Figure 2

Figure 2

Application of yeast for drug discovery for genetic diseases. (A) A small molecule (drug) is screened vs. the ∼5000 separate nonessential yeast gene deletion set and is compared to the known yeast deletion array synthetic lethal genetic interactions. The yeast gene deletion(s) with a similar set of interactors to the small molecule can point to the pathway or gene/protein targeted by the small molecule. (B) HIPHOP (haploinsufficiency profiling or homozygous profiling) makes use of the diploid haploinsufficiency collection of all yeast genes. The entire collection is exposed to a small molecule and the culture is allowed to grow. Using bar-coding technology, the yeast strain(s) whose growth is decreased compared to a no drug control can be identified (ID). The small-molecule drug target should show decreased growth in a strain that is haploinsufficient for its target compared to the other strains. (C) Several applications of synthetic genetic array technology can be used to identify drug targets. The example illustrated works on the principle that inducible overexpression of a human open reading frame (ORF) in yeast results in an easily measurable phenotype (often growth). The yeast strain containing the human ORF (uninduced) can be mated to each of the ∼5000 nonessential yeast gene deletion strains and, through a series of strain selection steps, can result in the isolation of haploid yeast strains each containing the human ORF under control of an inducible promoter in each of the ∼5000 individual yeast gene deletion strains. Expression of the human protein can be induced, and yeast gene deletion strains that prevent its toxicity point to potential drug targets whose inhibition could prevent the toxicity of the human protein.