentially transmitted from low to higher levels but does not reach homoplasmy. Single-cell analysis of the developing mouse oocytes showed the preferential increase in mutant over wild-type mtDNA in the absence of cell division. A similar inheritance pattern is seen in human pedigrees transmitting several pathogenic mtDNA mutations. In m.5024C>T mice, this can be explained by the preferential propagation of mtDNA during oocyte maturation, counterbalanced by purifying selection against high heteroplasmy levels. This could explain how a disadvantageous mutation in a carrier increases to levels that cause disease but fails to fixate, causing multigenerational heteroplasmic mtDNA disorders.
dc.languageeng
dc.publisherAmerican Association for the Advancement of Science (AAAS)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101653440
dc.sourceessn: 2375-2548
dc.titleMitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission.
dc.typeArticle
dc.date.updated2022-01-28T14:45:37Z
prism.issueIdentifier50
prism.publicationNameSci Adv
prism.volume7
dc.identifier.doi10.17863/CAM.80513
dcterms.dateAccepted2021-09-27
rioxxterms.versionofrecord10.1126/sciadv.abi5657
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidAryaman, Juvid [0000-0002-2605-052X]
dc.contributor.orcidWei, Wei [0000-0002-2945-3543]
dc.contributor.orcidKlimm, Florian [0000-0001-7209-5393]
dc.contributor.orcidBurr, Stephen P [0000-0001-8865-126X]
dc.contributor.orcidMacabelli, Carolina H [0000-0001-5865-9156]
dc.contributor.orcidSaitou, Mitinori [0000-0002-2895-6798]
dc.contributor.orcidChiaratti, Marcos R [0000-0001-8805-9469]
dc.contributor.orcidStewart, James B [0000-0002-2902-4968]
dc.contributor.orcidJones, Nick [0000-0002-4083-972X]
dc.contributor.orcidChinnery, Patrick F [0000-0002-7065-6617]
dc.identifier.eissn2375-2548
pubs.funder-project-idWellcome Trust (101876/Z/13/Z)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idWellcome Trust (212219/Z/18/Z)
pubs.funder-project-idMRC (MR/S035699/1)
cam.issuedOnline2021-12-08


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International