Mechanistic causes of sign epistasis and its applications.

Mapping genetic variations to phenotypic variations poses a significant challenge, as mutations often combine unexpectedly, diverging from assumed additive effects even in the same environment. These interactions are known as epistasis or genetic interactions. Sign epistasis, as a specific type of epistasis, involves a complete reversal of mutation effects within altered genetic backgrounds, presenting a substantial hurdle to phenotype prediction. Despite its importance, there is a limited systematic overview of the mechanistic causes of sign epistasis. This review explores the mechanistic causes, highlighting its occurrence in signalling cascades, peaked fitness landscapes, and physical interactions. Moving beyond theoretical discussions, we delve into the practical applications of sign epistasis in agriculture, evolution, and antibiotic resistance. In conclusion, this review aims to enhance the comprehension of sign epistasis and molecular dynamics, anticipating future endeavours in systematic biology engineering that leverage the knowledge of sign epistasis.