Grant: Project Grant

High-throughput sequencing has accelerated the pace at which gene-disease associations are established. However, we need to start addressing the next challenge: why two individuals with the same rare disease-causing variant may have different clinical presentation of the disease? Genetic modifiers are factors that can either alleviate or exacerbate the severity of the disease-causing variants. Identification of such modifiers provides important information about the biological functions of human disease genes and mechanistic role they play in the development of the disease. This in turn allows for better disease outcome prediction, planned prevention protocols and development of targeted treatments. Complexity of human biology makes it difficult to address this challenge effectively; however, fundamental aspects of human disease had been in past and will be in future efficiently addressed through analysis of orthologous genes using experimentally tractable model organisms. The goal of my research is to combine powers of unbiased mutagen-induced modifier screens using Caenorhabditis elegans model and whole genome sequencing (WGS) in order to accelerate discovery of new disease-associated genes, modifiers of known disease-associated genes and potential Orphan drug targets. To reach these goals, I will: (1) isolate modifiers by performing forward genetic screens on orthologous genes implicated in human rare disorders; (2) identify molecular basis of modifiers using WGS, state-of-the-art bioinformatics and molecular genetics techniques, and (3) characterize the phenotypes and mode of action of the genetic modifiers. This research is of high importance as it will establish C. elegans as a model organism for systematic high-throughput heritable genetic modifier screens with high potential for direct impact on diagnosis, prognosis and treatment of rare diseases, in particular the ones with no treatment options (currently >95% of rare diseases).