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dc.contributor.authorWinton, Douglasen
dc.contributor.authorMorrissey, Edwarden
dc.contributor.authorLourenco, Filipe Cen
dc.contributor.authorAbujudeh, Samen
dc.contributor.authorThorsen, Anne-Sofieen
dc.contributor.authorHazelwood, Leeen
dc.contributor.authorKemp, Richarden
dc.contributor.authorChristopher, Josephen
dc.contributor.authorPotter, Paul Ken
dc.date.accessioned2019-05-22T23:30:17Z
dc.date.available2019-05-22T23:30:17Z
dc.identifier.issn0016-6731
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/293055
dc.description.abstractMicrosatellite sequences have an enhanced susceptibility to mutation and can act as sentinels indicating elevated mutation rates and increased risk of cancer. The probability of mutant fixation within the intestinal epithelium is dictated by a combination of stem cell dynamics and mutation rate. Here we exploit this relationship to infer microsatellite mutation rates. First a sensitive, multiplexed and quantitative method for detecting somatic changes in microsatellite length was developed that allowed the parallel detection of mutant [CA]n sequences from hundreds of low-input tissue samples at up to 14 loci. The method was applied to colonic crypts in Mus musculus and enabled detection of mutant subclones down to 20% of the cellularity of the crypt (around 50 of 250 cells). By quantifying age-related increases in clone frequencies for multiple loci, microsatellite mutation rates in wild-type and Msh2- deficient epithelium were established. An average 388-fold increase in mutation per mitosis rate was observed in Msh2-deficient epithelium (2.4 x10-2) compared to wild- type epithelium (6.2 x10-5).
dc.publisherGenetics Society of America
dc.rightsAll rights reserved
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleQuantifying microsatellite mutation rates from intestinal stem cell dynamics in Msh2-deficient murine epitheliumen
dc.typeArticle
prism.endingPage665
prism.issueIdentifier3en
prism.publicationNameGeneticsen
prism.startingPage655
prism.volume212en
dc.identifier.doi10.17863/CAM.40204
dcterms.dateAccepted2019-05-14en
rioxxterms.versionofrecord10.1534/genetics.119.302268en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2019-05-14en
dc.contributor.orcidWinton, Douglas [0000-0001-6067-7927]
dc.identifier.eissn1943-2631
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (CB4230)
pubs.funder-project-idWELLCOME TRUST (103805/Z/14/Z)
cam.issuedOnline2019-07-01en
dc.identifier.urlhttps://www.genetics.org/content/212/3/655en
cam.orpheus.successWed Sep 02 09:54:18 BST 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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