Identification of variation in the sheep genome controlling gastrointestinal nematode resistance

The objective of this thesis was to identify Scottish Blackface lambs that differed in their resistance to gastrointestinal nematode (GIN) infection, characterise the host responses to infection in resistant and susceptible lambs, and identify genes and biological processes important for the difference in resistance status. An animal selection model was developed that reliably identified Scottish Blackface lambs that differed in resistance to GIN. After a controlled challenge with Teladorsagia circumcincta, resistant (low faecal egg count; FEC) animals displayed consistently lower FEC throughout the course of infection. This was largely a result of worm fecundity differences, with resistant animals containing shorter, less fecund adult females. There was also a significant correlation between the number of adult worms and FEC at slaughter. The anti-nematode response was mediated, at least in par, by IgA, with resistant animals having significantly higher levels of serum anti-nematode IgA throughout the infection. Taken together, these results indicate lower FEC in resistant Scottish Blackface lambs is primarily a result of reduced worm fecundity, although lower adult worm burden may also play a role. Gene expression in the abomasal lymph node was examined at 7 and 14 days post infection. A total of 194 and 144 genes were differentially expressed between resistant and susceptible lambs at 7 and 14 dpi respectively. At 7 dpi resistant animals appear to be generating a more effective immune response, whereas in susceptible animals this response is delayed until ~14 days post infection. The genes differentially expressed between resistant and susceptible animals were examined for evidence of selective pressure. A number of genes showed evidence of Ovis lineagespecific positive selection. Pathway analysis revealed that these genes were involved in the inflammatory response, dermatological diseases and conditions, and connective tissue disorders. This chapter represents the first large-scale comparative genomics study of selective pressure placed on the sheep genome, in particular by gastrointestinal nematodes. Association testing in the Scottish Blackface population was carried out using 57 markers in 13 candidate genes and 1000 markers in 7 genomic regions. A number of suggestive associations with FEC and weight traits were observed, however none were significant at the genome-wide level. The results from this study support the use of a panel of SNPs rather than individual SNPs for predicting nematode resistance, in agreement with the complexity of this polygenic trait