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

Xuan Xie, Xia Sun, Yuheng Wang, Ben Lehner () and Xianghua Li ()
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Xuan Xie: Zhejiang University - University of Edinburgh Institute, Zhejiang University School of Medicine
Xia Sun: Zhejiang University - University of Edinburgh Institute, Zhejiang University School of Medicine
Yuheng Wang: Zhejiang University - University of Edinburgh Institute, Zhejiang University School of Medicine
Ben Lehner: The Barcelona Institute of Science and Technology
Xianghua Li: Zhejiang University - University of Edinburgh Institute, Zhejiang University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41188-8

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