期刊
PLOS GENETICS
卷 10, 期 9, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1004585
关键词
-
资金
- Marie Curie Actions
- MAESTRA [ICT-2013-612944]
- European Research Council (ERC)
- ERASysBio+ ERANET
- MICINN [BFU2008-00365, BFU2011- 26206]
- AGAUR
- EMBO Young Investigator Program
- EU [277899 4DCellFate]
- EMBL-CRG Systems Biology Program
- UK Medical Research Council (MRC)
- MRC [MC_U120092689, MC_UP_1102/7] Funding Source: UKRI
- Medical Research Council [MC_UP_1102/7, MC_U120092689] Funding Source: researchfish
- ICREA Funding Source: Custom
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据