Abstract
The Tibetan grey wolf (Canis lupus chanco) occupies habitats on the Qinghai-Tibet Plateau, a high altitude (>3000 m) environment where low oxygen tension exerts unique selection pressure on individuals to adapt to hypoxic conditions. To identify genes involved in hypoxia adaptation, we generated complete genome sequences of nine Chinese wolves from high and low altitude populations at an average coverage of 25× coverage. We found that, beginning about 55,000 years ago, the highland Tibetan grey wolf suffered a more substantial population decline than lowland wolves. Positively selected hypoxia-related genes in highland wolves are enriched in the HIF signaling pathway (P = 1.57E-6), ATP binding (P = 5.62E-5), and response to an oxygen-containing compound (P≤5.30E-4). Of these positively selected hypoxia-related genes, three genes (EPAS1, ANGPT1, and RYR2) had at least one specific fixed non-synonymous SNP in highland wolves based on the nine genome data. Our re-sequencing studies on a large panel of individuals showed a frequency difference greater than 58% between highland and lowland wolves for these specific fixed non-synonymous SNPs and a high degree of LD surrounding the three genes, which imply strong selection. Past studies have shown that EPAS1 and ANGPT1 are important in the response to hypoxic stress, and RYR2 is involved in heart function. These three genes also exhibited significant signals of natural selection in high altitude human populations, which suggest similar evolutionary constraints on natural selection in wolves and humans of the Qinghai-Tibet Plateau.
Highlights
Species inhabiting the Qinghai-Tibet Plateau exist in low oxygen tension environments and must adapt to low oxygen tension [1]
Understanding the genetic mechanisms that allow some individuals to live at high altitudes under hypoxic conditions can provide insight into the evolutionary constraints of adaptation to extreme conditions and the development of hypoxia-related disease in humans
Comparing the complete genome sequences of 4 grey wolves from high altitude and 5 from low altitude, we identify three candidate genes for high-altitude adaptation (EPAS1, ANGPT1, and RYR2) that show strong signals of selection
Summary
Species inhabiting the Qinghai-Tibet Plateau exist in low oxygen tension environments and must adapt to low oxygen tension [1]. Documenting the genetic mechanisms for adaptation to hypoxia can provide insights into the process of evolution under extreme conditions and hypoxia-related disease in humans Compared with their lowland counterparts, Tibetan human populations show unique adaptations, such as low hypoxic pulmonary vasoconstrictor response, high levels of blood oxygen saturation, and low hemoglobin (Hb) levels [1,2]. Past studies of complete genomes have not found these genes to be under selection in other highland vertebrates, such as deer mice [11], the yak [12], the ground tit [13], and Tibetan antelope [14] These studies have used a comparative genomic approach involving the analysis of genome sequences from a variety of divergent species. A potentially more powerful approach utilizes complete genome sequences from populations of the same species, conditional on the knowledge of their demographic history and gene flow
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