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dc.contributor.authorWei, Wei
dc.contributor.authorKeogh, Michael J
dc.contributor.authorAryaman, Juvid
dc.contributor.authorGolder, Zoe
dc.contributor.authorKullar, Peter
dc.contributor.authorWilson, Ian
dc.contributor.authorTalbot, Kevin
dc.contributor.authorTurner, Martin R
dc.contributor.authorMcKenzie, Chris-Anne
dc.contributor.authorTroakes, Claire
dc.contributor.authorAttems, Johannes
dc.contributor.authorSmith, Colin
dc.contributor.authorSarraj, Safa Al
dc.contributor.authorMorris, Chris M
dc.contributor.authorAnsorge, Olaf
dc.contributor.authorJones, Nick S
dc.contributor.authorIronside, James W
dc.contributor.authorChinnery, Patrick
dc.date.accessioned2018-09-10T22:16:46Z
dc.date.available2018-09-10T22:16:46Z
dc.date.issued2019-04
dc.identifier.issn1098-3600
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/280058
dc.description.abstractPURPOSE: To systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders. METHODS: In this study we developed a pipeline to identify somatic variants from exome sequencing data in 1461 diseased and control human brains. Eighty-eight percent of the DNA samples were extracted from the cerebellum. Identified somatic variants were validated by targeted amplicon sequencing and/or PyroMark® Q24. RESULTS: We observed somatic coding variants present in >10% of sampled cells in at least 1% of brains. The mutational signature of the detected variants showed a predominance of C>T variants most consistent with arising from DNA mismatch repair, occurred frequently in genes that are highly expressed within the central nervous system, and with a minimum somatic mutation rate of 4.25 × 10-10 per base pair per individual. CONCLUSION: These findings provide proof-of-principle that deleterious somatic variants can affect sizeable brain regions in at least 1% of the population, and thus have the potential to contribute to the pathogenesis of common neurodegenerative diseases.
dc.description.sponsorshipWellcome Trust
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBrain
dc.subjectHumans
dc.subjectGenetic Diseases, Inborn
dc.subjectSequence Analysis, DNA
dc.subjectMutation
dc.subjectDNA Mismatch Repair
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectExome
dc.subjectWhole Exome Sequencing
dc.titleFrequency and signature of somatic variants in 1461 human brain exomes.
dc.typeArticle
prism.endingPage912
prism.issueIdentifier4
prism.publicationDate2019
prism.publicationNameGenet Med
prism.startingPage904
prism.volume21
dc.identifier.doi10.17863/CAM.27422
dcterms.dateAccepted2018-08-06
rioxxterms.versionofrecord10.1038/s41436-018-0274-3
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-04
dc.contributor.orcidChinnery, Patrick [0000-0002-7065-6617]
dc.identifier.eissn1530-0366
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (101876/Z/13/Z)
pubs.funder-project-idWellcome Trust (101876/B/13/A)
pubs.funder-project-idMRC (via University of Edinburgh) (162126)
pubs.funder-project-idWellcome Trust (212219/Z/18/Z)
cam.issuedOnline2018-09-14
cam.orpheus.successThu Jan 30 10:54:26 GMT 2020 - The item has an open VoR version.
rioxxterms.freetoread.startdate2100-01-01


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