Transcriptomics and Systems Biology of High Altitude Disease in Angus Cattle

High-altitude (>1800m) disease is a challenging problem in beef and dairy cattle. The disease is a consequence of hypoxia-induced right ventricular (RV) heart failure as per vascular inflammation of the pulmonary artery (PA) and hypertension. Pulmonary artery pressure has high heritability of 0.34 ± 0.05; however, minimal information exists of the genes involved. The transcriptomes of left and right ventricle, pulmonary artery, aorta, muscle, and lung were examined in samples harvested from fattening-yearling Angus steers phenotyped to be of low or high pulmonary arterial pressures (LPAP and HPAP; n = 10/group). Gene expression analyses from RNA-Seq data revealed the highest number of differentially expressed genes between groups were in RV (n=1,394) and aorta (n=1,173; p<0.01 and Fold-change>2). Also, splice variant analyses revealed the highest differential expression in RV (n=555), aorta (n=547) and PA (n=152; p<0.01 and Fold-change>2) between LPAP and HPAP animals. Pathway analyses of RV differentially expressed genes suggested importance of IL-8/IL-10 signaling, leukocyte extravasation, factors promoting cardiogenesis, coagulation, thrombin and cardiac hypertrophy signaling. Systems biology analyses of RV data suggested that 101 genes were acting as key regulators of 705 genes differentially expressed between LPAP and HPAP steers. Most of the key regulators had roles in angiogenesis and atherosclerosis, cardiomyopathy (NFATC1), movement of leukocytes and neutrophils (OLR1, PLAUR), failure of heart (CTGF), hypertrophy of heart ventricle (TREM1, GATA2, P38-MAPK) and vascularization (SYVN1). These approaches helped identify splice variants corresponding to key regulator genes in a polygenic disease induced by high-altitude in Angus cattle.