FB2025_01 , released February 20, 2025
Human Disease Model Report: hypoxia adaptation and chronic mountain sickness
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General Information
Name
hypoxia adaptation and chronic mountain sickness
FlyBase ID
FBhh0000796
Disease Ontology Term
Parent Disease
Overview

Drosophila populations adapted to survive at low levels of oxygen have been selected over many generations and have been used in studies of hypoxia adaptation. Notch (N) and genes encoding or regulating the Notch pathway appear to be under selection in these populations. Knockdown or loss of function of N reduces hypoxia tolerance; gain-of function mutations enhance tolerance. Other genes that appear to be under selection, and also appear to be under positive selection in high-altitude populations, include tzn (named for Tenzing Norgay), phu (named for Phurba Tashi), plh (named for Pasang Lhamu), and Arl8.

Based on a GWAS analysis of chronic mountain sickness (CMS) and non-CMS individuals in high-altitude populations, a number of candidate genes for adaptation to long-term exposure to hypoxia were identified. These were assessed in Drosophila using the orthologous fly genes. When down-regulated via RNAi, a number of the candidate genes were observed to significantly enhance hypoxia tolerance, including orthologs of known HIF (hypoxia-inducible factor) genes such as Ulp1 (orthologous to human SENP1). In addition, orthologs of several HIF-independent genes were observed to enhance hypoxia tolerance when down-regulated: Blimp-1 (orthologous to human PRDM1) and Oseg1 (orthologous to human IFT122).

[updated Mar. 2021 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: hypoxia adaptation and chronic mountain sickness
OMIM report

[CHRONIC MOUNTAIN SICKNESS, SUSCEPTIBILITY TO](https://omim.org/entry/616182)

Human gene(s) implicated

[CHRONIC MOUNTAIN SICKNESS, SUSCEPTIBILITY TO](https://omim.org/entry/616182)

Symptoms and phenotype

Chronic mountain sickness (CMS), or Monge disease, represents a state of maladaptation to high-altitude hypoxia in a member of a population acclimatized to high altitudes. CMS is characterized by severe polycythemia and an array of neurologic symptoms, including headache, fatigue, somnolence, and depression. Often, people with CMS suffer from strokes and myocardial infarctions in early adulthood because of increased blood viscosity. Studies have shown that CMS is common in Andeans, found occasionally in Tibetans, and absent from the Ethiopian population living on the East African high-altitude plateau (summary by Zhou et al., 2013; pubmed:23954164). Acute mountain sickness is experienced by unacclimatized travelers exposed to high altitude.

Genetics
Cellular phenotype and pathology
Molecular information
External links
    Disease synonyms
    chronic mountain sickness, susceptibility to
    CMS
    Monge's disease
    Monge disease
    Ortholog Information
    Human gene(s) in FlyBase
      Other mammalian ortholog(s) used
        D. melanogaster Gene Information (1)
        Gene Groups / Pathways
        Comments on ortholog(s)

        High-scoring ortholog of human NOTCH1, NOTCH2, and NOTCH3; lower-scoring ortholog of NOTCH4.

