Fig. 3: Ligand binding generates between-allele interactions and dominance.

a, b Three-state protein system with unfolded, folded, and ligand-bound states (Model 2), with two mutations of the same gene within- (a) or between alleles (b). Phenotypes are determined by the ligand-bound protein concentration marked with grey-shaded boxes. c, d Heatmaps showing how two mutations both affect the same biophysical parameters combine: protein-folding (the second column) or ligand-binding (the third column) when they are ordered by the phenotype. e, g Relationships between the observed and expected phenotypes with additive expectation when combining two detrimental mutants within (e) or between alleles (g). f, h–j Comparisons of interaction scores between different types of double mutant combinations: protein-folding vs. ligand-binding mutants within- (f) or between-alleles (h), between- vs. within-allele interactions of the protein-folding (i) or ligand-binding (j) mutants. The darker the colour, the higher the density of the simulated data points at the given between- vs. within-allele interactions. k Compound heterozygotes derived from two homozygous mutations within a three-state protein system (Model 2). l Heatmaps showing how two mutations both affect the same biophysical parameters combine: protein-folding (the second column) or ligand-binding (the third column) when they are ordered by the homozygous phenotype. m Relationships between the observed and expected phenotypes when combining two detrimental homozygous mutants. n Comparison of dominance between different types of double mutant combinations: protein-folding vs. ligand-binding mutants. o, p Comparisons of expected phenotypes (o) and dominance vs. between-allele interaction scores (p) for the same compound heterozygote mutants. The darker the colour, the higher the density of the simulated data points.