Systematic analysis of Ca(2+) homeostasis in Saccharomyces cerevisiae based on chemical-genetic interaction profiles

We investigated the global landscape of Ca(2+) homeostasis in budding yeast based on high-dimensional chemical-genetic interaction profiles. The morphological responses of 62 Ca(2+)-sensitive (cls) mutants were quantitatively analyzed with the image processing program CalMorph after exposure to a high concentration of Ca(2+). After a generalized linear model was applied, an analysis of covariance model was used to detect significant Ca(2+)–cls interactions. We found that high-dimensional, morphological Ca(2+)–cls interactions were mixed with positive (86%) and negative (14%) chemical-genetic interactions, whereas one-dimensional fitness Ca(2+)–cls interactions were all negative in principle. Clustering analysis with the interaction profiles revealed nine distinct gene groups, six of which were functionally associated. In addition, characterization of Ca(2+)–cls interactions revealed that morphology-based negative interactions are unique signatures of sensitized cellular processes and pathways. Principal component analysis was used to discriminate between suppression and enhancement of the Ca(2+)-sensitive phenotypes triggered by inactivation of calcineurin, a Ca(2+)-dependent phosphatase. Finally, similarity of the interaction profiles was used to reveal a connected network among the Ca(2+) homeostasis units acting in different cellular compartments. Our analyses of high-dimensional chemical-genetic interaction profiles provide novel insights into the intracellular network of yeast Ca(2+) homeostasis.