Cross, JamesDudas, Sandor2021-09-132021-09-132021-09Dudas, S. (2021). Identifying genetic factors of BSE susceptibility (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.http://hdl.handle.net/1880/113862Bovine spongiform encephalopathy (BSE) is a transmissible, neurologic disease of cattle that decimated the cattle industry in many countries when it was discovered to be zoonotic. This disease is caused by a unique pathogen believed to be entirely composed of a misfolded, degradation-resistant form of a host-encoded protein. No therapies or cure currently exist for BSE, and so understanding the pathogenesis and host genes involved in this process could guide work to find ways to prevent or treat this invariably fatal disease. To identify genes playing a role in BSE susceptibility in cattle, genetic analysis was carried out on cattle that were experimentally-infected with BSE and showed variable disease outcomes. Chapter 2 explores potential genetic reasons for an abnormal outcome following oral BSE challenge. This analysis found that breed composition contributes to BSE outcomes in these experimental animals as well as in Canadian BSE field case cattle. In Chapter 3, an in-depth single nucleotide polymorphism (SNP) chip was used to genotype more than 200 experimental BSE challenged cattle with variable disease outcomes. Several genes with the potential to impact cellular calcium levels were identified as contributing to BSE susceptibility. The results also indicated that relatedness of the animals and breed composition are playing a role in the disease status. With several genomic targets identified as important, the research in Chapter 4 explored these genomic regions with targeted next generation sequencing. This analysis flagged additional SNPs in or near genes that can potentially alter the expression of genes involved in BSE pathogenesis. Experimental BSE susceptibility appears to be polygenic, with several genes each contributing a small amount, and this seems to be linked to relatedness and breed. The genes identified are highly expressed in the central nervous system and play a role in the function, maintenance, and survival of cells critical to this tissue. Several genes are linked to intracellular calcium homeostasis, a critical process playing a role in prion and other protein misfolding, neurodegenerative diseases. Additional work to decipher the contribution of the host breed and the breed of the BSE inoculum is warranted to understand the observed breed effects.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.PrionBovine Spongiform EncephalopathyGeneticsNeuroscienceVeterinary Sciencedoctoral thesis10.11575/PRISM/39188