Natural Variation in and Underlie Condition-Specific Growth Defects in

Despite their ubiquitous use in laboratory strains, naturally occurring loss-of-function mutations in genes encoding core metabolic enzymes are relatively rare in wild isolates of Here, we identify a naturally occurring serine auxotrophy in a sake brewing strain from Japan. Through a cross with a honey wine (white tecc) brewing strain from Ethiopia, we map the minimal medium growth defect to , which encodes 3-phosphoserine aminotransferase and is orthologous to the human disease gene, To investigate the impact of this polymorphism under conditions of abundant external nutrients, we examine growth in rich medium alone or with additional stresses, including the drugs caffeine and rapamycin and relatively high concentrations of copper, salt, and ethanol. Consistent with studies that found widespread effects of different auxotrophies on RNA expression patterns in rich media, we find that the loss-of-function allele dominates the quantitative trait locus (QTL) landscape under many of these conditions, with a notable exacerbation of the effect in the presence of rapamycin and caffeine. We also identify a major-effect QTL associated with growth on salt that maps to the gene encoding the sodium exporter, We demonstrate that the salt phenotype is largely driven by variation in the promoter, which harbors a deletion that removes binding sites for the Mig1 and Nrg1 transcriptional repressors. Thus, our results identify natural variation associated with both coding and regulatory regions of the genome that underlie strong growth phenotypes.