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Chemical Genomics Reveals Importance of 'Nonessential' Yeast Genes

NEW YORK (GenomeWeb News) – Exposing yeast cells to chemical and environmental stressors can provide insights into the functions of many nonessential yeast genes, new research suggests.
 
Using chemical genomics, researchers from Stanford University and the University of Toronto demonstrated that the majority of yeast nonessential single deletions exhibit growth defects when exposed to certain chemical or environmental stress. They also identified new candidate multi-drug resistance genes and demonstrated how clustering genes based on their co-fitness can provide clues about their function. The work appeared online today in Science.
 
“The emergent field of chemical genomics promises that, by understanding the relations between small molecules and genes on a systems level, we might understand genomic responses to small molecule perturbants,” lead author Maureen Hillenmeyer, a doctoral candidate in Stanford University’s BioMedical Informatics Training Program, and her colleagues wrote.  
 
Roughly 80 percent of known protein coding genes in Saccharomyces cerevisiae are nonessential. And most of these single knockout strains have no obvious defects when grown in nutrient-rich media under ideal growth conditions in the lab. Previous studies suggest that only 15 percent of homozygous deletion strains exhibit a fitness defect under optimal lab growth conditions.
 
But what about yeast that aren’t living a pampered life in the lab? Hillenmeyer and her colleagues used chemical genomics to try to get to the bottom of whether nonessential genes are, as some suspect, redundant and, if not, what these genes do in the real world.
 
The team did 1,144 experiments to assess the growth of about 6,000 heterozygous and 5,000 homozygous yeast deletion strains in the presence of 400 small molecules or numerous environmental stresses — work designed to root out what really happens in cells when these genes are missing. The small-molecule chemical probes they used ranged from well characterized chemicals to relatively obscure compounds with yet-unknown biological activity.
 
In all, about 97 percent of the knockout strains exhibited a measurable growth defect when subjected to one form of chemical or environmental stress or another. Just 416 of the homozygous deletion strains and roughly 2,000 heterozygous deletion strains showed no detectable growth differences.
 
Notably, most of these strains were affected by more than one of the conditions tested. In this study, those that were sensitive to 20 percent or more of the small molecules tested were defined as lacking a multi-drug resistance, or MDR, gene.
 
Using this approach, the team not only verified known resistance genes, but also implicated hundreds more that were previously unknown. Many of these tended to cluster into groups of genes related to endosome transport, vacuolar degradation, and transcription. Other MDR genes were related to functions such as amino acid biosynthesis.
 
“This coordinated system of endocytosis and vacuolar or lysosomal degradation, conserved from yeast to humans, is a mechanism whereby the cell regulates transmembrane proteins,” the researchers suggested. “These results are consistent with recent findings in mammalian cells that MDR is correlated with changes in intracellular trafficking, although the exact contribution of these pathways to drug resistance is not known.”
 
When they clustered genes based on co-fitness under different conditions, they found sets of genes involved in shared biological processes — an observation that they validated in some cases by clustering the same genes based on known biological processes. For instance, Hillenmeyer and her team identified a heterozygous cluster containing all eight genes from the cytoskeletal folding chaperonin-containing T complex. Not surprisingly, these strains were sensitive to chemicals such as latrunculin and benomyl, which act on the cytoskeleton. They also found clusters representing genes in the proteasome core complex and others involved in peroxisome function
 
The results suggest the so-called nonessential S. cerevisiae genes have functional roles that contribute to growth under specific conditions and are not simply members of overlapping and redundant pathways. In fact, the authors concluded, genetic redundancy provides limited tolerance under stressful growth conditions.
 
“Our finding that nearly all genes in yeast are required for wild-type growth in at least one experimental condition addresses the debate concerning the purpose of nonessential genes,” the authors wrote. “The chemical-genetic interactions defined here are complementary to genetic interactions and should improve the resolution of genetic and chemical-genetic interaction maps, with applications such as predicting drug activities and synergies.”

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