Changes in gene regulation may play an important role in both adaptive evolution and genetic disease. Current knowledge of cis-regulatory sequences is based largely on canonical transcription factor binding sites that affect gene expression levels or developmental patterns at specific time-points. Yet, temporal changes in gene expression may often be more important to fitness than steady-state levels. The goal of the proposed research is to understand which noncoding mutations alter gene expression and which changes in gene expression have phenotypic consequences. To accomplish this goal, cis-regulatory sequence function and evolution will be investigated in budding yeast by first identifying cis-regulatory changes that affect fitness and then measuring their effects on gene expression. Fitness assays will be used because they require no assumption as to which mutations alter cis-regulatory sequence function, or how they affect gene expression. Changes in cis-regulatory sequences that affect fitness will be related to canonical binding sites and to their effects on expression dynamics and steady-state levels. Dissection of these relationships will enhance our ability to identify cis- regulatory mutations that underlie phenotypic variation and will help define the role of expression dynamics in the evolution of gene regulation.

Public Health Relevance

Mutations that alter gene regulation are thought to contribute to complex traits, including human disease. The proposed research will use budding yeast as a model system to improve our ability to identify regulatory mutations with phenotypic consequences and understand how their effects are mediated.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM080669-06A1
Application #
8584011
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Eckstrand, Irene A
Project Start
2007-08-10
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$288,800
Indirect Cost
$98,800
Name
Washington University
Department
Genetics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Swain Lenz, Devjanee; Riles, Linda; Fay, Justin C (2014) Heterochronic meiotic misexpression in an interspecific yeast hybrid. Mol Biol Evol 31:1333-42
Hyma, Katie E; Fay, Justin C (2013) Mixing of vineyard and oak-tree ecotypes of Saccharomyces cerevisiae in North American vineyards. Mol Ecol 22:2917-30
Fay, Justin C (2013) The molecular basis of phenotypic variation in yeast. Curr Opin Genet Dev 23:672-7
Fay, Justin C (2011) Weighing the evidence for adaptation at the molecular level. Trends Genet 27:343-9
Chun, Sung; Fay, Justin C (2011) Evidence for hitchhiking of deleterious mutations within the human genome. PLoS Genet 7:e1002240
Chun, Sung; Fay, Justin C (2009) Identification of deleterious mutations within three human genomes. Genome Res 19:1553-61
Kim, Hyun Seok; Fay, Justin C (2009) A combined-cross analysis reveals genes with drug-specific and background-dependent effects on drug sensitivity in Saccharomyces cerevisiae. Genetics 183:1141-51
Kim, Hyun Seok; Huh, Juyoung; Fay, Justin C (2009) Dissecting the pleiotropic consequences of a quantitative trait nucleotide. FEMS Yeast Res 9:713-22