Abstract
Incidence of angular limb deformities (ALD) have been described in many species of livestock and companion animals. Young, rapidly growing animals are at an increased risk for developing ALD. Although work has been done to identify the casual genetic basis of ALD, bone deformities are likely influenced by the environment, making clear genetic answers challenging to discover. Rambouillet rams from Wyoming, North Dakota and South Dakota annual ram performance tests have been observed to develop limb abnormalities consistent with ALD. Historical incidence of ALD in test rams has ranged from 3 to 18%. A genome-wide association study (GWAS) was conducted with 342 ram-test animals, including 40 ALD-affected rams and 302 unaffected rams collected over three consecutive years. Significant markers were identified within the genes tetraspanin 18 (TSPAN18; p-value = 4.87e-07) and neuregulin 3 (NRG3; p-value = 8.06e-07). In mice, Tspan18 has been proposed as a regulator of endothelial cell Orai1/Ca
2+
signaling. Orai1 has also been shown to mediate osteogenic differentiation via the bone morphogenic protein signaling pathway, which suggests the possibility for TSPAN18 involvement in differentiation of chondrocytes and osteocytes. The gene NRG3 is a member of the neuregulin family, which encodes ligands for epidermal growth factor receptors ERBB3 and ERBB4. The epidermal growth factor receptor system has described roles in the regulation of proliferation and differentiation of osteoblast, chondrocyte and osteoclast cells. Identifying genetic risk factors for ALD has the potential to improve animal welfare and animal production in at-risk breeds. This study proposes TSPAN18 and NRG3 as targets for further research towards identifying genetic risk factors for ALD in Rambouillet sheep of the NW United States.