The strength of weird ties: positive genetic interactions have greater scientific impact but are under-represented in the literature

Abstract

Genetic interactions, where the combined effect of perturbing two genes leads to a phenotype that deviates from the expectation based on the effects of the individual perturbations, often provide important information about the functional architecture of biological systems. These interactions are commonly classified as negative or positive based on whether the phenotype of the double mutant is less than or greater than what would be expected based on the single mutant effects. When the trait in question is fitness, systematic studies of pairwise deletions have shown that negative interactions typically link genes with similar functional annotations, while positive interactions typically link genes that are less obviously related and thus often viewed as less informative. However, research in the sociology of science suggests that transformative discoveries often arise from unexpected, cross-domain linkages. To evaluate these competing perspectives, we integrated large-scale genetic interaction data in yeast with literature annotations from the Saccharomyces Genome Database and citation data from iCite. We found that positive genetic interactions are associated with greater scientific impact, as measured by citation metrics, contrary to prevailing assumptions. Despite their greater impact, positive interactions are significantly underrepresented in the scientific literature. Interestingly, the advent of an unbiased mapping technology capable of detecting positive and negative interactions with equal facility did not alleviate this bias, implicating factors beyond mere discoverability. We also find that the research building on positive interactions forms a more interconnected body of follow-on work. Together, our analyses reveal the underappreciated value of positive genetic interactions and suggest that investigating cross-domain genetic links represents an under-exploited opportunity deserving of greater attention.