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Genetic basis of individual differences in the response to small-molecule drugs in yeast

Nature Genetics volume 39, pages 496502 (2007) | Download Citation

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Abstract

Individual response to small-molecule drugs is variable; a drug that provides a cure for some may confer no therapeutic benefit or trigger an adverse reaction in others. To begin to understand such differences systematically, we treated 104 genotyped segregants from a cross between two yeast strains with a collection of 100 diverse small molecules. We used linkage analysis to identify 124 distinct linkages between genetic markers and response to 83 compounds. The linked markers clustered at eight genomic locations, or quantitative-trait locus 'hotspots', that contain one or more polymorphisms that affect response to multiple small molecules. We also experimentally verified that a deficiency in leucine biosynthesis caused by a deletion of LEU2 underlies sensitivity to niguldipine, which is structurally related to therapeutic calcium channel blockers, and that a natural coding-region polymorphism in the inorganic phosphate transporter PHO84 underlies sensitivity to two polychlorinated phenols that uncouple oxidative phosphorylation. Our results provide a step toward a systematic understanding of small-molecule drug action in genetically distinct individuals.

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Acknowledgements

E.O.P. acknowledges F. Storici for technical advice and D. Altshuler for useful discussions. D.C.R acknowledges discussions with R. Schapire, S. Kulkarni and W. Schoendorf. RM11-1a (MATa leu2Δ ura3Δ), RM11-1b (MATα lys2Δ ura3Δ) and BY4716 (MATα lys2Δ) were gifts of B. Garvik (Fred Hutchison Cancer Research Center). This work was supported by the US National Institute of General Medicine Sciences (S.L.S.) and the US National Institute of Mental Health (L.K.). Work at Princeton was supported in part by a Center grant P50GM071508 from the US National Institute of General Medical Science/US National Institutes of Health. L.K. is a James S. McDonnell Centennial Fellow. S.L.S. is an Investigator at the Howard Hughes Medical Institute.

Author information

Affiliations

  1. Howard Hughes Medical Institute, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

    • Ethan O Perlstein
    •  & Stuart L Schreiber
  2. Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA.

    • Ethan O Perlstein
    •  & Stuart L Schreiber
  3. Lewis-Sigler Institute for Integrative Genomics and Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey 08544, USA.

    • Douglas M Ruderfer
    •  & Leonid Kruglyak
  4. Theoretical Division and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico 87544, USA.

    • David C Roberts
  5. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.

    • Stuart L Schreiber

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Stuart L Schreiber or Leonid Kruglyak.

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    Complete clustergram.

  2. 2.

    Supplementary Table 1

    Complete list of SMPs.

  3. 3.

    Supplementary Table 3

    Complete list of SMP/linkages.

  4. 4.

    Supplementary Table 4

    Collapsed list of SMP/linkages.

  5. 5.

    Supplementary Table 5

    Collapsed list of confidence intervals.

  6. 6.

    Supplementary Table 6

    Complete list of QTL hotspots.

  7. 7.

    Supplementary Table 7

    Primer sequences.

  8. 8.

    Supplementary Note

Excel files

  1. 1.

    Supplementary Table 2

    Raw data.

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DOI

https://doi.org/10.1038/ng1991

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