Abstract

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.

Public Health Relevance

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098287-02
Application #
8318601
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Eckstrand, Irene A
Project Start
2011-08-11
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$664,995
Indirect Cost
$198,422

  Institution

Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Skelly, Daniel A; Magwene, Paul M; Stone, Eric A (2016) Sporadic, Global Linkage Disequilibrium Between Unlinked Segregating Sites. Genetics 202:427-37
Skelly, Daniel A; Magwene, Paul M (2016) Population perspectives on functional genomic variation in yeast. Brief Funct Genomics 15:138-46
Strope, Pooja K; Skelly, Daniel A; Kozmin, Stanislav G et al. (2015) The 100-genomes strains, an S. cerevisiae resource that illuminates its natural phenotypic and genotypic variation and emergence as an opportunistic pathogen. Genome Res 25:762-74
Strope, Pooja K; Kozmin, Stanislav G; Skelly, Daniel A et al. (2015) 2? plasmid in Saccharomyces species and in Saccharomyces cerevisiae. FEMS Yeast Res 15:
Zhao, Ying; Strope, Pooja K; Kozmin, Stanislav G et al. (2014) Structures of naturally evolved CUP1 tandem arrays in yeast indicate that these arrays are generated by unequal nonhomologous recombination. G3 (Bethesda) 4:2259-69