Differential DNA mismatch repair underlies mutation rate variation across the human genome
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- dc.contributor.author Supek, Franca
- dc.contributor.author Lehner, Ben, 1978-ca
- dc.date.accessioned 2016-03-14T17:13:35Z
- dc.date.available 2016-03-14T17:13:35Z
- dc.date.issued 2015
- dc.description.abstract Cancer genome sequencing has revealed considerable variation in somatic mutation rates across the human genome, with mutation rates elevated in heterochromatic late replicating regions and reduced in early replicating euchromatin. Multiple mechanisms have been suggested to underlie this, but the actual cause is unknown. Here we identify variable DNA mismatch repair (MMR) as the basis of this variation. Analysing ∼17 million single-nucleotide variants from the genomes of 652 tumours, we show that regional autosomal mutation rates at megabase resolution are largely stable across cancer types, with differences related to changes in replication timing and gene expression. However, mutations arising after the inactivation of MMR are no longer enriched in late replicating heterochromatin relative to early replicating euchromatin. Thus, differential DNA repair and not differential mutation supply is the primary cause of the large-scale regional mutation rate variation across the human genome.ca
- dc.description.sponsorship This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2011-26206 and ‘Centro de Excelencia Severo Ochoa 2013-2017’ SEV-2012-0208), a European Research Council Consolidator grant IR-DC (616434), Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR),the EMBOYoung Investigator Program, the EMBL-CRG Systems Biology Program, FP7 project 4DCellFate (277899),FP7 project MAESTRA (ICT-2013-612944)and by Marie Curie Actionss
- dc.format.mimetype application/pdfca
- dc.identifier.citation Supek F, Lehner B. Differential DNA mismatch repair underlies mutation rate variation across the human genome. Nature. 2015; 521(7550): 81-84. DOI 10.1038/nature14173ca
- dc.identifier.doi http://dx.doi.org/10.1038/nature14173
- dc.identifier.issn 0028-0836
- dc.identifier.uri http://hdl.handle.net/10230/25990
- dc.language.iso engca
- dc.publisher Nature Publishing Groupca
- dc.relation.ispartof Nature. 2015; 521(7550): 81-84
- dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/277899
- dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2011-26206
- dc.rights © Nature Publishing Group. http://www.nature.com/nature/journal/v521/n7550/full/nature14173.htmlca
- dc.rights.accessRights info:eu-repo/semantics/openAccessca
- dc.subject.other Genòmicaca
- dc.subject.other ADNca
- dc.title Differential DNA mismatch repair underlies mutation rate variation across the human genomeca
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/acceptedVersionca