Genomic profiling of drug sensitivities via induced haploinsufficiency

Lowering the dosage of a single gene from two copies to one copy in diploid yeast results in a heterozygote that is sensitized to any drug that acts o n the product of this gene. This haploinsufficient phenotype thereby identi fies the gene product of the heterozygous locus as the likely drug target. We exploited this finding in a genomic approach to drug-target identificati on. Genome sequence information was used to generate molecularly tagged het erozygous yeast strains that were pooled, grown competitively in drug and a nalysed for drug sensitivity using high-density oligonucleotide arrays. Ind ividual heterozygous strain analysis verified six known drug targets. Paral lel analysis identified the known target and two hypersensitive loci in a m ixed culture of 233 strains in the presence of the drug tunicamycin, Our di scovery that both drug target and hypersensitive loci exhibit drug-induced haploinsufficiency may have important consequences in pharmacogenomics and variable drug toxicity observed in human populations.