title: Genetic basis of haloperidol resistance in Saccharomyces cerevisiae is complex and dose dependent.
abstract: The genetic basis of most heritable traits is complex. Inhibitory compounds and their effects in model organisms have been used in many studies to gain insights into the genetic architecture underlying quantitative traits. However, the differential effect of compound concentration has not been studied in detail. In this study, we used a large segregant panel from a cross between two genetically divergent yeast strains, BY4724 (a laboratory strain) and RM11_1a (a vineyard strain), to study the genetic basis of variation in response to different doses of a drug. Linkage analysis revealed that the genetic architecture of resistance to the small-molecule therapeutic drug haloperidol is highly dose-dependent. Some of the loci identified had effects only at low doses of haloperidol, while other loci had effects primarily at higher concentrations of the drug. We show that a major QTL affecting resistance across all concentrations of haloperidol is caused by polymorphisms in SWH1, a homologue of human oxysterol binding protein. We identify a complex set of interactions among the alleles of the genes SWH1, MKT1, and IRA2 that are most pronounced at a haloperidol dose of 200 µM and are only observed when the remainder of the genome is of the RM background. Our results provide further insight into the genetic basis of drug resistance.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, California, United States of America; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, California, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: Leonid
authors.initials: L
authors.lastname: Kruglyak
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D025141:Drug Resistance, Fungal / Q000235:genetics*; D020690:GTPase-Activating Proteins / Q000235:genetics; D006220:Haloperidol / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D008826:Microbial Sensitivity Tests; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; C064960:IRA2 protein, S cerevisiae; C092218:MKT1 protein, S cerevisiae; C089501:SWH1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D006220:Haloperidol