In an open access article entitled, “Magnitude and sign epistasis among deleterious mutations in a positive-sense plant RNA virus,” published online 11 April 2012, in Heredity (2012) 109, 71–77, J Lalić and S F Elena have shown how epistatic interactions between mutations in viral genomes determine traits such as resistance to antiviral drugs, virulence and host range. RNA viruses constitute an ideal material for this kind of study because of the compactness of their genomes, and seemingly little complexity. The investigators created 53 Tobacco etch potyvirus genotypes carrying pairs of single-nucleotide substitutions. They observed that epistasis was correlated with viral protein-protein interactions being largely positive between linked pairs of genes and negative between unlinked ones. The authors found that the degree of epistasis correlated negatively with the average effect of mutations. Overall, their results confirm the ones reported earlier for other viruses and further consolidate the view that positive epistasis is the average for small and compact genomes that lack genetic vigor.