Mutation rate heterogeneity at the sub-gene scale due to local DNA hypomethylation

Local mutation rates are highly heterogeneous across the human genome. This variability was better studied at the scale of megabase-sized chromosomal domains on the one extreme, and at the scale of oligonucleotides at the other extreme. The intermediate, kilobase-scale heterogeneity in mutation risk was less studied. Here, by analyzing thousands of somatic genomes, we considered the hypothesis there are mutation risk gradients along gene bodies, representing a genomic scale spanning roughly 1 kb – 10 kb, and that different mutational mechanisms are differently distributed across gene segments. The main intragenic heterogeneity concerns several kilobases at the transcription start site and further into 5’ ends of gene bodies, which are commonly hypomutated with respect to several mutational signatures, most prominently the ubiquitous mutational signature of C>T changes at CpG dinucleotides. Width and shape of this mutational coldspot at 5’ gene ends is variable across genes, and corresponds to variable interval of lowered DNA methylation across genes. These hypomutated genic intervals correspond to hypomethylation that can originate from various causes, including intragenic enhancers, Polycomb-marked regions, or chromatin loop anchor points. Tissue-specific DNA hypomethylation begets tissue-specific local hypomutation. However, direction of mutation rate effect is inverted for some mutational processes, where signatures of AID/APOBEC3 cytosine deaminase activity are actually increased in hypomethylated regions. Overall, local DNA methylation determines mutation rate heterogeneity at the sub-gene level, and can generate either mutational coldspots or hotspots, depending on the mutagen exposure history of a cell. ### Competing Interest Statement The authors have declared no competing interest.