Extended Data Fig. 7: Mechanisms underlying A3 clustered mutations generate many impactful changes, affecting disease genes.
From: DNA mismatch repair promotes APOBEC3-mediated diffuse hypermutation in human cancers
a, Coding regions in the human genome are enriched for CpG dinucleotides (NCG), but not with the A3-context TCW trinucleotides, compared to random expectation. b, Enrichment of mutations in exons versus introns (estimate of selection strength, x axis) and the enrichment in intergenic regions versus introns (estimate of redistribution of mutations towards regions containing genic DNA, y axis; flipped). The comparison of mutagenic agents against APOBEC was performed for selected tissues, matching the relevant tissue with the particular mutagen (tumor samples listed in Supplementary Table 7). Error bars are 95% C.I. from negative binomial regression; numbers in parenthesis are the tally of mutations. c, The differential functional impact of the tested mutagens across replication time (RT) bins. Left: total length of coding sequences (CDS) in the late and early RT bins, shaded by the RT sextiles that were merged to create the two bins (where 1 is the latest and 6 is the earliest RT). Middle: expected number of cancer gene CDS-affecting mutations in an average tumor sample (same sets of samples, genes and mutations as in Fig. 5a; y axis) for the late versus early RT bin (x axis), for various mutagens (colors); error bars are s.e.m. Right: fold-difference between the functional impact at the late versus early bin, for various mutagen types. d, e, The functional impact density (FID) of various mutational processes in a set of cell-essential genes (panel d) and neurodegenerative disease-associated genes (panel e). Slope shows the fraction of impactful genetic changes i.e. those affecting the CDS of at least one gene in the set. Points show the expected number of impactful changes resulting from a mutational process, on average, in a tumor genome affected by that mutational process. Error bars are s.e.m. ‘APOBEC-O4’ is A3 mutagenesis in omikli-rich tumors. ‘APOBEC-K2’ is A3 mutagenesis in kataegis-rich tumors.
