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

Nature Genetics volume 39, pages 496–502 (2007)Cite this article

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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Figure 1: Hierarchical clustering of final yield measurements of 104 BY and RM segregants treated with selected SMPs shows clustering of functional analogs, including a cluster of psychiatric disease drugs.
Figure 2: QTL hotspots.
Figure 3: Functional verification that the LEU2 locus determines response to the dihydropyridine niguldipine at chromosome III hotspot.
Figure 4: A missense mutation (leading to L259P) in PHO84 confers resistance to two polychlorinated phenols.

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References

  1. Weinstein, J.N. et al. An information-intensive approach to the molecular pharmacology of cancer. Science 275, 343–349 (1997).

    Article  CAS  Google Scholar 

  2. Dolan, M.E. et al. Heritability and linkage analysis of sensitivity to cisplatin-induced cytotoxicity. Cancer Res. 64, 4353–4356 (2004).

    Article  CAS  Google Scholar 

  3. Watters, J.W., Kraja, A., Meucci, M.A., Province, M.A. & McLeod, H.L. Genome-wide discovery of loci influencing chemotherapy cytotoxicity. Proc. Natl. Acad. Sci. USA 101, 11809–11814 (2004).

    Article  CAS  Google Scholar 

  4. Shukla, S.J. & Dolan, M.E. Use of CEPH and non-CEPH lymphoblast cell lines in pharmacogenetic studies. Pharmacogenomics 6, 303–310 (2005).

    Article  CAS  Google Scholar 

  5. Le Morvan, V. et al. Relationships between genetic polymorphisms and anticancer drug cytotoxicity vis-à-vis the NCI-60 panel. Pharmacogenomics 7, 843–852 (2006).

    Article  CAS  Google Scholar 

  6. Moisan, F., Longy, M., Robert, J. & Le Morvan, V. Identification of gene polymorphisms of human DNA topoisomerase I in the National Cancer Institute panel of human tumour cell lines. Br. J. Cancer 95, 906–913 (2006).

    Article  CAS  Google Scholar 

  7. Yarosh, D.B., Pena, A. & Brown, D.A. DNA repair gene polymorphisms affect cytotoxicity in the National Cancer Institute Human Tumour Cell Line Screening Panel. Biomarkers 10, 188–202 (2005).

    Article  CAS  Google Scholar 

  8. Stoehlmacher, J. et al. A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br. J. Cancer 91, 344–354 (2004).

    Article  CAS  Google Scholar 

  9. Hohmann, S. The Yeast Systems Biology Network: mating communities. Curr. Opin. Biotechnol. 16, 356–360 (2005).

    Article  CAS  Google Scholar 

  10. Foury, F. Human genetic disease: a cross-talk between man and yeast. Gene 195, 1–10 (1997).

    Article  CAS  Google Scholar 

  11. Steinmetz, L.M. et al. Systematic screen for human disease genes in yeast. Nat. Genet. 31, 400–404 (2002).

    Article  CAS  Google Scholar 

  12. Outeiro, T.F. & Giorgini, F. Yeast as a drug discovery platform in Huntington's and Parkinson's disease. Biotechnol. J. 1, 258–269 (2006).

    Article  CAS  Google Scholar 

  13. Ooi, S.L. et al. Global synthetic-lethality analysis and yeast functional profiling. Trends Genet. 22, 56–63 (2006).

    Article  CAS  Google Scholar 

  14. Sinha, H., Nicholson, B.P., Steinmetz, L.M. & McCusker, J.H. Complex genetic interactions in a quantitative trait locus. PloS Genet. 2, e13 (2006).

    Article  Google Scholar 

  15. Steinmetz, L.M. et al. Dissecting the architecture of a quantitative trait locus in yeast. Nature 416, 326–330 (2002).

    Article  CAS  Google Scholar 

  16. Deutschbauer, A.M. & Davis, R.W. Quantitative trait loci mapped to single-nucleotide resolution in yeast. Nat. Genet. 37, 1333–1340 (2005).

    Article  CAS  Google Scholar 

  17. Ben-Ari, G., Zenvirth, D., Sherman, A. & Klutstein, D.L. Four linked genes participate in controlling sporulation efficiency in budding yeast. PLoS Genet. (in the press) (2006).

