Polymorphisms and Splice Variants in a Polygenic Disease Induced By High-Altitude in Fattening Angus Steers Using RNA-Sequencing and Systems Biology

High-altitude (>1800m) disease is a challenging problem for beef 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. An indicator trait of this condition, pulmonary arterial pressure (PAP) has moderate to high heritability (0.2-0.4) when measured in yearling cattle; however, knowledge of candidate genes that can be used in genetic improvement for this trait and physiological-disease condition are minimal. The transcriptomes of RV,LV,PA, aorta, muscle, and lung were examined from fattening-yearling Angus steers phenotyped to be of low or high PAP (LPAP and HPAP;n=10/group). RNA-Seq data and analyses revealed the highest number of differentially expressed genes (DEG) between groups were in RV (n=1,394) and aorta (n=1,173;p<0.01;Fold-change>2). Also, splice variant analyses revealed the highest DEG in RV (n=555), aorta (n=547) and PA (n=152) between LPAP and HPAP animals. Pathway analyses of DEG in RV suggested importance of IL-8/IL-10 signaling, factors promoting cardiogenesis, coagulation, thrombin and cardiac hypertrophy. Systems biology analyses of RV data suggested that 101 genes were acting as key transcriptional regulators of 705 DEG between LPAP and HPAP steers. Most of the key regulators had roles in cardiomyopathy (NFATC1), movement of leukocytes/neutrophils (OLR1,PLAUR), failure of heart (CTGF), ventricle hypertrophy (TREM1,GATA2,P38-MAPK) and vascularization (SYVN1). Several SNP variants segregated specifically in either the LPAP or HPAP animals in key regulator genes. The integration of structural and functional genomic data associated with high-altitude disease will help to develop more robust approaches for genetic selection in beef cattle.