Abstract
Gastrointestinal nematodes (GIN) pose a severe threat to sheep production worldwide. Anthelmintic drug resistance coupled with growing concern regarding potential environmental effects of drug use have demonstrated the necessity of implementing other methods of GIN control. The aim of this study was to test for genetic variants associated with resistance or susceptibility to GIN in Katahdin sheep to improve the current understanding of the genetic mechanisms responsible for host response to GIN. Linear regression and case-control genome-wide association studies were conducted with high-density genotype data and cube-root transformed weaning fecal egg counts (tFEC) of 583 Katahdin sheep. The case-control GWAS identified two significant SNPs (P-values 1.49e-08 to 1.01e-08) within introns of the gene adhesion G protein-coupled receptor B3 (ADGRB3) associated with lower fecal egg counts. With linear regression, four significant SNPs (P-values 7.82e-08 to 3.34e-08) were identified within the first intron of the gene EGF-like repeats and discoidin domains 3 (EDIL3). These identified SNPs were in very high linkage disequilibrium (r 2 of 0.996–1), and animals with alternate homozygous genotypes had significantly higher median weaning tFEC phenotypes compared to all other genotypes. Significant SNPs were queried through public databases to identify putative transcription factor binding site (TFBS) and potential lncRNA differences between reference and alternate alleles. Changes in TFBS were predicted at two SNPs, and one significant SNP was found to be within a predicted lncRNA sequence with greater than 90% similarity to a known lncRNA in the bovine genome. The gene EDIL3 has been described in other species for its roles in the inhibition and resolution of inflammation. Potential changes of EDIL3 expression mediated through lncRNA expression and/or transcription factor binding may impact the overall immune response and reduce the ability of Katahdin sheep to control GIN infection. This study lays the foundation for further research of EDIL3 and ADGRB3 towards understanding genetic mechanisms of susceptibility to GIN, and suggests these SNPs may contribute to genetic strategies for improving parasite resistance traits in sheep.
Highlights
Gastrointestinal nematodes (GIN) are arguably considered to be one of the greatest health and economic threats to small ruminant production worldwide (Karrow et al, 2014; Escribano et al, 2019; Hassan et al, 2019; Chitneedi et al, 2020)
With the linear regression (LR) recessive inheritance model, four significant SNPs were identified within the first intron of the gene epidermal growth factor (EGF)-like repeats and discoidin domains 3 (EDIL3), known as developmental endothelial locus-1 (DEL-1) (Figure 1)
The gene EDIL3 encodes the protein epidermal growth factor (EGF)-like repeat and discoidin I-like domain-containing protein 3, a secreted glycoprotein which acts as an integrin ligand and has non-redundant roles in multiple stages of the immune response, including myelopoiesis, anti-inflammatory regulation of neutrophil infiltration and resolution of inflammation (Mitroulis et al, 2017; Chen et al, 2018; Hajishengallis and Chavakis 2019; Li et al, 2021)
Summary
Gastrointestinal nematodes (GIN) are arguably considered to be one of the greatest health and economic threats to small ruminant production worldwide (Karrow et al, 2014; Escribano et al, 2019; Hassan et al, 2019; Chitneedi et al, 2020). GIN infection contributes to substantial economic losses in both meat and dairy production (Charlier et al, 2020). Sheep that are susceptible to GIN may harbor thousands of worms and contribute to the continued contamination of parasite eggs into the environment (McRae et al, 2015); depending on the helminth species, individual female worms may produce between 100–15,000 eggs per day (Roeber et al, 2013; Emery et al, 2016). Sheep tend to become more tolerant of GIN infection (McRae et al, 2015; Benavides et al, 2016). For this reason, young animals are frequently used when examining potential genetic differences in susceptibility and resistance to GIN parasites
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