Fig. 4
Disruptive variants occur in important gene groups and at conserved genomic sites. a Fraction of disruptive variants that occur in non-constrained (n = 1349), disease-associated (n = 423), cancer-associated (n = 78), essential (n = 223), or LoF-intolerant genes (n = 270). b Fraction of interactions disrupted by variants that occur on interface residues or interface domains (n = 307) in comparison to interactions disrupted by variants that occur away from interaction interfaces (n = 41). c Distribution of Jensen–Shannon Divergence scores for amino acid residues at sites corresponding to disruptive and non-disruptive variants. Larger scores indicate more conserved sites. d Fraction of disruptive variants found in genomic regions where Fay and Wu’s H is significant measured across four different population groups and across overall population. e Fraction of mutations pairs that lead to the same disease for germline mutations that share two or more disrupted interactions (n = 42), share one or more disrupted interactions (n = 271), or do not share disrupted interactions (n = 599). f Schematic of interaction disruption profiles for SMAD4 disease-associated mutations E330K, G352R, and N13S. Corresponding disease names are labeled. g Co-crystal structure of SMAD4–SMAD3 interacting proteins (PDB ID: 1U7F). Disease-associated mutations are labeled. Structure covers SMAD4 residues 315-546 and therefore N13S mutation is not represented on this structure. Error bars in a, b, d, and e indicate +SE of proportion. P values in a, b, d, and e by one-tailed Z-test. P value in c by one-tailed U-test. See also Supplementary Fig. 4