  18. Brem, R.B., Yvert, G., Clinton, R. & Kruglyak, L. Genetic dissection of transcriptional regulation in budding yeast. Science 296, 752–755 (2002).

    Article  CAS  Google Scholar 

  19. Yvert, G. et al. Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Nat. Genet. 35, 57–64 (2003).

    Article  CAS  Google Scholar 

  20. Morley, M. et al. Genetic analysis of genome-wide variation in human gene expression. Nature 430, 743–747 (2004).

    Article  CAS  Google Scholar 

  21. Monks, S.A. et al. Genetic inheritance of gene expression in human cell lines. Am. J. Hum. Genet. 75, 1094–1105 (2004).

    Article  CAS  Google Scholar 

  22. Perlstein, E.O. et al. Revealing complex traits with small molecules and naturally recombinant yeast strains. Chem. Biol. 13, 319–327 (2006).

    Article  CAS  Google Scholar 

  23. Brem, R.B. & Kruglyak, L. The landscape of genetic complexity across 5,700 gene expression traits in yeast. Proc. Natl. Acad. Sci. USA 102, 1572–1577 (2005).

    Article  CAS  Google Scholar 

  24. Ruderfer, D.M., Pratt, S.C., Seidel, H.S. & Kruglyak, L. Population genomc analysis of outcrossing and recombination in yeast. Nat. Genet. 38, 1077–1081 (2006).

    Article  CAS  Google Scholar 

  25. Maro, B., Marty, M.C. & Bornens, M. In vivo and in vitro effects of the mitochondrial uncoupler FCCP on microtubules. EMBO J. 1, 1347–1352 (1982).

    Article  CAS  Google Scholar 

  26. Fogel, S., Welch, J.W. & Maloney, D.H. The molecular genetics of copper resistance in Saccharomyces cerevisiae – a paradigm for non-conventional yeasts. J. Basic Microbiol. 28, 147–160 (1988).

    Article  CAS  Google Scholar 

  27. Tamura, K. et al. A hap1 mutation in a laboratory strain of Saccharomyces cerevisiae results in decreased expression of ergosterol-related genes and cellular ergosterol content compared to sake yeast. J. Biosci. Bioeng. 98, 159–166 (2004).

    Article  CAS  Google Scholar 

  28. Rogers, B. et al. The pleiotropic drug ABC transporters from Saccharomyces cerevisiae. J. Mol. Microbiol. Biotechnol. 3, 207–214 (2001).

    CAS  PubMed  Google Scholar 

  29. Tenreiro, S. et al. AQR1 gene (ORF YNL065w) encodes a plasma membrane transporter of the major facilitator superfamily that confers resistance to short-chain monocarboxylic acids and quinidine in Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 292, 741–748 (2002).

    Article  CAS  Google Scholar 

  30. Bolster, D.R., Vary, T.C., Kimball, S.R. & Jefferson, L.S. Leucine regulates translation initiation in rat skeletal muscle via enhanced eIF4G phosphorylation. J. Nutr. 134, 1704–1710 (2004).

    Article  CAS  Google Scholar 

  31. Weinbach, E.C. Biochemical basis for the toxicity of pentachlorophenol. Proc. Natl. Acad. Sci. USA 43, 393–397 (1957).

    Article  CAS  Google Scholar 

  32. Somerville, L. The metabolism of fungicides. Xenobiotica 16, 1017–1030 (1986).

    Article  CAS  Google Scholar 

  33. Bun-Ya, M., Nishimura, M., Harashima, S. & Oshima, Y. The PHO84 gene of Saccharomyces cerevisiae encodes an inorganic phosphate transporter. Mol. Cell. Biol. 11, 3229–3238 (1991).

    Article  CAS  Google Scholar 

  34. Thomas, M.R. & O'Shea, E.K. An intracellular phosphate buffer filters transient fluctuations in extracellular phosphate levels. Proc. Natl. Acad. Sci. USA 102, 9565–9570 (2005).

    Article  CAS  Google Scholar 

  35. Cordes, F.S., Bright, J.N. & Sansom, M.S. Proline-induced distortions of transmembrane helices. J. Mol. Biol. 323, 951–960 (2002).

