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


The causal path from a genetic variant to a complex phenotype such as disease progression is often not known. Studying gene expression variation is one approach to identify the mediating genes, however, it is difficult to distinguish causative from correlative genes. This becomes a challenge especially when studying developmental and physiological traits, since they involve dynamic processes contributing to the variation and only single static expression profiling is performed. As a proof of concept, we addressed this challenge here in yeast, by studying genome-wide gene expression in the presence of the causative polymorphism of MKT1 as the sole genetic variant, during the time phase when it contributes to sporulation efficiency variation. Our analysis during early sporulation identified mitochondrial retrograde signaling and nitrogen starvation as novel regulators, acting additively to regulate sporulation efficiency. Furthermore, we showed that PUF3, a known interactor of MKT1 had an independent role in sporulation. Our results highlight the role of differential mitochondrial signaling for efficient meiosis, providing insights into the factors regulating infertility. In addition, our study has implications for characterizing the molecular effects of causal genetic variants on dynamic biological processes during development and disease progression.


Vyšlo v časopise: Temporal Expression Profiling Identifies Pathways Mediating Effect of Causal Variant on Phenotype. PLoS Genet 11(6): e32767. doi:10.1371/journal.pgen.1005195
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1005195

Souhrn

The causal path from a genetic variant to a complex phenotype such as disease progression is often not known. Studying gene expression variation is one approach to identify the mediating genes, however, it is difficult to distinguish causative from correlative genes. This becomes a challenge especially when studying developmental and physiological traits, since they involve dynamic processes contributing to the variation and only single static expression profiling is performed. As a proof of concept, we addressed this challenge here in yeast, by studying genome-wide gene expression in the presence of the causative polymorphism of MKT1 as the sole genetic variant, during the time phase when it contributes to sporulation efficiency variation. Our analysis during early sporulation identified mitochondrial retrograde signaling and nitrogen starvation as novel regulators, acting additively to regulate sporulation efficiency. Furthermore, we showed that PUF3, a known interactor of MKT1 had an independent role in sporulation. Our results highlight the role of differential mitochondrial signaling for efficient meiosis, providing insights into the factors regulating infertility. In addition, our study has implications for characterizing the molecular effects of causal genetic variants on dynamic biological processes during development and disease progression.


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