Distribution of spontaneous CpG-associated G:C → A:T mutations in the lacZ gene of muta™ mice: Effects of CpG methylation, the sequence context of CpG sites, and severity of mutations on the activity of the lacZ gene product

Hironobu Ikehata, Masaki Takatsu, Yusuke Saito, Tetsuya Ono

研究成果: Article査読

23 被引用数 (Scopus)

抄録

In our previous study using transgenic Muta™ mice, G:C → A:T transitions at 5′-CG-3′ (CpG) sites, which are the most common mammalian spontaneous mutation, were detected in 197 of 330 spontaneous lacZ mutants. These transitions were recovered at only 27 of the 357 mutable G:C pairs within CpG sites where the transition could produce a missense or termination codon in the lacZ gene. To address the underlying mechanism for the uneven distribution of mutated CpG sites, the CpG methylation status of the Muta lacZ gene was analyzed by a bisulfite method. All the CpG sites examined in the coding region were evenly methylated at a high level, and no site-specific methylation was evident. Analysis of the sequence context around the mutated CpG sites, however, revealed that 21 of these 27 sites contained a CpG flanked by a pyrimidine on the 5′ side, and that 187 of the 197 mutants resulted from substitutions at these sites. Moreover, we found five hotspots among those sites, the location of which was intimately related to the enzymatic activity of the gene product: one site produced a nonsense codon; three sites, one of which corresponded to the nucleophile at the active site, resided in the substrate-binding pocket; and the other site was located in a region conserved in the β-galactosidase family. These results strongly suggest that recovery of lacZ mutations at each site largely depend on the adjacent sequence context and the extent to which the mutation damages the enzymatic activity of the gene product.

本文言語English
ページ(範囲)301-311
ページ数11
ジャーナルEnvironmental and Molecular Mutagenesis
36
4
DOI
出版ステータスPublished - 2000

ASJC Scopus subject areas

  • 疫学
  • 遺伝学(臨床)
  • 健康、毒物学および変異誘発

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