Kuzmin, E. et al. Science 360, eaao1729 (2018).

Genetic interactions can go in two directions: in positive interactions, both mutations enhance the fitness of a cell to a degree beyond a simple additive effect, whereas synthetic lethality can result from the combined effects of two mutations that on their own would not have been fatal for the cell. Studies of such interactions, often performed in budding yeast for the ease of linking genotype to growth phenotype, mostly involve mutations in two genes. Kuzmin et al. expanded the view to trigenic interactions by constructing ~200,000 yeast triple mutants and quantitatively measuring negative interactions, for their greater signal-to-noise ratio. The researchers found interactions distributed over many genes, rather than concentrated around a set of highly connected genes. More than 30% of the trigenic interactions were not anticipated from double-mutant strains and provide new functional information.