Dynamic epistasis for different alleles of the same gene

TL;DR

This study reveals that epistatic interactions vary significantly among different alleles of the same gene, influencing genetic and evolutionary processes, with implications for understanding genome dynamics and mutation purging.

Contribution

It demonstrates that epistatic interactions are dynamically rewired among alleles, a novel insight into gene interaction variability and its evolutionary consequences.

Findings

Different alleles can epistatically interact with distinct gene sets.

Higher mutational severity alleles tend to have more negative epistasis in eukaryotes.

Epistatic dynamics can accelerate purging of deleterious mutations in eukaryotes.

Abstract

Epistasis refers to the phenomenon in which phenotypic consequences caused by mutation of one gene depend on one or more mutations at another gene. Epistasis is critical for understanding many genetic and evolutionary processes, including pathway organization, evolution of sexual reproduction, mutational load, ploidy, genomic complexity, speciation, and the origin of life. Nevertheless, current understandings for the genome-wide distribution of epistasis are mostly inferred from interactions among one mutant type per gene, whereas how epistatic interaction partners change dynamically for different mutant alleles of the same gene is largely unknown. Here we address this issue by combining predictions from flux balance analysis and data from a recently published high-throughput experiment. Our results show that different alleles can epistatically interact with very different gene sets. Furthermore, between two random mutant alleles of the same gene, the chance for the allele with more severe mutational consequence to develop a higher percentage of negative epistasis than the other allele is 50-70% in eukaryotic organisms, but only 20-30% in bacteria and archaea. We developed a population genetics model that predicts that the observed distribution for the sign of epistasis can speed up the process of purging deleterious mutations in eukaryotic organisms. Our results indicate that epistasis among genes can be dynamically rewired at the genome level, and call on future efforts to revisit theories that can integrate epistatic dynamics among genes in biological systems.