Broad long-term objectives:
In Specific Aim 1, we will sequence and annotate the genomes of an additional 88 genetically diverse S. cerevisiae strains, bringing the total of such strains to 96, which will serve as the bases for Specific Aims 2-4.
In Specific Aim 2, we will use haploid association mapping to identify candidate pharmacogenetic QTGs controlling resistance to 5- fluoropyrimidines, which are clinically used anti-cancer and/or antifungal agents, and membrane stressors, many of which are clinically used antifungal agents.
In Specific Aim 3, we will use genome wide association, in a 4,560 member F1 population, to identify candidate pharmacogenetic QTGs. In parallel, we will QTL map, in 500 and 600 member F2 populations, pharmacogenetic QTLs. The haploid association mapping and genome wide association will identify candidate QTGs in many QTLs. Similarly, the QTL mapping will identify many haploid association mapping and genome wide association true/false associations and false negatives. Finally, in Specific Aim 4, we will use high throughput F1 RHA to test candidate QTGs, evaluate epistasis vs. genetic heterogeneity and determine F1 population-wide QT/QTL architecture.
Our understanding of quantitative traits, which includes pharmacogenetic variations in human drug efficacy and side effects, is poor. Improving our understanding of quantitative traits and of pharmacogenetics is aided by tractable model systems, such as Saccharomyces cerevisiae. In this study, we develop a novel S. cerevisiae genetic resource population that allows for high throughput haploid association mapping and genome wide association. The health relatedness of this project lies in our study in S. cerevisiae of quantitative pharmacogenetics of a set of anti-cancer and anti-fungal drugs. Therefore, our study in S. cerevisiae of quantitative pharmacogenetics will aid our understanding of quantitative traits in general and of pharmacogenetics in particular.