Fig. 4: Missense mutations in FBXW7.
From: Mutations observed in somatic evolution reveal underlying gene mechanisms
a Distribution of calculated ∆∆G values of missense mutations in FBXW7 in normal skin. Distribution expected under the neutral null hypothesis, light red, and the distribution observed, dark red. b Sliding window of missense mutation frequency across FBXW7 in normal skin. Observed distribution shown with a bold black line, the expected distribution based on the mutational spectrum shown with a thin grey line. Dimerization domain, blue bar; F-box domain, green bar; WD40 domain, orange bar. c Distribution of distances of missense mutations in skin from the FBXW7 substrate (in this instance a 12-residue section of Cyclin E in PDB 2OVQ30). Distribution expected under the neutral null hypothesis, light blue, and the distribution observed, dark blue. d Structure of the FBXW7 WD40 domain (PDB 2OVQ30) bound to Cyclin E (red). Commonly mutated residues are highlighted. Blue and green residues contain at least four missense mutations in the normal skin dataset. Green residues also contain at least two missense mutations in normal oesophagus dataset. The three main hotspot residues in cancer (R465, R479 and R505) shown in orange. e Distribution of calculated ∆∆G values of missense mutations in skin, where all mutations within 8 Å of the FBXW7 substrate have been excluded from both the null model and the observed data. Distribution expected under the neutral null hypothesis, light red, and the distribution observed, dark red. P values in a, c, e calculated using the Monte Carlo test (Supplementary Note 10). ****P ≤ 0.0001, ns P > 0.05.
