Evolution of Restriction-Modification Systems Consisting of One Restriction Endonuclease and Two DNA Methyltransferases.

Some restriction-modification systems contain two DNA methyltransferases. In the present work, we have classified such systems according to the families of catalytic domains present in the restriction endonucleases and both DNA methyltransferases. Evolution of the restriction-modification systems containing an endonuclease with a NOV_C family domain and two DNA methyltransferases, both with DNA_methylase family domains, was investigated in detail. Phylogenetic tree of DNA methyltransferases from the systems of this class consists of two clades of the same size. Two DNA methyltransferases of each restriction-modification system of this class belong to the different clades. This indicates independent evolution of the two methyltransferases. We detected multiple cross-species horizontal transfers of the systems as a whole, as well as the cases of gene transfer between the systems.

Comparative analysis of context-dependent mutagenesis using human and mouse models.

Substitution rates strongly depend on their nucleotide context. One of the most studied examples is the excess of C > T mutations in the CG context in various groups of organisms, including vertebrates. Studies on the molecular mechanisms underlying this mutation regularity have provided insights into evolution, mutagenesis, and cancer development. Recently several other hypermutable motifs were identified in the human genome. There is an increased frequency of T > C mutations in the second position of the words ATTG and ATAG and an increased frequency of A > C mutations in the first position of the word ACAA. For a better understanding of evolution, it is of interest whether these mutation regularities are human specific or present in other vertebrates, as their presence might affect the validity of currently used substitution models and molecular clocks. A comprehensive analysis of mutagenesis in 4 bp mutation contexts requires a vast amount of mutation data. Such data may be derived from the comparisons of individual genomes or from single nucleotide polymorphism (SNP) databases. Using this approach, we performed a systematical comparison of mutation regularities within 2-4 bp contexts in Mus musculus and Homo sapiens and uncovered that even closely related organisms may have notable differences in context-dependent mutation regularities.

Comparative analysis of context-dependent mutagenesis in humans and fruit flies.

In general, mutation frequencies are context-dependent: specific adjacent nucleotides may influence the probability to observe a specific type of mutation in a genome. Recently, several hypermutable motifs were identified in the human genome. Namely, there is an increased frequency of T>C mutations in the second position of the words ATTG and ATAG and an increased frequency of A>C mutations in the first position of the word ACAA. Previous studies have also shown that there is a remarkable difference between the mutagenesis of humans and drosophila. While C>T mutations are overrepresented in the CG context in humans (and other vertebrates), this mutation regularity is not observed in Drosophila melanogaster. Such differences in the observed regularities of mutagenesis between representatives of different taxa might reflect differences in the mechanisms involved in mutagenesis. We performed a systematical comparison of mutation regularities within 2-4 bp contexts in Homo sapiens and Drosophila melanogaster and found that the aforementioned contexts are not hypermutable in fruit flies. It seems that most mutation contexts affect mutation rates in a similar manner in H. sapiens and D. melanogaster; however, several important exceptions are noted and discussed.