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.
Highlights
The budding yeast Saccharomyces cerevisiae has become a powerful model for elucidating fundamental principles and mechanisms of complex trait genetics [1]
We found that loci associated with haloperidol resistance are dosedependent
We showed that variants in the oxysterol-binding-protein-like domain of the gene SWH1 underlie the major locus detected at all doses of haloperidol
Summary
The budding yeast Saccharomyces cerevisiae has become a powerful model for elucidating fundamental principles and mechanisms of complex trait genetics [1]. In Saccharomyces cerevisiae (which does not contain the pharmacologically relevant haloperidol targets), haloperidol exerts effects on vesicle transport and amino acid metabolism [17], demonstrating perturbations of fundamental cellular physiology upon exposure to the drug. Haloperidol, a cationic amphiphilic drug, has been shown at concentrations of 10–200 mM to cause defects in phospholipid metabolism/transport [18,19] and trigger autophagy upon accumulation [20] in yeast, and to result in degradation of membranes [21] in vitro. An early biochemical study showed that haloperidol binds to Erg in yeast, and causes decreased ergosterol levels [23]. Erg functions in the ergosterol biosynthesis pathway, suggesting haloperidol’s interference with sterol metabolism and trafficking
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