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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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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. |
format | Online Article Text |
id | pubmed-4161303 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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