Figure 4.

Epistatic interactionsbetween mutations.A, epistatic interactions between two mutations (SNP1 [blue dot] and SNP2 [red dot], both on one allele [cis] or on two different alleles [trans]) decrease the magnitude of the mutational effect (antagonistic effect 1), increase the magnitude of the mutational effect (synergistic effect 2), or completely change the sign of the effect (3, positive, or negative sign-changing epistasis). SNP1 and SNP2 can both be missense mutations or sSNPs or a combination thereof. B, example of positive sign epistasis described in CFTR. Both the c.2562T>G sSNP (red) or the disease-causing missense SNP (blue) alter the translation speed at the affected codons and decrease CFTR channel function. There is no epistasis when both mutations are on different alleles (trans). In cis, both mutations synergize (continuous line with color coded segments impacted by the corresponding mutation) into a positive sign epistasis and alter the translation profile (dotted line) to more closely resemble that of the WT CFTR (blue continuous line, upper profile). CFTR, cystic fibrosis transmembrane conductance regulator; sSNP, synonymous SNP.