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

• Published in: Nature communications 2023-09, Vol.14 (1), p.5551-5551, Article 5551
• Main Authors: Xie, Xuan, Sun, Xia, Wang, Yuheng, Lehner, Ben, Li, Xianghua
• Format: Article
• Language: English
• Subjects: 49/31; 631/181/2474; 631/208/1516; 631/208/2490; Alleles; Biotechnology; Chromosomes; Diploids; Dominance; Epistasis; Folding; Force measurement; Genetics; Humanities and Social Sciences; Ligands; Molecular interactions; multidisciplinary; Mutation; Parameterization; Phenotypes; Plasticity; Protein folding; Proteins; Science; Science (multidisciplinary); Thermodynamic models
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41188-8

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. The authors examine how mutations combine to alter phenotypes in biophysical models of proteins and conclude that non-additive interactions (epistasis and dominance) are frequent, context-dependent and so challenging to predict in even the simplest of biological systems.