Whole-Genome Resequencing Reveals Genomic Signatures Underlying High-Altitude Adaptation in Ethiopian Indigenous Cattle

High-altitude environments impose severe physiological challenges on mammals, yet the genetic basis of adaptation in Ethiopian indigenous cattle remains poorly understood. Here, we analyzed whole-genome resequencing data from 70 Ethiopian indigenous cattle representing seven breeds (Abigar, Barka, Boran, Felata, Fogera, Gojjam-Highland, and Horro) distributed across elevations ranging from 523 to 3410 m, obtained from the NCBI Sequence Read Archive. After alignment to the ARS-UCD2.0 reference genome, we identified 49,196,624 high-confidence SNPs and performed population genomic analyses (PCA, phylogenetic reconstruction, and ADMIXTURE), along with genome-wide selection scans using FST and nucleotide diversity (θπ), and in silico virtual knockout of candidate genes in bovine lung single-cell transcriptomics. Population structure analyses revealed marked genetic differentiation between low- and mid-to-high-altitude populations, with substantial genetic connectivity and shared ancestry among high-altitude groups. We identified 398 candidate selective regions showing concordant FST and θπ signals, encompassing 1816 candidate genes, significantly enriched in hypoxia-related and vascular remodeling pathways (phospholipase D, Ras, ErbB, Wnt, Hedgehog). Two hub candidate genes, PIK3CA and RHOA, were prioritized; virtual perturbation of PIK3CA altered extracellular matrix, focal adhesion, and integrin networks, whereas RHOA perturbation activated immune and inflammatory programs (NF-κB, phagocytosis, chemokine pathways) with upregulation of TYROBP, IL1B, TLR4, and NLRP3. Our findings indicate that Ethiopian cattle have evolved distinct genomic signatures associated with adaptation to chronic high-altitude environments, in which PIK3CA and RHOA may represent candidate regulators associated with extracellular matrix organization and immune-related transcriptional regulation, respectively, thereby providing new insights into mammalian adaptation to extreme environments.