    Article  CAS  Google Scholar 

  36. Yeh, P., Tschumi, A.I. & Kishony, R. Functional classification of drugs by properties of their pairwise interactions. Nat. Genet. 38, 489–494 (2006).

    Article  CAS  Google Scholar 

  37. Borissy, A.A. et al. Systematic discovery of multicomponent therapeutics. Proc. Natl. Acad. Sci. USA 100, 7977–7982 (2003).

    Article  Google Scholar 

  38. Staunton, J.E. et al. Chemosensitivity prediction by transcriptional profiling. Proc. Natl. Acad. Sci. USA 98, 10787–10792 (2001).

    Article  CAS  Google Scholar 

  39. Marton, M.J., Vazquez de Aldana, C.R., Qui, H., Chakraburtty, K. & Hinnebusch, A.G. Evidence that GCN1 and GCN20, translational regulators of GCN4, function on elongating ribosomes in activation of eIFalpha kinase GCN2. Mol. Cell. Biol. 17, 4474–4489 (1997).

    Article  CAS  Google Scholar 

  40. Coller, J. & Parker, R. General translational repression by activators of mRNA decapping. Cell 122, 875–886 (2005).

    Article  CAS  Google Scholar 

  41. Zhou, X.F., Yang, X., Wang, Q., Coburn, R.A. & Morris, M.E. Effects of dihydropyridines and pyridines on multidrug resistance mediated by breast cancer resistance protein: in vitro and in vivo studies. Drug Metab. Dispos. 33, 1220–1228 (2005).

    Article  CAS  Google Scholar 

  42. Urban, T.J. et al. Functional genomics of membrane transporters in human populations. Genome Res. 16, 223–230 (2006).

    Article  CAS  Google Scholar 

  43. Jensen, L.T., Ajua-Alemanji, M. & Culotta, V.C. The Saccharomyces cerevisiae high affinity phosphate transporter encoded by PHO84 also functions in manganese homeostasis. J. Biol. Chem. 278, 42036–42040 (2003).

    Article  CAS  Google Scholar 

  44. Broman, K.W., Wu, H., Sen, S. & Churchill, G.A. R/qtl: QTL mapping in experimental crosses. Bioinformatics 19, 889–890 (2003).

    Article  CAS  Google Scholar 

  45. Storici, F., Durham, C.L., Gordenin, D.A. & Resnick, M.A. Chromosomal site-specific double-strand breaks are efficiently targeted for repair by oligonucleotides in yeast. Proc. Natl. Acad. Sci. USA 100, 14994–14999 (2003).

    Article  CAS  Google Scholar 

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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

Authors and Affiliations

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

    Ethan O Perlstein & Stuart L Schreiber

  2. Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, 02138, Massachusetts, USA

    Ethan O Perlstein & Stuart L Schreiber

  3. Lewis-Sigler Institute for Integrative Genomics and Department of Ecology and Evolutionary Biology, Princeton University, Princeton, 08544, New Jersey, USA

    Douglas M Ruderfer & Leonid Kruglyak

  4. Theoretical Division and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, 87544, New Mexico, USA

    David C Roberts

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

    Stuart L Schreiber

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  1. Ethan O Perlstein
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Correspondence to Stuart L Schreiber or Leonid Kruglyak.

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Supplementary information

Supplementary Figure 1

Complete clustergram. (PDF 907 kb)

Supplementary Table 1

Complete list of SMPs. (PDF 33 kb)

Supplementary Table 2

Raw data. (XLS 620 kb)

Supplementary Table 3

Complete list of SMP/linkages. (PDF 73 kb)

Supplementary Table 4

Collapsed list of SMP/linkages. (PDF 48 kb)

Supplementary Table 5

Collapsed list of confidence intervals. (PDF 64 kb)

Supplementary Table 6

Complete list of QTL hotspots. (PDF 19 kb)

Supplementary Table 7

Primer sequences. (PDF 12 kb)

Supplementary Note (PDF 17 kb)

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Perlstein, E., Ruderfer, D., Roberts, D. et al. Genetic basis of individual differences in the response to small-molecule drugs in yeast. Nat Genet 39, 496–502 (2007). https://doi.org/10.1038/ng1991

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