title: Temporal expression profiling identifies pathways mediating effect of causal variant on phenotype.
abstract: 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 MKT1 allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of MKT1 expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an MKT1-dependent role of novel modulators, namely, RTG1/3, regulators of mitochondrial retrograde signaling, and DAL82, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional MKT1 allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, RTG3. Furthermore, our approach showed that MKT1 contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate MKT1-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.
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors.forename: Saumya
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Radhakrishnan
authors.affiliation: Gene Center, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Pandu
authors.initials: P
authors.lastname: Raharja-Liu
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors.forename: Gen
authors.initials: G
authors.lastname: Lin
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany; Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America; Stanford Genome Technology Center, Stanford University, Palo Alto, California, United States of America.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Steinmetz
authors.affiliation: Gene Center, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Julien
authors.initials: J
authors.lastname: Gagneur
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Sinha
mesh_terms: D000483:Alleles; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D016681:Genome, Fungal; D008540:Meiosis; D008957:Models, Genetic; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D013172:Spores, Fungal / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D015533:Transcriptional Activation; D059467:Transcriptome
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C082970:DAL82 protein, S cerevisiae; C092218:MKT1 protein, S cerevisiae; C104438:RTG3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators