Temporal Expression Profiling Identifies Pathways Mediating Effect of Causal Variant on Phenotype

<div><p>Even with identification of multiple causal genetic variants for common human diseases, understanding the molecular processes mediating the causal variants’ effect on the disease remains a challenge. This understanding is crucial for the development of therapeutic strategies to prevent and treat disease. While static profiling of gene expression is primarily used to get insights into the biological bases of diseases, it makes differentiating the causative from the correlative effects difficult, as the dynamics of the underlying biological processes are not monitored. Using yeast as a model, we studied genome-wide gene expression dynamics in the presence of a causal variant as the sole genetic determinant, and performed allele-specific functional validation to delineate the causal effects of the genetic variant on the phenotype. Here, we characterized the precise genetic effects of a functional <i>MKT1</i> allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of <i>MKT1</i> expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an <i>MKT1</i>-dependent role of novel modulators, namely, <i>RTG1/3</i>, regulators of mitochondrial retrograde signaling, and <i>DAL82</i>, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional <i>MKT1</i> allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, <i>RTG3</i>. Furthermore, our approach showed that <i>MKT1</i> contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate <i>MKT1</i>-pleiotropic effects during mitotic growth. These results uncover interesting regulatory links between meiosis and mitochondrial retrograde signaling. In this study, we highlight the advantage of analyzing allele-specific transcriptional dynamics of mediating genes. Applications in higher eukaryotes can be valuable for inferring causal molecular pathways underlying complex dynamic processes, such as development, physiology and disease progression.</p>