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Genomic profiling of drug sensitivities via induced haploinsufficiency

Academic Article
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Overview

authors

  • Giaever, G.
  • Shoemaker, D. D.
  • Jones, T. W.
  • Liang, H.
  • Winzeler, Elizabeth
  • Astromoff, A.
  • Davis, R. W.

publication date

  • March 1999

journal

  • Nature Genetics  Journal

abstract

  • 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 on the product of this gene. This haploinsufficient phenotype thereby identifies the gene product of the heterozygous locus as the likely drug target. We exploited this finding in a genomic approach to drug-target identification. Genome sequence information was used to generate molecularly tagged heterozygous yeast strains that were pooled, grown competitively in drug and analysed for drug sensitivity using high-density oligonucleotide arrays. Individual heterozygous strain analysis verified six known drug targets. Parallel analysis identified the known target and two hypersensitive loci in a mixed culture of 233 strains in the presence of the drug tunicamycin. Our discovery 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.

subject areas

  • Anti-Bacterial Agents
  • Benomyl
  • Cell Division
  • Fungal Proteins
  • Fungicides, Industrial
  • Gene Dosage
  • Genes, Fungal
  • Haplotypes
  • Heterozygote
  • Hydro-Lyases
  • Phenotype
  • Saccharomyces cerevisiae
  • Tunicamycin
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Identity

International Standard Serial Number (ISSN)

  • 1061-4036

Digital Object Identifier (DOI)

  • 10.1038/6791

PubMed ID

  • 10080179
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Additional Document Info

start page

  • 278

end page

  • 283

volume

  • 21

issue

  • 3

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