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. 1. Introduction The average rates of point mutations in multicellular eukaryotic genomes are usually between 10？7 and 10？10 mutations per nucleotide per generation [1, 2]. However, the rates of point mutations may be dramatically altered by their genomic context. In some cases, this context-dependent change in mutation frequency can be attributed to known molecular mechanisms involved in mutagenesis. For example, the increased frequency of C>T mutations in the word CG in humans (and other vertebrates) is attributed to the methylation of cytosines by context-specific DNA methyltransferases [3]. This mutation regularity is absent in D. melanogaster [4], in which cytosine methylation occurs, but appears to be restricted to early embryonic development and is not specific to cytosines followed by guanines [5]. Many other examples of context-dependent mutagenesis have been reported [4, 6–9]. Recently, an increased rate of T>C mutations in the second position of the words ATTG and ATAG and an increased rate of A>C mutations in the first position of the ACAA word were reported in the human genome [10]. This was achieved by calculating the values called “minimal contrast” and “mutation bias” for 2–4？bp mutation contexts to evaluate if the addition of specific nucleotides to the 5′ or 3′ end of 1–3？bp words