A Functional Variomics Tool for Discovering Drug-Resistance Genes and Drug Targets

SummaryComprehensive discovery of genetic mechanisms of drug resistance and identification of in vivo drug targets represent significant challenges. Here we present a functional variomics technology in the model organism Saccharomyces cerevisiae. This tool analyzes numerous genetic variants and effectively tackles both problems simultaneously. Using this tool, we discovered almost all genes that, due to mutations or modest overexpression, confer resistance to rapamycin, cycloheximide, and amphotericin B. Most significant among the resistance genes were drug targets, including multiple targets of a given drug. With amphotericin B, we discovered the highly conserved membrane protein Pmp3 as a potent resistance factor and a possible target. Widespread application of this tool should allow rapid identification of conserved resistance mechanisms and targets of many more compounds. New genes and alleles that confer resistance to other stresses can also be discovered. Similar tools in other systems, such as human cell lines, will also be useful.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► A functional variomics tool for drug-target identification is described
► This tool compares favorably with other target-identification tools
► This tool will greatly facilitate the linking of phenotypes to point mutations
► This work discovered Pmp3 as a target of amphotericin B