Cytosine Methylation Affects the Mutability of Neighboring Nucleotides in Germline and Soma.
Genetics
; 214(4): 809-823, 2020 04.
Article
em En
| MEDLINE
| ID: mdl-32079595
ABSTRACT
Methylated cytosines deaminate at higher rates than unmethylated cytosines, and the lesions they produce are repaired less efficiently. As a result, methylated cytosines are mutational hotspots. Here, combining rare polymorphism and base-resolution methylation data in humans, Arabidopsis thaliana, and rice (Oryza sativa), we present evidence that methylation state affects mutation dynamics not only at the focal cytosine but also at neighboring nucleotides. In humans, contrary to prior suggestions, we find that nucleotides in the close vicinity (±3 bp) of methylated cytosines mutate less frequently. Reduced mutability around methylated CpGs is also observed in cancer genomes, considering single nucleotide variants alongside tissue-of-origin-matched methylation data. In contrast, methylation is associated with increased neighborhood mutation risk in A. thaliana and rice. The difference in neighborhood mutation risk is less pronounced further away from the focal CpG and modulated by regional GC content. Our results are consistent with a model where altered risk at neighboring bases is linked to lesion formation at the focal CpG and subsequent long-patch repair. Our findings indicate that cytosine methylation has a broader mutational footprint than is commonly assumed.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Genes de Plantas
/
Ilhas de CpG
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Metilação de DNA
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Taxa de Mutação
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Genetics
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Reino Unido