The importance of epistasis in the evolution of viral pathogens

Understanding the genetic and genomic underpinnings of infectious disease outbreaks has emerged as a frontier of epidemiology. This systematic review argues that epistasis—where the phenotypic effects of mutations or gene variants are dictated by the presence of other mutations or genes—should become a central feature of genomic epidemiology. To demonstrate this, we present the results of a review of existing literature on the role of epistasis in viruses, focusing on three major human viral systems: (i) influenza, (ii) SARS-CoV-2, (iii) human immunodeficiency virus (HIV). In order to explore the generality of these patterns, we also examine two other bodies of literature, mainly focusing on non-human viruses: (iv) experimental evolution of viruses and (v) tobacco etch virus (TEV). Our systematic review of these five bodies of literature highlights that positive magnitude and sign (change in the direction of fitness effect of mutations) epistasis have been reported most often. Nevertheless, there was variation in the frequency of the type of epistatic interactions reported in all five systems. Our systematic review also highlights factors such as the over/under-representation of viral strains/types, host species, and genes studied. Biases in the methods used in these systems could have shaped the nature of epistatic interactions reported in each system. Moving forward, we suggest collaborations between genomic epidemiology and evolutionary biology to implement the identification and measurement of epistasis in studying the evolution of viral pathogens.