Explore the vast range of titles available.

High altitude represents some of the most extreme environments worldwide. The genetic changes underlying adaptation to such environments have been recently identified in multiple animals but remain unknown in horses. Here, we sequence the complete genome of 138 domestic horses encompassing a whole altitudinal range across China to uncover the genetic basis for adaptation to high-altitude hypoxia. Our genome data set includes 65 lowland animals across ten Chinese native breeds, 61 horses living at least 3,300 m above sea level across seven locations along Qinghai-Tibetan Plateau, as well as 7 Thoroughbred and 5 Przewalski’s horses added for comparison. We find that Tibetan horses do not descend from Przewalski’s horses but were most likely introduced from a distinct horse lineage, following the emergence of pastoral nomadism in Northwestern China ∼3,700 years ago. We identify that the endothelial PAS domain protein 1 gene (EPAS1, also HIF2A) shows the strongest signature for positive selection in the Tibetan horse genome. Two missense mutations at this locus appear strongly associated with blood physiological parameters facilitating blood circulation as well as oxygen transportation and consumption in hypoxic conditions. Functional validation through protein mutagenesis shows that these mutations increase EPAS1 stability and its hetero dimerization affinity to ARNT (HIF1B). Our study demonstrates that missense mutations in the EPAS1 gene provided key evolutionary molecular adaptation to Tibetan horses living in high-altitude hypoxic environments. It reveals possible targets for genomic selection programs aimed at increasing hypoxia tolerance in livestock and provides a textbook example of evolutionary convergence across independent mammal lineages.

The transcription factor HIF1A is activated by disturbed blood flow in arteries and contributes to early atherosclerosis by promoting endothelial cell (EC) glycolysis and inflammation. The related molecule EPAS1 (HIF2A) co-operates with HIF1A in several systems, but its role in atherogenesis is unknown. Here we used murine models and cultured human endothelial cells to analyse the role of EPAS1 in atherosclerosis. En face staining of EC in the murine aorta revealed that EPAS1 is enriched at sites of disturbed blood flow that are prone to atherosclerosis initiation. EC-specific deletion of Epas1 (Epas1EC-KO) led to enhanced lesion formation in a murine model of hypercholesterolemia, indicating an atheroprotective function. Mechanistically, gene silencing in cultured ECs revealed that EPAS1 maintains EC proliferation by inducing fatty acid beta-oxidation. Consistently, single cell RNAseq in Epas1EC-KO mice revealed that Epas1 is required to maintain an EC cluster enriched for regulators of cell proliferation. We conclude that EPAS1 reduces atherosclerosis initiation at sites of disturbed flow by maintaining EC proliferation by inducing regulators of cell cycle and fatty acid metabolism. This endothelial pathway has implications for therapeutic strategies to prevent early atherosclerosis.Conflict of InterestNO

Recent studies suggest that admixture with archaic hominins played an important role in facilitating biological adaptations to new environments. For example, interbreeding with Denisovans facilitated the adaptation to high-altitude environments on the Tibetan Plateau. Specifically, the EPAS1 gene, a transcription factor that regulates the response to hypoxia, exhibits strong signatures of both positive selection and introgression from Denisovans in Tibetan individuals. Interestingly, despite being geographically closer to the Denisova Cave, East Asian populations do not harbor as much Denisovan ancestry as populations from Melanesia. Recently, two studies have suggested two independent waves of Denisovan admixture into East Asians, one of which is shared with South Asians and Oceanians. Here, we leverage data from EPAS1 in 78 Tibetan individuals to interrogate which of these two introgression events introduced the EPAS1 beneficial sequence into the ancestral population of Tibetans, and we use the distribution of introgressed segment lengths at this locus to infer the timing of the introgression and selection event. We find that the introgression event unique to East Asians most likely introduced the beneficial haplotype into the ancestral population of Tibetans around 48,700 (16,000–59,500) y ago, and selection started around 9,000 (2,500–42,000) y ago. Our estimates suggest that one of the most convincing examples of adaptive introgression is in fact selection acting on standing archaic variation.

