Natural Genetic Variation Underlies Chemotherapeutic Drug Responses in Caenorhabditis elegans

Brady, Shannon Colleen

doi:https://doi.org/10.21985/n2-0a7z-wb22

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Natural Genetic Variation Underlies Chemotherapeutic Drug Responses in Caenorhabditis elegans

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Individuals within a species vary in complex phenotypes, such as responses to toxins. This drug-response variation causes patients who are treated with the same medicine to experience a range of side effects, ultimately decreasing the efficacy of some drugs. Particular genetic variants among individuals might contribute to differential drug responses, and these biomarkers could be used to predict treatment outcomes. However, detecting these genetic variants is difficult in human populations because of statistical power limitations and confounding environmental variation. The model organism Caenorhabditis elegans can be used to understand how genetic variants underlie drug responses across divergent strains. In this dissertation, I describe how I used linkage mapping to detect quantitative trait loci (QTL) that contribute to toxin-response differences between two divergent strains, N2 and CB4856. First, I discuss a study in which I identified a nematode-specific gene, scb-1, that causes differences in responses to the chemotherapeutic drug bleomycin. Variation in expression of this gene likely underlies bleomycin-response differences across recombinant lines derived from the N2 and CB4856 strains. Additionally, I localized epistatic regions that contribute to bleomycin hypersensitivity. Next, I discuss the identification of regions of the genome that are enriched for toxin-response QTL. The detection of these hotspots suggests that pleiotropic loci might modulate drug responses in C. elegans. I also discuss the relative contributions of additive and interacting loci toward responses to each of these toxins. The results of these two projects suggest that toxin resistance might be selected in nature, especially in the case of bleomycin. My work on linkage mapping in C. elegans highlights the power of this system to detect additive and epistatic QTL and frames the importance of these findings in the light of evolution.

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