Incompatibility and interchangeability in molecular evolution

This is a Preprint and has not been peer reviewed. The published version of this Preprint is available: This is version 1 of this Preprint.

Add a Comment

You must log in to post a comment.


There are no comments or no comments have been made public for this article.


Download Preprint


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.



Evolution, Life Sciences, Molecular Genetics


Cytonuclear, Epistasis, horizontal gene transfer, hybridization, Protein-Protein Interactions


Published: 2022-11-02 02:06


CC BY Attribution 4.0 International

Additional Metadata

Data and Code Availability Statement:
Not applicable