Daniel B Sloan, Jessica M Warren, Alissa M Williams, Shady A Kuster, Evan S Forsythe

There is remarkable variation in the rate at which genetic incompatibilities in molecular interactions accumulate. In some cases, minor changes – even single nucleotide substitutions – create major epistatic incompatibilities when hybridization forces new variants to function in a novel genetic background from an isolated population. In other cases, genes or even entire functional pathways can be horizontally transferred between anciently divergent evolutionary lineages that span the tree of life with little evidence of incompatibilities. In this review, we explore whether there are general principles that can explain why certain genes are prone to epistatic incompatibilities while others maintain interchangeability. We summarize evidence pointing to four genetic features that may contribute to greater resistance to functional replacement: 1) function in multisubunit enzyme complexes and protein-protein interactions, 2) sensitivity to changes in gene dosage, 3) rapid rate of sequence evolution, and 4) overall importance to cell viability, which creates sensitivity to small perturbations in molecular function. We discuss the relative levels of support for these different hypotheses and lay out future directions that may help explain the striking contrasts in patterns of incompatibility and interchangeability throughout the history of molecular evolution.