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

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 Bos grunniens and Bos javanicus 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 (>1800m) and low-altitude adapted breeds (<1500m) revealed candidate genes (ACSS2, ALDOC, EPAS1, EGLN1, NUCB2) and pathways that are putatively involved in hypoxia adaptation. Immunohistochemical, real-time PCR and CRISPR/cas9 ACSS2-knockout analyses suggests that the up-regulation of ACSS2 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 B. t. taurus 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.

对牛进行驯化及后续选育以培育适应不同环境的品种与生物学类群的过程，将祖先群体的遗传多样性拆解为多个独特的现代演化支系。针对极端环境适应性的全基因组选择，在全基因组范围内留下了可被检测到的选择信号。本研究使用42个牛品种的高密度基因型数据，明确了牦牛（Bos grunniens）与爪哇野牛（Bos javanicus）对中国瘤牛品种形成的影响——这一影响使得中国瘤牛从印度起源的瘤牛类群中发生分化。本研究同时在多数中国牛品种中发现了基因渐渗、遗传混合与基因流的相关证据。通过对比高海拔（>1800m）与低海拔（<1500m）适应性牛品种的选择信号分析，本研究揭示了一批候选基因（ACSS2、ALDOC、EPAS1、EGLN1、NUCB2）以及推测参与低氧适应的生物学通路。免疫组织化学实验、实时荧光定量PCR（real-time PCR）以及CRISPR/Cas9介导的ACSS2基因敲除分析结果表明：肝脏中ACSS2的表达上调，可通过缺氧诱导因子通路促进细胞对低氧环境的代谢适应。高海拔适应性演化涉及两步过程：在被培育为公认品种之前，中国家牛指名亚种（Bos taurus taurus）便已发生了来自高海拔适应性牦牛的等位基因渐渗，随后再经过选育作用固定相关性状。除选育作用外，与本地适应性牛种群的遗传混合及基因渐渗，同样推动了中国牛群对高海拔环境的适应。