Abstract Population genomic analyses of high-altitude humans and other vertebrates have identified numerous candidate genes for hypoxia adaptation, and the physiological pathways implicated by such analyses suggest testable hypotheses about underlying mechanisms. Studies of highland natives that integrate genomic data with experimental measures of physiological performance capacities and subordinate traits are revealing associations between genotypes (e.g., hypoxia-inducible factor gene variants) and hypoxia-responsive phenotypes. The subsequent search for causal mechanisms is complicated by the fact that observed genotypic associations with hypoxia-induced phenotypes may reflect second-order consequences of selection-mediated changes in other (unmeasured) traits that are coupled with the focal trait via feedback regulation. Manipulative experiments to decipher circuits of feedback control and patterns of phenotypic integration can help identify causal relationships that underlie observed genotype–phenotype associations. Such experiments are critical for correct inferences about phenotypic targets of selection and mechanisms of adaptation.

The high-altitude transverse valleys [>3,000 m above sea level (masl)] of the Himalayan arc from Arunachal Pradesh to Ladahk were among the last habitable places permanently colonized by prehistoric humans due to the challenges of resource scarcity, cold stress, and hypoxia. The modern populations of these valleys, who share cultural and linguistic affinities with peoples found today on the Tibetan plateau, are commonly assumed to be the descendants of the earliest inhabitants of the Himalayan arc. However, this assumption has been challenged by archaeological and osteological evidence suggesting that these valleys may have been originally populated from areas other than the Tibetan plateau, including those at low elevation. To investigate the peopling and early population history of this dynamic high-altitude contact zone, we sequenced the genomes (0.04×–7.25×, mean 2.16×) and mitochondrial genomes (20.8×–1,311.0×, mean 482.1×) of eight individuals dating to three periods with distinct material culture in the Annapurna Conservation Area (ACA) of Nepal, spanning 3,150–1,250 y before present (yBP). We demonstrate that the region is characterized by long-term stability of the population genetic make-up despite marked changes in material culture. The ancient genomes, uniparental haplotypes, and high-altitude adaptive alleles suggest a high-altitude East Asian origin for prehistoric Himalayan populations.

Objectives Chondrocyte ferroptosis contributes to osteoarthritis (OA) progression, and D‐mannose shows therapeutic value in many inflammatory conditions. Here, we investigated whether D‐mannose interferes in chondrocyte ferroptotic cell death during osteoarthritic cartilage degeneration. Materials and methods In vivo anterior cruciate ligament transection (ACLT)‐induced OA mouse model and an in vitro study of chondrocytes in an OA microenvironment induced by interleukin‐1β (IL‐1β) exposure were employed. Combined with Epas1 gene gain‐ and loss‐of‐function, histology, immunofluorescence, quantitative RT‐PCR, Western blot, cell viability and flow cytometry experiments were performed to evaluate the chondroprotective effects of D‐mannose in OA progression and the role of hypoxia‐inducible factor 2 alpha (HIF‐2 α) in D‐mannose‐induced ferroptosis resistance of chondrocytes. Results D‐mannose exerted a chondroprotective effect by attenuating the sensitivity of chondrocytes to ferroptosis and alleviated OA progression. HIF‐2α was identified as a central mediator in D‐mannose‐induced ferroptosis resistance of chondrocytes. Furthermore, overexpression of HIF‐2α in chondrocytes by Ad‐Epas1 intra‐articular injection abolished the chondroprotective effect of D‐mannose during OA progression and eliminated the role of D‐mannose as a ferroptosis suppressor. Conclusions D‐mannose alleviates osteoarthritis progression by suppressing HIF‐2α‐mediated chondrocyte sensitivity to ferroptosis, indicating D‐mannose to be a potential therapeutic strategy for ferroptosis‐related diseases. D‐Mannose effectively alleviates osteoarthritis progression by suppressing cartilage degeneration. D‐mannose protects osteoarthritic chondrocytes by attenuating sensitivity to ferroptosis. HIF‐2α is vital in potentiating the susceptibility of chondrocytes to ferroptosis. HIF‐2α is a central mediator in D‐mannose‐induced ferroptosis resistance.

