Computational analysis of GAL pathway pinpoints mechanisms underlying natural variation

• Main Authors: Hong, J. (Author), Hua, B. (Author), Palme, J. (Author), Springer, M. (Author)
• Format: Article
• Language: English
• Published: Public Library of Science 2021
• Subjects: Article; biological model; biology; carbohydrate metabolism; Computational Biology; computer model; computer simulation; Computer Simulation; concentration (parameter); fungal strain; fungus isolation; Gal3 protein, S cerevisiae; GAL80 protein, S cerevisiae; galactose; Galactose; gene expression regulation; Gene Expression Regulation, Fungal; genetic variation; Genetic Variation; genetics; glucose transporter; mathematical model; Metabolic Networks and Pathways; metabolism; Models, Biological; Monosaccharide Transport Proteins; mutation; Mutation; negative feedback; nonhuman; nutrimetabolomics; phenotype; Phenotype; phenotypic variation; quantitative trait; Quantitative Trait, Heritable; repressor protein; Repressor Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae protein; Saccharomyces cerevisiae Proteins; transcription factor; Transcription Factors; yeast
• Online Access: View Fulltext in Publisher

 Quantitative traits are measurable phenotypes that show continuous variation over a wide phenotypic range. Enormous effort has recently been put into determining the genetic influences on a variety of quantitative traits with mixed success. We identified a quantitative trait in a tractable model system, the GAL pathway in yeast, which controls the uptake and metabolism of the sugar galactose. GAL pathway activation depends both on galactose concentration and on the concentrations of competing, preferred sugars such as glucose. Natural yeast isolates show substantial variation in the behavior of the pathway. All studied yeast strains exhibit bimodal responses relative to external galactose concentration, i.e. a set of galactose concentrations existed at which both GAL-induced and GAL-repressed subpopulations were observed. However, these concentrations differed in different strains. We built a mechanistic model of the GAL pathway and identified parameters that are plausible candidates for capturing the phenotypic features of a set of strains including standard lab strains, natural variants, and mutants. In silico perturbation of these parameters identified variation in the intracellular galactose sensor, Gal3p, the negative feedback node within the GAL regulatory network, Gal80p, and the hexose transporters, HXT, as the main sources of the bimodal range variation. We were able to switch the phenotype of individual yeast strains in silico by tuning parameters related to these three elements. Determining the basis for these behavioral differences may give insight into how the GAL pathway processes information, and into the evolution of nutrient metabolism preferences in different strains. More generally, our method of identifying the key parameters that explain phenotypic variation in this system should be generally applicable to other quantitative traits. Copyright: © 2021 Hong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.