TY - JOUR

T1 - Mutation rate heterogeneity at the sub-gene scale due to local DNA hypomethylation

AU - Mas-Ponte, David

AU - Supek, Fran

PY - 2024

Y1 - 2024

N2 - 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 dinucleotides. The width and shape of this mutational coldspot at 5′ gene ends is variable across genes, and corresponds to variable interval of lowered DNA methylation depending on gene activity level and regulation. Such hypomutated loci, at 5′ gene ends or elsewhere, correspond to DNA hypomethylation that can associate with various landmarks, including intragenic enhancers, Polycomb-marked regions, or chromatin loop anchor points. Tissue-specific DNA hypomethylation begets tissue-specific local hypomutation. Of note, direction of mutation risk is inverted for AID/APOBEC3 cytosine deaminase activity, whose signatures are enriched in hypomethylated regions.

AB - 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 dinucleotides. The width and shape of this mutational coldspot at 5′ gene ends is variable across genes, and corresponds to variable interval of lowered DNA methylation depending on gene activity level and regulation. Such hypomutated loci, at 5′ gene ends or elsewhere, correspond to DNA hypomethylation that can associate with various landmarks, including intragenic enhancers, Polycomb-marked regions, or chromatin loop anchor points. Tissue-specific DNA hypomethylation begets tissue-specific local hypomutation. Of note, direction of mutation risk is inverted for AID/APOBEC3 cytosine deaminase activity, whose signatures are enriched in hypomethylated regions.

U2 - 10.1093/nar/gkae252

DO - 10.1093/nar/gkae252

M3 - Journal article

C2 - 38587182

VL - 52

SP - 4393

EP - 4408

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 8

ER -