Impact of DNA physical properties on local sequence bias of human mutation

In selectively neutral regions of the human genome, nucleotide substitutions do not occur at random with respect to the local DNA sequence neighborhood. However, apart from the hypermutability of methylated CpG dinucleotides, which can explain the overrepresentation of nucleotide transitions in this context, the sequence‐specific factors underlying point mutation bias remain largely to be determined, both in nature and in quantitative impact. One hypothesis suggests that the physical characteristics of a DNA context could have a modulating effect on its mutability, adjusting the impact of damage or the efficiency of repair. Here, we report a genome‐wide computational test of this hypothesis, in which we utilize a constrained set of human non‐CpG SNPs as the source of selectively neutral germline mutations. Interestingly, we observe that the quantitative context‐dependencies of some substitution types display significant associations to measures of local structural topography and helix stability in DNA. Most prominently, we find that the local sequence bias of transition mutations is significantly associated with the sequence‐dependent level of helix instability imposed by the potentially underlying DNA mismatches. The results of our work indicate the extent to which DNA physical properties could have shaped the recent point mutational spectrum in the human genome. Hum Mutat 31:1–10, 2010. © 2010 Wiley‐Liss, Inc.