        Orthologs and Alignments from DRSC
        DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
        Other Genes Used: Viral, Bacterial, Synthetic (0)
          Summary of Physical Interactions (54 groups)
          protein-protein
          Interacting group
          Assay
          References
          electron microscopy, molecular weight, two hybrid, enzyme linked immunosorbent assay
          anti bait coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, western blot, anti tag western blot
          anti bait coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot
          pull down, western blot
          experimental knowledge based
          pull down, western blot, anti tag coimmunoprecipitation
          anti bait coimmunoprecipitation, western blot, two hybrid, anti tag coimmunoprecipitation, autoradiography
          proximity ligation assay, fluorescence microscopy
          affinity technology, tag visualisation by alkaline phosphatase activity
          pull down, autoradiography, anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation
          affinity technology, tag visualisation by alkaline phosphatase activity, atomic force microscopy, tag visualisation, inferred by author, anti bait coimmunoprecipitation, western blot, enzyme linked immunosorbent assay, bead aggregation assay, fluorescence microscopy, cross-linking study, phenotype-based detection assay, pull down
          pull down, western blot, autoradiography, two hybrid, anti bait coimmunoprecipitation
          two hybrid, anti tag coimmunoprecipitation, western blot, anti tag western blot, cosedimentation in solution, predetermined participant, nuclear magnetic resonance
          two hybrid, anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, western blot, pull down, two hybrid
          protease assay, western blot, inferred by author
          anti tag coimmunoprecipitation, anti tag western blot
          three hybrid, protein three hybrid, anti tag coimmunoprecipitation, peptide massfingerprinting
          pull down, western blot
          pull down, western blot
          pull down, western blot
          coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, western blot
          pull down, western blot, anti tag coimmunoprecipitation
          two hybrid, pull down, autoradiography
          anti tag coimmunoprecipitation, western blot, anti tag western blot
          anti tag coimmunoprecipitation, western blot
          experimental knowledge based
          experimental knowledge based
          anti tag coimmunoprecipitation, anti tag western blot
          anti bait coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, western blot
          fluorescence microscopy, inferred by author, anti bait coimmunoprecipitation, cross-linking study, western blot, affinity technology, tag visualisation by alkaline phosphatase activity, pull down, anti tag coimmunoprecipitation, bead aggregation assay, tag visualisation, confocal microscopy
          anti bait coimmunoprecipitation, western blot
          pull down, anti tag western blot, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation
          pull down, molecular weight estimation by staining, western blot, nuclear magnetic resonance, autoradiography, isothermal titration calorimetry, predetermined participant
          pull down, anti tag western blot, cosedimentation, autoradiography, three hybrid, molecular sieving, molecular weight estimation by staining, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, peptide massfingerprinting, two hybrid, isothermal titration calorimetry, predetermined participant, protein three hybrid, electron microscopy, electrophoretic mobility shift assay, electrophoretic mobility supershift assay, coimmunoprecipitation
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, western blot, pull down, two hybrid
          anti bait coimmunoprecipitation, western blot
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot
          anti tag coimmunoprecipitation, anti tag western blot
          anti bait coimmunoprecipitation, cross-linking study, western blot
          inferred by author, confocal microscopy, bead aggregation assay
          anti bait coimmunoprecipitation, Identification by mass spectrometry, western blot, anti tag western blot
          RNA-protein
          Interacting group
          Assay
          References
          nucleic acid uv cross-linking assay, autoradiography, anti bait coimmunoprecipitation, quantitative reverse transcription pcr
          pull down, quantitative reverse transcription pcr
          Alleles Reported to Model Human Disease (Disease Ontology) (24 alleles)
          Models Based on Experimental Evidence ( 11 )
          Allele
          Disease
          Evidence
          References
          Modifiers Based on Experimental Evidence ( 21 )
          Allele
          Disease
          Interaction
          References
          is exacerbated by CatHMS00990
          is ameliorated by CatUAS.cUa
          is exacerbated by Sod2HMS00499
          is ameliorated by Sod2UAS.cMa
          is exacerbated by cncHMS00650
          is ameliorated by cncUAS.cSa
          ameliorates  carcinoma
          Alleles Representing Disease-Implicated Variants
          Genetic Tools, Stocks and Reagents
          Sources of Stocks
          Contact lab of origin for a reagent not available from a public stock center.
          Bloomington Stock Center Disease Page
          Related mammalian, viral, bacterial, or synthetic transgenes
          Allele
          Transgene
          Publicly Available Stocks
          Selected Drosophila transgenes
          Allele
          Transgene
          Publicly Available Stocks
          RNAi constructs available
          Allele
          Transgene
          Publicly Available Stocks
          Selected Drosophila classical alleles
          Allele
          Allele class
          Mutagen
          Publicly Available Stocks
          amorphic allele - genetic evidence
          Delta2-3 transposase
          loss of function allele
          spontaneous
          loss of function allele
          spontaneous
          amorphic allele - genetic evidence
          X ray
          loss of function allele
          X ray
          loss of function allele
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          gamma ray
          loss of function allele
          X ray
          loss of function allele
          X ray
          loss of function allele
          X ray
          loss of function allele
          X ray
          loss of function allele
          ethyl methanesulfonate
          loss of function allele
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          X ray
          loss of function allele
          X ray
          loss of function allele
          ethyl methanesulfonate
          loss of function allele
          loss of function allele
          X ray
          loss of function allele
          X ray
          loss of function allele
          ethyl methanesulfonate
          loss of function allele
          X ray
          loss of function allele
          X ray
          loss of function allele
          loss of function allele
          loss of function allele
          ethyl methanesulfonate
          loss of function allele
          X ray
          amorphic allele - genetic evidence
          loss of function allele
          spontaneous
          loss of function allele
          ethyl methanesulfonate
          loss of function allele
          X ray
          loss of function allele
          X ray
          loss of function allele
          ethyl methanesulfonate
          amorphic allele - genetic evidence
          References (15)