Dissecting Dynamic Genetic Variation That Controls Temporal Gene Response in Yeast

Inter-individual variation in regulatory circuits controlling gene expression is a powerful source of functional information. The study of associations among genetic variants and gene expression provides important insights about cell circuitry but cannot specify whether and when potential variants dynamically alter their genetic effect during the course of response. Here we develop a computational procedure that captures temporal changes in genetic effects, and apply it to analyze transcription during inhibition of the TOR signaling pathway in segregating yeast cells. We found a high-order coordination of gene modules: sets of genes co-associated with the same genetic variant and sharing a common temporal genetic effect pattern. The temporal genetic effects of some modules represented a single state-transitioning pattern; for example, at 10–30 minutes following stimulation, genetic effects in the phosphate utilization module attained a characteristic transition to a new steady state. In contrast, another module showed an impulse pattern of genetic effects; for example, in the poor nitrogen sources utilization module, a spike up of a genetic effect at 10–20 minutes following stimulation reflected inter-individual variation in the timing (rather than magnitude) of response. Our analysis suggests that the same mechanism typically leads to both inter-individual variation and the temporal genetic effect pattern in a module. Our methodology provides a quantitative genetic approach to studying the molecular mechanisms that shape dynamic changes in transcriptional responses.Author Summary: Genetic variation is postulated to play a major role in transcriptional responses to stimulation. Such process involves two inter-related dynamic processes: first, the time-dependent changes in gene expression, and second, the time-dependent changes in genetic effects. Although the dynamics of gene expression has been extensively investigated, the dynamics of genetic effects yet remain poorly understood. Here we develop DyVER, a method that combines genotyping with time-series gene expression data to uncover the timing of transitions in the magnitude of genetic effects. We examine gene expression in yeast segregants during rapamycin response, finding several distinct ways of change in the magnitude of genetic effects over time. These include impulse-like and sustained transitions in genetic effects, acting both in cis and trans. Our findings suggest that associations of genes with the same genetic variant often occur via the same timing of state transition in genetic effects. Furthermore, the results uncover a previously unknown variant whose impulse-like temporal genetic effect suggests a novel molecular function for determining the timing rather than the magnitude of response. Our results show that steady-state association studies miss important genetic information, and demonstrate the power of DyVER to render a comprehensive map of dynamic changes in genetic effects.