From Context-Dependence of Mutations to Molecular Mechanisms of Mutagenesis

Abstract

Mutation frequencies vary significantly along nucleotide sequences such that mutations often concentrate at certain positions called hotspots. Mutation hotspots in DNA reflect intrinsic properties of the mutation process, such as sequence specificity, that manifests itself at the level of interaction between mutagens, DNA, and the action of the repair and replication machineries. The nucleotide sequence context of mutational hotspots is a fingerprint of interactions between DNA and repair/replication/modification enzymes, and the analysis of hotspot context provides evidence of such interactions. The hotspots might also reflect structural and functional features of the respective DNA sequences and provide information about natural selection. We discuss analysis of 8-oxoguanineinduced mutations in pro-and eukaryotic genes, polymorphic positions in the human mitochondrial DNA and mutations in the HIV-1 retrovirus. Comparative analysis of 8oxoguanine-induced mutations and spontaneous mutation spectra suggested that a substantial fraction of spontaneous A•T→C•T mutations is caused by 8-oxoGTP in nucleotide pools. In the case of human mitochondrial DNA, significant differences between molecular mechanisms of mutations in hypervariable segments and coding part of DNA were detected. Analysis of mutations in the HIV-1 retrovirus suggested a complex interplay between molecular mechanisms of mutagenesis and natural selection.

A Sequence Motif Associated with Intrinsic Mutation Hot-Spots in Human Cancers

“…For example, the APC gene is composed of 15 exons, nevertheless, about two thirds of the total mutations are clustered in the 5' region of exon 15 [20]. We hypothesized the DNA motif(s) can result in local high rate of mutation and this motif can be a marker for selection of most probable regions for mutation screening [21]. In support of this hypothesis, we used computational analysis method to examine surrounding regions of mutation hotspots in 20 human cancer genes.…”

“…Some previous researches characterized the role of nucleotide sequences and hotspot of mutations [19,21,31]. One well-known example of intrinsic mutation hotspots is CpG di-nucleotides [32].…”

“…The CATCGCTTRRT motif is signal of recombination in Bacillus subtilis mal gene [36]. Although these studies have characterized the role of DNA motifs in replication, recombination, and mutagenesis at the sequence level, none have investigated the relation between sequence motifs and hotspot of mutations in human cancer genes [21].…”

CpG methylation accounts for a recurrent mutation (c.1222C>T) in the humanPAH gene

“…This suggests that not all mCpG sites are equally mutable (Ikehata et al, 2000;Rogozin et al, 2005). Context of nucleotide sequence may distinguish which CpG sites are hypermutable and which are not.…”

An Analytical Model of Gene Evolution with 9 Mutation Parameters: An Application to the Amino Acids Coded by the Common Circular Code

“…Several other processes may influence codon usage (Jukes and Bhushan, 1986;Campbell et al, 1999;Llopart and Aguade, 2000;Smith and Eyre-Walker, 2001;Konu and Li, 2002;Krakauer and Jansen, 2002;Rogozin et al, 2005) (see also the review (Ermolaeva, 2001)). In particular, codon choice may depend on its context, i.e.…”