Fig. 5: Natural saturation mutagenesis.
From: Sex and smoking bias in the selection of somatic mutations in human bladder
a, Percentage of amino acid residues in each gene with zero, one, two or three or more mutations across the 79 samples. b, Theoretical and observed kinetic of natural saturation mutagenesis for TP53, EP300 and FGFR3 as cumulative depth of sequencing increases. Grey line, theoretical kinetic of saturation mutagenesis (assuming no selection). Red circle, saturation achieved across the cohort. Red dashed line, observed kinetic (obtained by downsampling). c, Natural saturation mutagenesis of TP53 in normal bladder urothelium. From top to bottom, distribution of truncating, missense and synonymous mutations along the coding sequence of the gene; site selection computed for each amino acid residue of TP53 protein product; solvent accessibility along the protein sequence; TP53 protein product domains; duplex sequencing depth per amino acid residue. Left top, TP53 protein product three-dimensional structure with significant site selection of residues highlighted in blue. d, Experimental functional impact51 of TP53 mutations not observed, observed, or observed with significant site selection across the 79 samples. Only mutations with experimental functional impact reported in ref. 51 are included. e, dN/dS truncating and dN/dS missense values for each domain of TP53 protein product. The vertical lines represent the 95% confidence intervals of the dN/dS estimate. Solid border represents significant dN/dS values (P value < 0.05) according to Omega (Supplementary Note 6); N = 79 samples. f, Natural saturation mutagenesis of the TERT promoter. From top to bottom, distribution of mutations; site selection computed for observed mutations; experimental functional impact values of mutations in the TERT promoter according to ref. 55; distribution of mutations observed in the TERT promoter across 8,136 tumours (Supplementary Note 6). g, Experimental functional impact55 of mutations not observed, observed or observed in the TERT promoter with significant site selection across the 79 samples. h, Relationship between site selection and experimental functional impact value55 of all mutations observed in the TERT promoter.
