Originally published as Genetics Published Articles Ahead of Print on August 31, 2009.

Genetics, Vol. 183, 1141-1151, November 2009, Copyright © 2009
doi:10.1534/genetics.109.108068

A Combined-Cross Analysis Reveals Genes With Drug-Specific and Background-Dependent Effects on Drug Sensitivity in Saccharomyces cerevisiae

Hyun Seok Kim^*,1 and Justin C. Fay^*,,2

^* Computational Biology Program and Department of Genetics, Washington University, St. Louis, Missouri 63108

² Corresponding author: Department of Genetics, Washington University, 4444 Forest Park Ave., St. Louis, MO 63108.
E-mail: jfay{at}genetics.wustl.edu

Effective pharmacological therapy is often inhibited by variable drug responses and adverse drug reactions. Dissecting the molecular basis of different drug responses is difficult due to complex interactions involving multiple genes, pathways, and cellular processes. We previously found a single nucleotide polymorphism within cystathionine β-synthase (CYS4) that causes multi-drug sensitivity in a vineyard strain of Saccharomyces cerevisiae. However, not all variation was accounted for by CYS4. To identify additional genes influencing drug sensitivity, we used CYS4 as a covariate and conducted both single- and combined-cross linkage mapping. After eliminating numerous false-positive associations, we identified 16 drug-sensitivity loci, only 3 of which had been previously identified. Of 4 drug-sensitivity loci selected for validation, 2 showed replicated associations in independent crosses, and two quantitative trait genes within these regions, AQY1 and MKT1, were found to have drug-specific and background-dependent effects. Our results suggest that drug response may often depend on interactions between genes with multi-drug and drug-specific effects.

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