Haploinsufficiency drug screen

Gene haploinsufficiency is generally bad news for a diploid organism because loss of that gene means that the organism is unable to survive. Now, in a multi-center effort called the Saccharomyces Genome Deletion Project, researchers have exploited the trait to identify drug targets ( Nature Genet. 21, 278—283, 1999). In their approach, each deletion strain lacks one copy of a given gene and carries in its place a unique DNA "bar code" that allows scientists to identify it on a DNA microarray. When the strains are cultured with the different deletions together, those in which the single-copy deletion causes a growth disadvantage gradually disappear and these strains identify genes that exhibit haploinsufficiency. Similarly, a drug that inhibits a particular gene product will place strains with only one copy of that protein's gene at a competitive disadvantage, resulting in their death. By comparing the drug-induced haploinsufficiency data with the original data, the scientists are able to find the drug's protein targets. The initial proof-of-concept experiment used 233 deletion strains, but the Genome Deletion Project will ultimately yield a much larger set of mutants. Guri Giaver, a researcher in the department of biochemistry at the Stanford University School of Medicine and first author on the new study, says "there is no foreseeable technical reason to think. . .that the system cannot scale to accommodate the complete genome set of 6,000 strains."

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Dove, A. Haploinsufficiency drug screen. Nat Biotechnol 17, 317 (1999). https://doi.org/10.1038/7847

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