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

Abstract

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.

Figure 1

Mutation bias and minimal contrasts of mutation contexts in D. melanogaster. Each dot represents a mutation context. Triangles represent the {A>C ∣3, CCA} (as well as complementary contexts) and contexts that had this context as a subcontext. Most dots are in pairs because complementary contexts have similar mutation bias and minimal contrast values.

Figure 2

Mutation bias and minimal contrast for D. melanogaster and H. sapiens. Each dot represents a mutation context (blue in D. melanogaster, red in H. sapiens). Dots are overlapping and are usually in pairs because complementary contexts have similar mutation bias and minimal contrast values.

Figure 3

The difference between H. sapiens and D. melanogaster mutation bias ((a) and (b)) and minimal contrast ((c) and (d)) for 2–4 bp mutation contexts. Each dot represents a mutation context. The X axis represents the contexts minimal contrast values, and the Y axis represents the contexts mutation bias. The minimal contrast and mutation bias values are given for H. sapiens ((a) and (c)) and for D. melanogaster ((b) and (d)), and the color scheme indicates the difference between minimal contrasts. Thus, red dots on (a) and (c) represent contexts that are hypermutable in humans comparing to drosophila, while green dots represent contexts that are hypermutable in D. melanogaster comparing to H. sapiens. This scheme is reversed for (b) and (d).