Hydroxymethylated cytosines are associated with elevated C to G transversion rates

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• dc.contributor.author Supek, Fran
• dc.contributor.author Lehner, Ben, 1978-
• dc.contributor.author Hajkova, Petra
• dc.contributor.author Warnecke, Tobias
• dc.date.accessioned 2024-10-21T06:20:41Z
• dc.date.available 2024-10-21T06:20:41Z
• dc.date.issued 2014
• dc.description.abstract It has long been known that methylated cytosines deaminate at higher rates than unmodified cytosines and constitute mutational hotspots in mammalian genomes. The repertoire of naturally occurring cytosine modifications, however, extends beyond 5-methylcytosine to include its oxidation derivatives, notably 5-hydroxymethylcytosine. The effects of these modifications on sequence evolution are unknown. Here, we combine base-resolution maps of methyl- and hydroxymethylcytosine in human and mouse with population genomic, divergence and somatic mutation data to show that hydroxymethylated and methylated cytosines show distinct patterns of variation and evolution. Surprisingly, hydroxymethylated sites are consistently associated with elevated C to G transversion rates at the level of segregating polymorphisms, fixed substitutions, and somatic mutations in tumors. Controlling for multiple potential confounders, we find derived C to G SNPs to be 1.43-fold (1.22-fold) more common at hydroxymethylated sites compared to methylated sites in human (mouse). Increased C to G rates are evident across diverse functional and sequence contexts and, in cancer genomes, correlate with the expression of Tet enzymes and specific components of the mismatch repair pathway (MSH2, MSH6, and MBD4). Based on these and other observations we suggest that hydroxymethylation is associated with a distinct mutational burden and that the mismatch repair pathway is implicated in causing elevated transversion rates at hydroxymethylated cytosines.
• dc.description.sponsorship FS recibió apoyo en parte de las Acciones Marie Curie y de la subvención ICT-2013-612944 (MAESTRA). BL recibió financiación de una subvención inicial del Consejo Europeo de Investigación (ERC), ERASysBio+ ERANET, MICINN BFU2008-00365 y BFU2011-26206, AGAUR, el Programa de Jóvenes Investigadores de EMBO, el proyecto Marco 7 de la UE 277899 4DCellFate y del Programa de Biología de Sistemas EMBL-CRG. PH y TW recibieron apoyo financiero básico del Consejo de Investigación Médica (MRC) del Reino Unido. Los financiadores no tuvieron ningún papel en el diseño del estudio, la recopilación y el análisis de datos, la decisión de publicar o la preparación del manuscrito.
• dc.format.mimetype application/pdf
• dc.identifier.citation Supek F, Lehner B, Hajkova P, Warnecke T. Hydroxymethylated cytosines are associated with elevated C to G transversion rates. PLoS Genet. 2014 Sep 11;10(9):e1004585. DOI: 10.1371/journal.pgen.1004585
• dc.identifier.doi http://dx.doi.org/10.1371/journal.pgen.1004585
• dc.identifier.issn 1553-7404
• dc.identifier.uri http://hdl.handle.net/10230/68245
• dc.language.iso eng
• dc.publisher Public Library of Science (PLoS)
• dc.relation.ispartof PLoS Genetics. 2014 Sep 11;10(9):e1004585
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/277899
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2008-00365
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2011-26206
• dc.rights © 2014 Supek et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other Citocines
• dc.subject.other Càncer
• dc.subject.other Genoma humà
• dc.title Hydroxymethylated cytosines are associated with elevated C to G transversion rates
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion