Natural variation in DNA sequences between individuals occurs as a result of mutations over time. Variations in DNA sequence can lead to differences in the ultimate outcome, or phenotype, of the individual carrying these genetic variants. Using the model yeast Saccharomyces cerevisiae, our group has identified regions of the genome in which differences in DNA sequence result in heritable differences in the level of specific proteins that are made by genes distinct from the changed regions. Our focus is on changes to protein levels that occur independently of changes in expression of the mRNAs that code for these proteins. We will identify the specific base-pair changes in DNA sequence that are responsible to better understand the mechanisms by which changes in DNA lead to changes in the level of other proteins. Many of the proteins we found to be regulated in this way are necessary for the uptake and catabolism of glucose by cells. We will specifically identify which DNA sequences lead to different rates of glucose uptake in order to understand how glucose transporters are regulated. We will also use mass spectrometry chemical analysis to measure the contents of cells and determine whether these changes in protein level lead to changes in the growth of cells, or alternatively whether some of these differences are a way by which cells enact metabolic homeostasis.

Natural variation in DNA sequences between individuals occurs as a result of mutations over time. Genetic variation can lead to differences in the ultimate outcome, or phenotype, of the individuals carrying these different sequences. Natural variation in some regions of the genome results in heritable differences in the level of proteins that are made by genes located far from the varying sequences, suggesting the presence of variation in regulators of protein abundance. Many of the proteins regulated in this fashion are involved in allowing cells to take up and metabolize nutrients. This project will examine the mechanisms linking genetic variation to how cells regulate the level of metabolic enzymes and other proteins in order to better predict the phenotype of cells based on DNA sequence.