RT Journal Article
SR Electronic
T1 Dominance vs. epistasis: the biophysical origins and plasticity of genetic interactions within and between alleles
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.04.03.486855
DO 10.1101/2022.04.03.486855
A1 Xuan Xie
A1 Ben Lehner
A1 Xianghua Li
YR 2022
UL http://biorxiv.org/content/early/2022/04/04/2022.04.03.486855.abstract
AB A central challenge in genetics, evolutionary biology and biotechnology is to understand and predict how mutations combine to alter phenotypes, including molecular activities, fitness and disease. In diploid organisms, two mutations in the same gene can either combine on the same chromosome or on different chromosomes, with interactions between the mutations quantified as epistasis and dominance, respectively. However, a direct comparison of the extent, sign and stability of interactions within and between alleles is lacking. Here we show that, even in the simplest biophysical systems, interactions between mutations are frequent, context-dependent and different when variants are combined within and between alleles. Whereas protein folding alone generates epistasis, the addition of a single molecular interaction is sufficient to cause dominance. Epistasis and dominance interactions change quantitatively, qualitatively and differently as a system becomes more complicated or the conditions change. Altering the concentration of a ligand can, for example, switch an allele from dominant to recessive. Our results show that 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 epistasis and dominance will require either detailed mechanistic understanding and experimental parameterization or brute-force measurement and learning.Competing Interest StatementThe authors have declared no competing interest.