The relationship between protein function and fitness alters the complementation of mutations affecting protein function.

<p>Regions where mutations have recessive effects (0< <i>h</i><0.5) are shown in gray and additive effects (<i>h</i> = 0.5) are shown as a dashed line. The Physiological Theory predicts that (A) the hyperbolic relationship between protein function and fitness results in additive mutation effects only when the wildtype fitness is near zero (B). At moderate (C) and high (D) wildtype fitnesses, deleterious and beneficial mutations are predicted to be recessive and dominant, respectively. The sigmoidal fitness function predicted for proteins that display cooperative binding (E) causes a stronger dependence of dominance coefficients on wildtype fitness. For instance, the sigmoidal relationship yields recessive beneficial mutations when wildtype fitness is low (F), but dominant beneficial mutations when wildtype fitness is moderate (G) and high (H).