The Genetic Architecture in Saccharomyces Cerevisiae That Contributes to Variation in Drug Response to the Antifungals Benomyl and Ketoconazole

FEMS Yeast Res. 2017 May 1;17(3). doi: 10.1093/femsyr/fox027.

Abstract

The genetic basis of variation in drug response was investigated in individual Saccharomyces cerevisiae strains that exhibited different susceptibility to two antifungal agents: benomyl and ketoconazole. Following dose-response screening of 25 strains, 4 were selected on the basis of resistance or sensitivity relative to the standard laboratory strain BY. UWOPS87-2421 and L-1374 were respectively resistant and sensitive to benomyl; DBVPG6044 and Y12 were respectively resistant and sensitive to ketoconazole. We used advanced intercross lines and next generation sequencing-bulk segregant analysis to characterise the quantitative trait loci (QTL) underpinning drug responses after drug selection. Drug response was controlled by multiple QTL, ranging from a minimum of 5 to a maximum of 60 loci, almost all of which were not the primary drug target. For each drug, the resistant and the sensitive strain exhibited a number of shared loci, but also had strain-specific QTL. In our analysis, it was possible to estimate genetic effect of QTL, and a number of those shared between resistant and sensitive strains exhibited variable effect on the response phenotype. Thus, drug responses arise as a result of different genetic architectures, depending on the genetic background of the individual strain in question.

Keywords: benomyl; individual drug response; ketoconazole; next-generation sequencing bulk segregant analysis; quantitative trait loci.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / pharmacology*
  • Benomyl / pharmacology*
  • Crosses, Genetic
  • Culture Media / chemistry
  • Drug Resistance, Fungal / genetics*
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Ketoconazole / pharmacology*
  • Microbial Sensitivity Tests
  • Phenotype
  • Quantitative Trait Loci*
  • Saccharomyces cerevisiae / drug effects*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development
  • Species Specificity

Substances

  • Antifungal Agents
  • Culture Media
  • Ketoconazole
  • Benomyl