PhD Public Seminar - Maria Mercado
PhD Public Seminar - Maria Mercado
Supervisor: Dr. Andy Fraser
Title: Investigating Natural Variation in Acute Drug Phenotypes in Caenorhabditis elegans
Date: February 28, 10:00 AM
Location: MSB 4279
Abstract:
Parasitic helminth infections affect about one-quarter of the human population and continue to negatively impact global health and agriculture, especially in developing countries. In an era of prevalent anthelmintic resistance, there is a growing need to understand the molecular and genetic factors that drive the development of these resistances. While there is an abundance of research in characterizing the chronic response to many anthelmintics, there is a gap in our knowledge of how these parasites rewire and modulate key pathways in response to acute treatment of a drug. In this dissertation, I investigate how natural genetic variation in C. elegans shapes the acute response to a variety of drugs and small molecules. While I initially focus on mapping the acute response to ivermectin, one of the most widely used anthelmintics on the market, I also explore how genetic variation may play a role in the species’ ability to conduct an alternative form of anaerobic metabolism that is induced by treatment with potassium cyanide (KCN). This rewired metabolic circuit relies on rhodoquinone (RQ), an alternative electron carrier in place of ubiquinone (Q). Since many of these parasites can survive extended periods of hypoxia within their host through alternative metabolic pathways, the resulting use of RQ-dependent metabolism (RQDM) offers a promising avenue for identifying novel targets.
Using a combination of genome-wide association mapping and bulk segregant techniques, I identify both known and novel QTL in the acute response to ivermectin, as well as a major QTL underlying variation in RQDM. Validation of the RQDM QTL identified a candidate gene in wah-1, a mitochondrial flavoprotein that is implicated in the proper regulation of electron transport chain (ETC) function and complex assembly. Taken together, this work highlights the power of quantifying C. elegans responses to acute chemical perturbations and using the changes in their locomotive phenotypes over time to map phenotypic variation and identify potentially causal genetic variants.