Methylation-mediated deamination of 5-methylcytosine appears to give rise to mutations causing human inherited disease in CpNpG trinucleotides, as well as in CpG dinucleotides.
Hum Genomics
; 4(6): 406-10, 2010 Aug.
Article
em En
| MEDLINE
| ID: mdl-20846930
ABSTRACT
The cytosine-guanine (CpG) dinucleotide has long been known to be a hotspot for pathological mutation in the human genome. This hypermutability is related to its role as the major site of cytosine methylation with the attendant risk of spontaneous deamination of 5-methylcytosine (5mC) to yield thymine. Cytosine methylation, however, also occurs in the context of CpNpG sites in the human genome, an unsurprising finding since the intrinsic symmetry of CpNpG renders it capable of supporting a semi-conservative model of replication of the methylation pattern. Recently, it has become clear that significant DNA methylation occurs in a CpHpG context (where H = A, C or T) in a variety of human somatic tissues. If we assume that CpHpG methylation also occurs in the germline, and that 5mC deamination can occur within a CpHpG context, then we might surmise that methylated CpHpG sites could also constitute mutation hotspots causing human genetic disease. To test this postulate, 54,625 missense and nonsense mutations from 2,113 genes causing inherited disease were retrieved from the Human Gene Mutation Database (http//www.hgmd.org). Some 18.2 per cent of these pathological lesions were found to be C â T and G â A transitions located in CpG dinucleotides (compatible with a model of methylation-mediated deamination of 5mC), an approximately ten-fold higher proportion than would have been expected by chance alone. The corresponding proportion for the CpHpG trinucleotide was 9.9 per cent, an approximately two-fold higher proportion than would have been expected by chance. We therefore estimate that â¼5 per cent of missense/nonsense mutations causing human inherited disease may be attributable to methylation-mediated deamination of 5mC within a CpHpG context.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fosfatos de Dinucleosídeos
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Repetições de Trinucleotídeos
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Metilação de DNA
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5-Metilcitosina
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Doenças Genéticas Inatas
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Mutação
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article