Mutations compensating for cell polarity defects change the gene-fitness relationship on a genome-wide scale

Functional defects resulting from deleterious mutations can often be restored during evolution by compensatory mutations elsewhere in the genome. Importantly, this process can generate the molecular diversity seen in networks regulating the same biological function. How the capacity for compensatory evolution is embedded in the structure of biological networks is still unresolved. Here, we study a case in Saccharomyces cerevisiae where a genetic perturbation in a module related to polarity establishment is compensated by making additional gene deletions. A transposon mutagenesis screen revealed that compensatory evolution altered the gene-fitness relation of approximately 13% of the annotated genes. Interestingly, a nearly equal number of genes become more and less tolerant to disruptions, indicating substantial functional rewiring of genes. Grouping the affected genes by their biological function, we find that they are involved in a diverse set of processes, of which many have no clear link to cell polarity. Our results show that mutations compensating for defects in one functional module can have global consequences that influence the evolutionary direction of many other cellular processes.