Genomic Exploration of Infectious and Genetic Disease in Canids

Abstract

KENNERLY, ERIN MICHELLE. Genomic Explorations of Infectious and Genetic Disease in Canids. (Under the direction of Gregory C. Gibson) Wild and domesticated dogs have long been of interest to humans as both companions and working animals. Selection for desired traits like behavior, size, and shapes has resulted in over 350 genetically distinct breeds, but inevitably less desirable traits like susceptibility to disease and congenital genetic disorders have been carried through in certain breeds of dogs. Because of their genetic history and close relation to humans, canids are an ideal model system to study the interaction between environment and genetics in the promotion of complex diseases and disorders. In this thesis, I explore the use of emerging genomic tools to study infectious disease, the effect of habitat change in red wolves, and pharmacogenetic response to epilepsy treatment across breeds of dogs. In the first study, heterologous microarrays were used to examine the effect of captive and free ranging habitats on peripheral blood gene expression in red wolves. An algorithm was developed to simultaneously estimate both genetic and environmental factors that contribute to differential gene expression profiles. The first two principal components of overall expression variation defined effects predominantly of habitat and genetic relatedness. Genes associated with stress pathways were the most differentially expressed as determined by gene ontology analysis. I applied microarray technology to define the extent of immune related changes in gene expression associated with a hookworm infection in beagle pups. Measured immunoglobulin levels indicated an active immune response, and gene expression profile changes involving 305 transcripts were evident between time points. However gene expression changes associated with both Th1 and Th2 immune response were evident preventing a clear characterization of the immune response associated with a hookworm infection. Lastly, I use a pharmacogenetic approach to identify genetic variation associated with Phenobarbital drug response in epileptic dogs. Using 384 genetic markers in 30 genes in a case control study between Phenobarbital responsive and nonresponsive epileptic dogs. I identified associations in SCN2A2, KCNQ3, ABCC4, GABRA2 and Epoxide hydrolase gene, which may be predictive of drug response. Because of the strong effects of breed structure, these should be studied more thoroughly before they are considered as the basis of a genetic test for drug response. As with many genomic experiments these studies provide insight and the starting point for further studies into the relationship between genes and phenotypes.