Individuals of the same species exhibit extensive phenotypic variation. The genetic component of this variation is caused by variants in the DNA code that differ between individuals. What are the molecular mechanisms through which these natural variants produce their effects? The goal of this project is to identify causal genetic variants that underlie natural variation between individuals, and to gain a molecular understanding of how these genetic variants affect the continuum of phenotypic variation.
This project focuses on differences in the sporulation efficiency of natural isolates of the baker's yeast, Saccharomyces cerevisiae. Sporulation efficiency is a trait that is linked intrinsically to the metabolic activities of yeast. Building on previous work in this system, the principal investigator's laboratory will identify genetic variants responsible for differences in sporulation efficiency, assess the magnitude of their effects, and determine their interactions with each other. Through these experiments the spectrum of important genetic variants will be better understood. With causal variants in hand, the molecular mechanisms through which natural genetic variants exert their effects on phenotypic variation will then be investigated. Furthermore, genetic analyses will be combined with a thermodynamic model of natural variation in yeast sporulation. This model will then be employed to guide experiments to understand how natural variants affect the key molecular interactions within the sporulation pathway. It is anticipated that these experiments will uncover the mechanisms underlying the effects of these natural genetic variants.
Understanding the molecular basis of complex, quantitative natural variation is a major challenge in Genetics. Such an understanding is key to improving models of evolution. Understanding variation in yeast metabolism in particular will have immediate practical benefits, such as an improved ability to rationally design strains for biofuel production.
Broader impacts:
Part of the broader impacts of this research will come from the experiments themselves. The experiments span a range of disciplines from statistical genetics to molecular biology to thermodynamics. The students and postdocs who execute the experiments are necessarily interdisciplinary. They must be facile at both computational and experimental biology. The training of these students will advance the NSF's mission to train scientists who cut across disciplines.
The principal investigator also participates in the Opportunities in Genomic Research (OGR) program run through the Washington University Genome Sequencing Center, and in the BioMedRap program run through the Division of Biological and Biomedical Sciences. As part of these programs each year the laboratory hosts undergraduate minority students. The students are trained and mentored by the principal investigator and by members of the lab. The students present their work in lab meetings and give oral presentations at a symposium when they leave the lab. The programs also provide career counseling and tutoring for the GRE exams. Some of the experiments in this project involve simple genetic crosses which provide novice undergraduates a route to make progress during their time in the lab. These crosses are an excellent way to teach Mendel's laws of segregation and independent assortment, as well as involving undergraduates in research. At the end of each year an outside consultant is brought in to assess the program, make suggestions, and track the progress of students who have been through the program.
