Compensatory evolution of interacting gene products through multifunctional intermediates.
When two mutations are singly deleterious but neutral or beneficial together, compensatory evolution can occur. The accumulation of derived, compensated genotypes contributes to the evolution of genetic incompatibilities between diverging populations or species. Previous two locus/two allele models have shown that compensatory evolution is appreciable only with tight linkage, the possibility of nearly simultaneous mutations, and/or a way to overcome negative selection against the singly mutated genotype. These conditions are often not met. Even when they are met, compensatory evolution is still predicted to be extremely slow, and in many scenarios selective advantage of the compensated genotype does little to accelerate it. Despite these obstacles, empirical studies suggest that it occurs readily. We describe here a set of related two locus/three allele models that invoke plausible neutral intermediates capable of productive interaction with both ancestral and compensated products of the interacting locus. These models are explored with analytical and computer simulation methods. The effect of these stepping-stone alleles on the evolution of ancestor-descendant incompatibilities is often profound, making the difference between evolution and stasis in several situations, including in small populations, when codominance or haploidy prevents shielding of mismatched genotypes, and in the absence of positive selection on the derived genotype. However, in large populations these intermediates can either speed or slow the evolution of incompatible genotypes relative to the two-allele case, depending on the specific fitness model. These results suggest that population size, the source of adaptive benefit, and the structural details of heteromeric gene product complexes interact to influence the path by which intergenic incompatibility evolves.