Blunted nitric oxide regulation in Tibetans under high-altitude hypoxia

He, Yaoxi; Qi, Xuebin; Ouzhuluobu,; Liu, Shiming; Li, Jun; Hui, Zhang; Baimakangzhuo,; Bai, Caijuan; Zheng, Wangshan; Guo, Yongbo; Duojizhuoma,; Baimayangji,; Dejiquzong, -; Bianba,; Gonggalanzi,; Pan, Yongyue; Qula,; Kangmin,; Cirenyangji,; Guo, Wei; Yangla,; Peng, Yi; Zhang, Xiaoming; Xiang, Kun; Yang, Zhaohui; Wang, Liangbang; Gengdeng,; Zhang, Yanfeng; Wu, Tianyi; Su, Bing; Cui, Chaoying

doi:10.1093/nsr/nwy037

Cited by 34 publications

(21 citation statements)

References 47 publications

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“…12b ), which may imply a general regulatory mechanism for the blunted response. For example, GCH1 and NOS3 are involved in the blunted nitric oxide regulation in Tibetans under high-altitude hypoxia 38 , 39 . In the 1146 selected genes, 38 genes show significant expression differences between Tibetan and Han ( p -value < 0.05).…”

Section: Discussionmentioning

confidence: 99%

Chromatin accessibility landscape and regulatory network of high-altitude hypoxia adaptation

Xin

Zhang

et al. 2020

Nat Commun

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High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and RNA-seq data on cultured HUVECs under hypoxic and normoxic conditions. We further develop a variant interpretation methodology (vPECA) to identify active selected REs (ASREs) and associated regulatory network. We discover three causal SNPs of EPAS1, the key adaptive gene for Tibetans. These SNPs decrease the accessibility of ASREs with weakened binding strength of relevant TFs, and cooperatively down-regulate EPAS1 expression. We further construct the downstream network of EPAS1, elucidating its roles in hypoxic response and angiogenesis. Collectively, we provide a systematic approach to interpret phenotype-associated noncoding variants in proper cell types and relevant dynamic conditions, to model their impact on gene regulation.

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Section: Discussionmentioning

confidence: 99%

Chromatin accessibility landscape and regulatory network of high-altitude hypoxia adaptation

Xin

Zhang

et al. 2020

Nat Commun

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“…Comparative genomics has been extensively used to investigate the genetic bases of adaptation to extreme environments [6,7,9,10,14,[28][29][30][31]. In this study, comprehensive transcriptome analyses from leaves and roots of S. alba across salinity conditions were performed to probe the genetic mechanisms underlying salt adaptation.…”

Section: Discussionmentioning

confidence: 99%

Molecular adaptation to salinity fluctuation in tropical intertidal environments of a mangrove tree Sonneratia alba

Feng

et al. 2020

BMC Plant Biol

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Background: Mangroves have adapted to intertidal zones-the interface between terrestrial and marine ecosystems. Various studies have shown adaptive evolution in mangroves at physiological, ecological, and genomic levels. However, these studies paid little attention to gene regulation of salt adaptation by transcriptome profiles. Results: We sequenced the transcriptomes of Sonneratia alba under low (fresh water), medium (half the seawater salinity), and high salt (seawater salinity) conditions and investigated the underlying transcriptional regulation of salt adaptation. In leaf tissue, 64% potential salinity-related genes were not differentially expressed when salinity increased from freshwater to medium levels, but became up-or down-regulated when salt concentrations further increased to levels found in sea water, indicating that these genes are well adapted to the medium saline condition. We inferred that both maintenance and regulation of cellular environmental homeostasis are important adaptive processes in S. alba. i) The sulfur metabolism as well as flavone and flavonol biosynthesis KEGG pathways were significantly enriched among up-regulated genes in leaves. They are both involved in scavenging ROS or synthesis and accumulation of osmosis-related metabolites in plants. ii) There was a significantly increased percentage of transcription factor-encoding genes among up-regulated transcripts. High expressions of salt tolerance-related TF families were found under high salt conditions. iii) Some genes up-regulated in response to salt treatment showed signs of adaptive evolution at the amino acid level and might contribute to adaptation to fluctuating intertidal environments. Conclusions: This study first elucidates the mechanism of high-salt adaptation in mangroves at the whole-transcriptome level by salt gradient experimental treatments. It reveals that several candidate genes (including salt-related genes, TFencoding genes, and PSGs) and major pathways are involved in adaptation to high-salt environments. Our study also provides a valuable resource for future investigation of adaptive evolution in extreme environments.

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“…SPO2 was measured at forefinger tip with a hand-held pulse oximeter (Nellcor NPB-40, CA) at rest, and the fingertip was cleaned with 19 alcohol swab before measurement. Serum NO levels were measured by protocol as we described before 61 .…”

Section: Physiological Traits Measurement and Association Analysis Ofmentioning

confidence: 99%

De novo assembly of a Tibetan genome and identification of novel structural variants associated with high altitude adaptation

Ouzhuluobu

Lou

et al. 2019

Preprint

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Structural variants (SVs) may play important roles in human adaption to extreme environments such as high altitude but have been under-investigated. Here, combining long-read sequencing with multiple scaffolding techniques, we assembled a high-quality Tibetan genome (ZF1), with a contig N50 length of 24.57 mega-base pairs (Mb) and a scaffold N50 length of 58.80 Mb. The ZF1 assembly filled 80 remaining N-gaps (0.25 Mb in total length) in the reference human genome (GRCh38). Markedly, we detected 17,900SVs, among which the ZF1-specific SVs are enriched in GTPase activity that is required for activation of the hypoxic pathway. Further population analysis uncovered a 163-bp intronic deletion in the MKL1 gene showing large divergence between highland Tibetans and lowland Han Chinese. This deletion is significantly associated with lower systolic pulmonary arterial pressure, one of the key adaptive physiological traits in Tibetans. Moreover, with the use of the high quality de novo assembly, we observed a much higher rate of genome-wide archaic hominid (Altai Neanderthal and Denisovan) shared nonreference sequences in ZF1 (1.32%-1.53%) compared to other East Asian genomes (0.70%-0.98%), reflecting a unique genomic composition of Tibetans. One such archaic-hominid shared sequence, a 662bp intronic insertion in the SCUBE2 gene, is enriched and associated with better lung function (the FEV1/FVC ratio) in Tibetans. Collectively, we generated the first high-resolution Tibetan reference genome, and the identified SVs may serve as valuable resources for future evolutionary and medical studies.

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Blunted nitric oxide regulation in Tibetans under high-altitude hypoxia

Cited by 34 publications

References 47 publications

Chromatin accessibility landscape and regulatory network of high-altitude hypoxia adaptation

Chromatin accessibility landscape and regulatory network of high-altitude hypoxia adaptation

Molecular adaptation to salinity fluctuation in tropical intertidal environments of a mangrove tree Sonneratia alba

De novo assembly of a Tibetan genome and identification of novel structural variants associated with high altitude adaptation

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