Global genetic rewiring during compensatory evolution in the yeast polarity network

Functional defects resulting from deleterious mutations can often be restored during evolution by compensatory mutations. Importantly, this process can generate the genetic diversity seen in networks regulating the same biological function in different species. How the options for compensatory evolution depend on the molecular interactions underlying these functions is currently unclear. We investigate how gene deletions compensating for a defect in the polarity pathway of Saccharomyces cerevisiae impact the fitness landscape. Using a transposon mutagenesis screen, we demonstrate that gene disruption tolerance has changed on a genome-wide scale in the compensated strain. An analysis of the functional associations between the affected genes reveals that compensation impacts cellular processes that have no clear connection to cell polarity. Moreover, genes belonging to the same process tend to show the same direction of tolerance change, indicating that compensation rewires the fitness contribution of cellular processes rather than of individual genes. In conclusion, our results strongly suggest that functional overlap between modules and the interconnectedness of the molecular interaction network play major roles in mediating compensatory evolution.