Dominance vs epistasis: the biophysical origins and plasticity of genetic interactions within and between alleles

Xie, Xuan; Sun, Xia; Wang, Yuheng; Lehner, Ben, 1978-; Li, Xianghua

doi:http://dx.doi.org/10.1038/s41467-023-41188-8

Dominance vs epistasis: the biophysical origins and plasticity of genetic interactions within and between alleles

License

Citation

Xie X, Sun X, Wang Y, Lehner B, Li X. Dominance vs epistasis: the biophysical origins and plasticity of genetic interactions within and between alleles. Nat Commun. 2023 Sep 9;14(1):5551. DOI: 10.1038/s41467-023-41188-8

Abstract

An important challenge in genetics, evolution and biotechnology is to understand and predict how mutations combine to alter phenotypes, including molecular activities, fitness and disease. In diploids, mutations in a gene can combine on the same chromosome or on different chromosomes as a "heteroallelic combination". However, a direct comparison of the extent, sign, and stability of the genetic interactions between variants within and between alleles is lacking. Here we use thermodynamic models of protein folding and ligand-binding to show that interactions between mutations within and between alleles are expected in even very simple biophysical systems. Protein folding alone generates within-allele interactions and a single molecular interaction is sufficient to cause between-allele interactions and dominance. These interactions change differently, quantitatively and qualitatively as a system becomes more complex. Altering the concentration of a ligand can, for example, switch alleles from dominant to recessive. Our results show that intra-molecular epistasis and dominance should be widely expected in even the simplest biological systems but also reinforce the view that they are plastic system properties and so a formidable challenge to predict. Accurate prediction of both intra-molecular epistasis and dominance will require either detailed mechanistic understanding and experimental parameterization or brute-force measurement and learning.