Introgression, admixture and selection facilitate genetic adaptation to high-altitude environments in Chinese cattle

<p>Domestication and subsequent selection of cattle to form breeds and biological types that can adapt to different environments partitioned ancestral genetic diversity into distinct modern lineages. Genome-wide selection particularly for adaptation to extreme environments left detectable signatures genome-wide. We used high-density genotype data for 42 cattle breeds and identified the influence of <em>Bos grunniens</em> and <em>Bos javanicus</em> on the formation of Chinese indicine breeds that led to their divergence from India-origin Zebu. We also found evidence for introgression, admixture, and migration in most of the Chinese breeds. Selection signature analyses between high-altitude (&gt;1800m) and low-altitude adapted breeds (&lt;1500m) revealed candidate genes (<em>ACSS2</em>, <em>ALDOC,</em> <em>EPAS1</em>,<em> EGLN1, NUCB2</em>) and pathways that are putatively involved in hypoxia adaptation. Immunohistochemical, real-time PCR and CRISPR/cas9 <em>ACSS2</em>-knockout analyses suggests that the up-regulation of <em>ACSS2</em> expression in the liver promotes the metabolic adaptation of cells to hypoxia via the hypoxia-inducible factor pathway. High altitude adaptation involved the introgression of alleles from high-altitude adapted Yaks into Chinese <em>B. t. taurus </em>prior to their formation into recognized breeds and followed by selection. In addition to selection, adaptation to high altitude environments has been facilitated by admixture and introgression with locally adapted cattle populations.</p>