GENETIC AND BIOLOGICAL DETERMINANTS OF RESPIRATORY DISEASE SUSCEPTIBILITY
Title: Scrapie resistance in ARQ sheep
Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 8, 2008
Publication Date: July 16, 2008
Citation: Laegreid, W.W., Clawson, M.L., Heaton, M.P., Green, B.T., Orourke, K.I., Knowles Jr, D.P. 2008. Scrapie resistance in ARQ sheep. Journal of Virology. 82(20):10318-10320. Available: DOI:10.1128/JVI.00710-08.
Interpretive Summary: Transmissible spongiform encephalopathies (TSEs) are a class of fatal neurodegenerative disorders that occur in humans, ruminants, cats and mink. TSEs are known as prion diseases because they all involve abnormally or irregularly folded prion proteins. Classical scrapie is a TSE of sheep and variation in the ovine prion gene correlates with susceptibility and resistance to this disease. Individuals with the ARR variant of the prion protein are considered resistant, while those with the VRQ and ARQ variants are considered susceptible. However, some sheep with the ARQ variant do not develop clinical scrapie following exposure. Additionally, the ARQ variant has recently been found to have nine genetic subtypes within the prion gene. These observations indicated that a genetic subset of ARQ sheep may actually have resistance to scrapie. In this study, ARQ sheep with known survival curves following classical scrapie challenge were analyzed for an association between their ARQ genetic subtypes and survival time. Individuals with at least one copy of a particular ARQ genetic subtype showed significantly prolonged survival and those with two copies of the subtype (homozygous) never developed scrapie. The implicated ARQ subtype has the amino acid threonine at position 112 of the prion protein (T112) rather than a methionine. Prion proteins with T112 are known to resist folding into the abnormal form of scrapie. Thus, this study shows that T112 is a marker for ARQ sheep that are resistant to classical scrapie and provides a possible mechanism for that resistance. These results have implications for scrapie eradication programs where ARQ sheep have previously been considered as a homogeneous group, leading to potentially unnecessary losses of economically important germplasm.
Variation in the ovine prion protein amino acid sequence influences scrapie progression, with sheep homozygous for A**136 R**154 Q**171 considered susceptible. This study examined the association of survival time of scrapie-exposed ARQ sheep with variation elsewhere in ovine prion gene. Four single nucleotide polymorphism alleles were associated with prolonged survival. One nonsynonymous allele (T112) associated with an additional 687 days survival to scrapie-exposed sheep compared to M112 sheep (odds ratio 42.5, P=0.00014). The only two sheep homozygous for T112 (TARQ) did not develop scrapie, suggesting that the allelic effect may be additive. These results provide evidence that TARQ sheep are genetically resistant to development of classical scrapie.