biostudies-literatureMas-Ponte DEuropean Commission Horizon2020European Research CouncilCatalan governmentSpanish governmentCaixaResearchSevero Ochoa FPI fellowship4393-4408https://www.ebi.ac.uk/biostudies/studies/S-EPMC11077091biostudies-literatureUnknown52(8)Local mutation rates in human are highly heterogeneous, with known variability at the scale of megabase-sized chromosomal domains, and, on the other extreme, at the scale of oligonucleotides. The intermediate, kilobase-scale heterogeneity in mutation risk is less well characterized. Here, by analyzing thousands of somatic genomes, we studied mutation risk gradients along gene bodies, representing a genomic scale spanning roughly 1-10 kb, hypothesizing that different mutational mechanisms are differently distributed across gene segments. The main heterogeneity concerns several kilobases at the transcription start site and further downstream into 5' ends of gene bodies; these are commonly hypomutated with several mutational signatures, most prominently the ubiquitous C > T changes at CpG dinNucleic acids researchMutation rate heterogeneity at the sub-gene scale due to local DNA hypomethylation.PMC11077091SGR 00616757700965193BES-2017–079820PID2020-118795GB-I00HR22-00402Mas-Ponte DSupek FfalseMutation rate heterogeneity at the sub-gene scale due to local DNA hypomethylation.Local mutation rates in human are highly heterogeneous, with known variability at the scale of megabase-sized chromosomal domains, and, on the other extreme, at the scale of oligonucleotides. The intermediate, kilobase-scale heterogeneity in mutation risk is less well characterized. Here, by analyzing thousands of somatic genomes, we studied mutation risk gradients along gene bodies, representing a genomic scale spanning roughly 1-10 kb, hypothesizing that different mutational mechanisms are differently distributed across gene segments. The main heterogeneity concerns several kilobases at the transcription start site and further downstream into 5' ends of gene bodies; these are commonly hypomutated with several mutational signatures, most prominently the ubiquitous C > T changes at CpG din2024-01-01T00:00:00Z2024 May2026-04-15T03:21:54.791Z2026-04-15T03:14:49.187ZS-EPMC110770913858718210.1093/nar/gkae252