Co-occurrence of essential gene dispensability and bypass suppressor mutations across species

Essential genes that become dispensable upon specific changes in the genetic background represent a valuable model to understand the incomplete penetrance of loss-of-function mutations and the emergence of drug resistance mechanisms. Systematic identification of dispensable essential genes has recently challenged the canonical binary categorization of gene essentiality. Here, we compiled data from multiple studies on essential gene dispensability in Saccharomyces cerevisiae to comprehensively characterize these genes. In analyses spanning different evolutionary time-scales, ranging from S. cerevisiae strains to human cell lines, dispensable essential genes exhibited distinct phylogenetic properties compared to other essential and non-essential genes. Integration of interactions with suppressor genes unveiled the emergent high functional modularity of the bypass suppression network. Also, dispensable essential and suppressor gene pairs reflected simultaneous changes in the mutational landscape of S. cerevisiae strains. Importantly, species in which dispensable essential genes were non-essential tended to carry bypass suppressor mutations in their genomes. Overall, our study offers a comprehensive view of dispensable essential genes and illustrates how their interactions with bypass suppressor genes reflect evolutionary outcomes. ### Competing Interest Statement The authors have declared no competing interest.