Local Determinants of the Mutational Landscape of the Human Genome

The latest issue of Cell has a nice review (Open Access, I believe) summarizing our knowledge on the biochemical processes that generate mutations:

https://doi.org/10.1016/j.cell.2019.02.051

Abstract

Large-scale chromatin features, such as replication time and accessibility influence the rate of somatic and germline mutations at the megabase scale. This article reviews how local chromatin structures –e.g., DNA wrapped around nucleosomes, transcription factors bound to DNA– affect the mutation rate at a local scale. It dissects how the interaction of some mutagenic agents and/or DNA repair systems with these local structures influence the generation of mutations. We discuss how this local mutation rate variability affects our understanding of the evolution of the genomic sequence, and the study of the evolution of organisms and tumors.

Here’s a nice summary figure:


Figure 1. Mutations Result from the Interplay between DNA Lesions Generated by Damaging Agents and DNA Repair Machineries

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Some of the results summarized in this review are very much in line with @T_aquaticus’s excellent discussion of the fact that Mutations Are Consistent With Biochemistry. For example, C>T mutations occur less commonly within nucleosome-bound DNA. Likewise, C>T substitutions between humans and chimps are more common within linker regions than within nucleosome cores:

The availability of techniques to map the positions of nucleosomes in recent years (Brogaard et al., 2012, Langley et al., 2014, Mieczkowski et al., 2016, Voong et al., 2016, Zhang et al., 2015) have fueled studies dedicated to answer the question of whether mutations distribute differentially between nucleosomes and linkers. Tolstorukov and collaborators observed in 2011 that germline SNVs appeared more frequent at bulk nucleosomes, but not at those bearing certain histone marks, than at linkers (Tolstorukov et al., 2011). On the other hand, they reported that germline indels appeared less frequently at any type of nucleosomes than at linkers. In the interpretation of these results, the authors favored a model in which purifying selection—rather than the differential rate of mutations generation—plays the predominant role in the depletion for germline indels and SNVs at nucleosomes bearing certain histone marks. A study of the rate of de novo substitutions and indels in yeast showed similar results (Lujan et al., 2014), while another, comparing the rates of different substitution types, reported that C>T transitions occur less frequently at nucleosomal DNA (Chen et al., 2012). Coherently, the analysis of the human-chimpanzee divergence found that while divergent sites in general tend to occur more frequently within nucleosomes, the frequency of C>T substitutions is reduced with respect to linkers (Prendergast and Semple, 2011). C>T substitutions largely result from the spontaneous deamination of cytosines and 5mCs (see above). This deamination reaction is more likely to occur in transient single-stranded DNA regions, due to “breathing”—i.e., local opening of the DNA double helix—which is hindered by the structural constraints imposed on the DNA wrapped around nucleosomes (Makova and Hardison, 2015). Thus, in this case, the differential rate of damage generation at nucleosomes versus linkers—i.e., the first step of the model mutational process outlined above—is likely to contribute to the heterogeneity of the mutation rate.

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I was just about to quote that very section. Thanks for bringing attention to this paper.

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