Genomic solutions for selective breeding towards increased disease resistance in sheep

Abstract

Gastrointestinal parasitism is a global problem for grazing ruminants which can be addressed sustainably by breeding animals to be more resistant to disease caused by gastrointestinal parasites. This thesis sets out to estimate the genetic parameters of parasitic infection associated with natural nematode and coccidian infections, productivity and immunological phenotypes associated with immune responses including various cytokines and immunoglobulin A (IgA). The thesis sheds light on the genetic architecture of these traits and uses animal genomic and phenotypic data to identify candidate genes associated with resistance to disease. Individual animal phenotypic data on faecal egg counts from different nematode species (Strongyles (FECS), Nematodirus (FECN) and faecal oocyst counts (FOC) from coccidian parasites were collected on Scottish Blackface lambs together with a faecal soiling score in the breach area ‘dag’ score (DAG) and live weight (LWT). Data from 3,731 Scottish Blackface sheep lambs reared on one experimental farm at SRUC (Castlelaw) were used from 2011 to 2017. Parasitic infection traits (FEC, FOC and DAG) were shown to be heritable (0.09±0.02 to 0.17±0.03) exhibiting significant genetic variation among individuals to underpin a selective breeding programme with the goal of enhancing animal resistance. FECS was shown to be positively (genetically) correlated with FECN (0.74±0.09) and FOC (0.39±0.15). Additionally, DAG was negatively (genetically) correlated with LWT (-0.33±0.15). Significant and positive associations between FECS and FECN, and FECS and FOC at around 3 months of age show that co-selection for increased resistance to different parasites is feasible. Furthermore, selection for increased resistance is unlikely to adversely affect LWT, as no significant antagonistic relationship was found between faecal counts and LWT. Significant antagonistic phenotypic correlations between LWT and DAG, and LWT and FECS/FECN indicate that the expression of manifestation of disease in lambs via the DAG score may be a meaningful indicator of the impact of parasitic burden on productivity. Additionally, whole blood stimulation assays were used to characterise the adaptive immune response of 1,040 lambs measured in 2016-2017, with either pokeweed mitogen (PWM, a lectin that non-specifically activates lymphocytes irrespectively of their antigen specificity), and Teladorsagia circumcincta (T-ci) larval antigen to activate parasite-specific T lymphocytes. The type of adaptive immune response was determined by quantifying the cytokines interferon-gamma (IFN-γ), interleukin (IL)-4, and IL-10, which relate to T-helper type 1 (Th1), Th2 and regulatory T cell (Treg) responses, respectively. T-ci specific IgA within serum was also quantified. Heritability estimates for each immune trait, and genetic and phenotypic correlations with parasitic infection and productivity phenotypes were estimated. Heritabilities of cytokine production varied from low to high (0.14±0.06 to 0.77±0.09), while IgA heritability was found to be moderate (0.41±0.09). A positive genetic correlation was found between FOC and PWM-induced IFN-γ (IFN-γ(PWM)) production (0.67±0.30) while a negative correlation was found between FOC and T-ci induced IL-10 (IL-10(T-ci)) (-0.84±0.31). Live weight was negatively, genetically correlated with IFN-γ responses (-0.54±0.18 and -0.51±0.20). Overall, IFN-γ and IL-4 responses were positively correlated (from 0.50±0.15 to 0.74±0.21), providing little evidence of cross-regulation of Th1 and Th2 immunity within individual sheep. The results show a negative correlation between IL-10(PWM) and IL-4(T.ci)¬, which might indicative of a regulatory function of IL-10 over IL-4. Furthermore, Immunoglobulin A was shown to be genetically correlated with IL-10(PWM) and IL-4(T-ci) (0.85±0.17 and 0.32±0.17, respectively). The results suggest that while selection for high IFN-γ responsiveness may be beneficial for coccidian parasite control, selection for this trait may negatively affect productivity, which will need to be considered in genetic improvement programmes. DNA samples from a subset of 1,766 animals in the study were collected and whole genome sequenced. The genotypic effects on each one of the traits described above were quantified, including the additive and dominance effects as well as the proportion of additive genetic variance due to each SNP locus. A total of 15 SNPs were associated at least at a suggestive level with FECS, FECN, DAG, IgA, PWM-induced IFN-γ and IL-4, and T-ci-induced IL-10. A total of 52 genes closely related to immune function were found to be in close proximity to these SNPs. While most of the SNPs were not significant beyond a suggestive level, this study was able to confirm the polygenic nature of both parasitic infection and immunological traits such as FEC and IgA. The results highlight several C-type lectins and killer cell lectin-like family members close to a SNP associated with FECN, and several genes encoding IL-1 cytokine family members associated with a SNP associated with IgA. There were also several potential candidate genes belonging to, or in close proximity to, the Major Histocompatibility Complex (MHC) which, due to its importance in the control of immune responses, could play important roles in resistance to such parasitic infections. These include HFE and butyrophilin coding genes, associated with IFN-γ(PWM), and IL-17 coding genes associated with IgA. The results reveal a largely complex and polygenic genetic control on resistance to parasitic infection and immunological traits in this Scottish Blackface sheep population. Lastly, these results also suggested that the studied animal traits are amenable to improvement with genomic selection

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This paper was published in Edinburgh Research Archive.

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