Analyzing High-Order Epistasis from Genotype-Phenotype Maps Using ‘Epistasis’ Package

Epistasis is the phenomenon about the interactions between genes, leading to complex phenotypic effects. The interactions between three or more mutations called “high-order epistasis” aroused significant interests in recent studies. However, there are still debates for analysis of high-order epistasis due to the non-linear model complexity and statistical artifacts. A recent “epistasis” Python package was therefore developed to characterize high-order epistasis by estimating non-linear scaling for mutation effects to extract high-order epistasis using linear models. This method successfully discovered statistically significant high-order epistasis on several real genotype-phenotype maps. We provided a concise and step-by-step guide to apply the “epistasis” by reproducing the high-order epistasis discoveries on real genotype-phenotype data using the latest API of the package.