Deciphering genomic basis of unique adaptation of Ladakhi cattle to Trans-Himalayan high-altitude region of Leh-Ladakh in India

In this study, whole genome sequence data of Ladakhi cattle from high altitude region of Leh-Ladakh and Sahiwal cattle from arid, semi-arid tropical region were compared. To gain a deeper understanding of the selective footprints in the genomes of Ladakhi and Sahiwal cattle, two strategies namely run of homozygosity (ROH), and fixation index (F_ST) were employed. A total of 975 and 1189 ROH regions were identified in Ladakhi and Sahiwal cattle, respectively. Several genes associated with high-altitude adaptation were enriched in many of the ROH hot spots in genome of Ladakhi cattle such as; HIF1A, VEGFA, VEGFC, EPHB1, ZEB1, CAV3, TEK, SENP2, GATA6, RAD51 and ADAMTSL4 etc.. The F_ST value of 0.32 also indicated strong genetic differentiation between Ladakhi and Sahiwal cattle. A total of 3616 genomic regions were identified to be under selection in the two cattle breeds. The F_ST selection signature analysis led to identification of several genes such as HIF1A, VEGFC, ZEB1, SOD1, EGLN3, EPAS1, ZNF, DYSF, ADAM, SENP2, MMP16, and CDK2 etc., that could be associated with high altitude adaptation in Ladakhi cattle. Additionally, several pathways, including HIF1A signaling pathway, VEGF signaling pathway, DNA repair, and angiogenesis, associated with adaptation to high-altitude hypoxic environments in Ladakhi cattle. The phylogenetic, PCA and admixture analysis separated the individuals of Ladakhi and Sahiwal cattle according to their geographic origin. In the present study, the WGS data has helped to identify key genes and genic regions that contribute to high altitude adaptation in Ladakhi cattle.