System-Level Analysis of Genes and Functions Affecting Survival During Nutrient Starvation in Saccharomyces cerevisiae

An essential property of all living organisms is the ability to exit from active cell division and persist in a quiescent state. For single-celled microbes this primarily occurs in response to nutrient deprivation. We studied the genetic requirements for survival of Saccharomyces cerevisiae when starved for either of two nutrients: phosphate or leucine. We measured the survival of virtually all haploid null yeast mutants in mixed populations using a quantitative sequencing method that accurately estimates the abundance of each mutant on the basis of frequency of unique molecular barcodes. Starvation for phosphate results in a population half-life of 337 hours whereas starvation for leucine results in a half-life of 27.7 hours. To determine a quantitative measure of survival of the individual mutants in each population we developed a statistical framework that accounts for the multiple sources of experimental variation. From the identities of the genes in which mutations strongly affect survival, we identified several cellular processes already implicated as affecting survival upon nutrient starvation, including autophagy, chromatin remodeling and cytoskeletal function. In addition, we found evidence that mitochondrial function and oxidative metabolism are required for successful cell cycle exit, aging and survival. Our experimental and analytical methods represent an efficient and quantitative approach to characterizing genetic functions and networks with unprecedented resolution.