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Hydroxymethylated Cytosines Are Associated with Elevated C to G Transversion Rates

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, n...

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Autores principales: Supek, Fran, Lehner, Ben, Hajkova, Petra, Warnecke, Tobias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161303/
https://www.ncbi.nlm.nih.gov/pubmed/25211471
http://dx.doi.org/10.1371/journal.pgen.1004585
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author Supek, Fran
Lehner, Ben
Hajkova, Petra
Warnecke, Tobias
author_facet Supek, Fran
Lehner, Ben
Hajkova, Petra
Warnecke, Tobias
author_sort Supek, Fran
collection PubMed
description 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.
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spelling pubmed-41613032014-09-17 Hydroxymethylated Cytosines Are Associated with Elevated C to G Transversion Rates Supek, Fran Lehner, Ben Hajkova, Petra Warnecke, Tobias PLoS Genet Research Article 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. Public Library of Science 2014-09-11 /pmc/articles/PMC4161303/ /pubmed/25211471 http://dx.doi.org/10.1371/journal.pgen.1004585 Text en © 2014 Supek et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Supek, Fran
Lehner, Ben
Hajkova, Petra
Warnecke, Tobias
Hydroxymethylated Cytosines Are Associated with Elevated C to G Transversion Rates
title Hydroxymethylated Cytosines Are Associated with Elevated C to G Transversion Rates
title_full Hydroxymethylated Cytosines Are Associated with Elevated C to G Transversion Rates
title_fullStr Hydroxymethylated Cytosines Are Associated with Elevated C to G Transversion Rates
title_full_unstemmed Hydroxymethylated Cytosines Are Associated with Elevated C to G Transversion Rates
title_short Hydroxymethylated Cytosines Are Associated with Elevated C to G Transversion Rates
title_sort hydroxymethylated cytosines are associated with elevated c to g transversion rates
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161303/
https://www.ncbi.nlm.nih.gov/pubmed/25211471
http://dx.doi.org/10.1371/journal.pgen.1004585
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