The genetics of transcriptional responses to stress in yeast

Alteration of gene expression levels is a key cellular strategy for responding to internal and external challenges. While expression quantitative trait loci (eQTLs) are known to influence steady-state transcript levels, their role in mediating rapid physiological transitions remains poorly understood. Using a high-throughput, “one-pot” single-cell RNA-seq approach, we mapped eQTLs in yeast immediately before and after two acute environmental shifts: salt perturbation of actively cycling cells and nutrient repletion of cells after one week of starvation. We defined and characterized major cell populations in different physiological states and identified context-specific eQTLs as well as genetic determinants of state occupancy. We focused on distant eQTL hotspots, which capture the majority of expression heritability in yeast crosses. We found that the effects of hotspots on gene expression are highly dynamic in response to acute environmental perturbations, and that they influence biological processes directly relevant to adaptation to the new conditions. By integrating gene set enrichment analysis with computational prediction of variant effects, we prioritized candidate causal genes and variants underlying the hotspots. We observed extensive overlaps between hotspot loci, physiological state QTL, and fitness QTL. These findings reveal how regulatory variation rapidly modulates cellular responses to environmental changes, suggesting a mechanistic bridge between genetic variation, gene expression, and organismal fitness.