The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha–beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 h of hypoxia in primary endothelial cells and then is dramatically reduced by 8 h. In contrast, HIF-2 is maximal at 8 h and remains elevated up to 24 h. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α ( HIF1A ) compared to HIF-2α ( EPAS1 ) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia.

Age-associated defects in T cell-mediated immunity can increase the risk of cancers, but how aging influences adoptive T-cell therapy (ACT) for cancers remains unclear. Here, using a mouse model of melanoma, we demonstrate that aging diminishes anti-tumor activity of engineered CD8 T cells expressing a tumor-specific T cell receptor (CD8 TCR-T cells) in ACT for solid tumors. Aged CD8 TCR-T cells cannot control tumor growth in either young or aged mice. Aged CD8 TCR-T cells are unable to accumulate efficiently in tumors and have higher tendency to become terminally exhausted T cells with lower expression of endothelial PAS domain-containing protein 1 (Epas1) compared to young cells. Crispr-mediated ablation of Epas1 promotes terminal exhaustion of young CD8 T cells in tumors, diminishing their anti-tumor activity in young mice. Conversely, retroviral expression of Epas1 enhances anti-tumor activity of aged CD8 TCR-T cells. These findings suggest that aging-induced reduction of Epas1 expression impairs anti-tumor activity of CD8 T cells in ACT against solid tumors, which can be therapeutically improved by expression of exogenous Epas1.

Overexpression of hypoxia-inducible factors led to tumor angiogenesis and tumor progression. However, unlike HIF-1α, the role of EPAS1/HIF-2α in papillary thyroid carcinoma (PTC) was unknown. Here, we aimed to investigate the role of EPAS1/HIF-2α in PTC. EPAS1/HIF-2α expression of fresh frozen tumor samples and adjacent tissues in Tongji Hospital of 46 PTC patients was detected by RT-PCR. Gene expression datasets of PTC patients were gained from The Cancer Genome Atlas (TCGA) database. The Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) were used to explore the potential biological function of EPAS1/HIF-2α. The effect of EPAS1/HIF-2α on immune microenvironment of PTC was analyzed in R package \"estimate\". The sensitivity to various targeted drugs was quantified in R package \"pRRophetic\", while the sensitivity to immunotherapy was estimated based on TCIA website. We found higher EPAS1/HIF-2α mRNA expression in PTC was associated with lower N stage, M stage, and better progression-free time (PFS) and disease-free time (DFS). Further, biological function analysis indicated that EPAS1/HIF-2α was mainly involved in PI3K-Akt signaling pathway. EPAS1/HIF-2α expression was positively related with CD8+ T cell infiltration and negatively related to PD-L1 expression and tumor mutation burden. Patients with low EPAS1/HIF-2α expression were more than likely to get a profit from Sorafenib, Dabrafenib, Cetuximab, Bosutinib, and immune checkpoint blockade. Our results suggested that EPAS1/HIF-2α played an unanticipated tumor-suppressive role in PTC. EPAS1/HIF-2α contributed to anti-tumor immunity by promoting CD8+ T cell infiltration and inhibiting PD-L1 expression in PTC.

Genetic introgression not only provides material for adaptive evolution but also confounds our understanding of evolutionary history. This is particularly true for canids, a species complex in which genome sequencing and analysis has revealed a complex history of admixture and introgression. Here, we sequence 19 new whole genomes from high-altitude Tibetan and Himalayan wolves and dogs and combine these into a larger data set of 166 whole canid genomes. Using these data, we explore the evolutionary history and adaptation of these and other canid lineages. We find that Tibetan and Himalayan wolves are closely related to each other, and that ∼39% of their nuclear genome is derived from an as-yet-unrecognized wolf-like lineage that is deeply diverged from living Holarctic wolves and dogs. The EPAS1 haplotype, which is present at high frequencies in Tibetan dog breeds and wolves and confers an adaptive advantage to animals living at high altitudes, was probably derived from this ancient lineage. Our study underscores the complexity of canid evolution and demonstrates how admixture and introgression can shape the evolutionary trajectories of species.