Cell-specific gene expression plasticity in response to hypoxia promotes high-altitude adaptive evolution.

The complex and dynamic relationship between plasticity and genetic adaptation in response to a changing environment represents a longstanding and controversial debate in evolutionary biology. In particular, the molecular and cellular mechanisms underlying this relationship have not been explored. Here, we conducted a plain-to-plateau animal translocation experiment using sheep as a model. We obtained brain, heart and lung tissues from normoxia-adapted, normoxia-to-hypoxia translocated and hypoxia-adapted sheep. We generated 27 scRNA-seq and 54 snRNA-seq datasets for tissues from 27 animals and analyzed gene expression in 236,805 cells and 906,315 nuclei. We revealed cell-specific gene expression plasticity, which is overwhelmingly reversed by genetic adaptation at the cellular level. We discovered a high level of reversing plasticity specifically in immune cells, which promotes genetic adaptation through strong selection on reversing genes to achieve the required level of fitness for adaptation. We revealed a correlative pattern of cellular expression plasticity underlying acclimatization to hypoxia via a common regulatory network (the activator protein 1 family (AP-1)→hypoxia-inducible factor (HIF)∣- BHLHE41 network) and cell plasticity (e.g., microglial activation in the brain and capillary endothelial cell to endothelial-to-mesenchymal transition cell (CEC-to-EndMT) transformation in the heart) in the three organs. Additionally, time-series cellular transcriptional analysis of hypoxia-related disease genes implied a greater contribution of high-scoring cell types (e.g., alveolar type 1 cells in the lung) and plastic disease genes to the incidence and progression of these diseases. Our study generates the first cellular transcriptomes of vital organs under hypoxia acclimatization and provides new insights into hypoxia adaptation and hypoxic diseases.