Dataset Information

AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia.

ABSTRACT: Red blood cells (RBCs) are key players in systemic oxygen transport. RBCs respond to in vitro hypoxia through the so-called oxygen-dependent metabolic regulation, which involves the competitive binding of deoxyhemoglobin and glycolytic enzymes to the N-terminal cytosolic domain of band 3. This mechanism promotes the accumulation of 2,3-DPG, stabilizing the deoxygenated state of hemoglobin, and cytosol acidification, triggering oxygen off-loading through the Bohr effect. Despite in vitro studies, in vivo adaptations to hypoxia have not yet been completely elucidated. Within the framework of the AltitudeOmics study, erythrocytes were collected from 21 healthy volunteers at sea level, after exposure to high altitude (5260 m) for 1, 7, and 16 days, and following reascent after 7 days at 1525 m. UHPLC-MS metabolomics results were correlated to physiological and athletic performance parameters. Immediate metabolic adaptations were noted as early as a few hours from ascending to >5000 m, and maintained for 16 days at high altitude. Consistent with the mechanisms elucidated in vitro, hypoxia promoted glycolysis and deregulated the pentose phosphate pathway, as well purine catabolism, glutathione homeostasis, arginine/nitric oxide, and sulfur/H2S metabolism. Metabolic adaptations were preserved 1 week after descent, consistently with improved physical performances in comparison to the first ascendance, suggesting a mechanism of metabolic memory.

SUBMITTER: D'Alessandro A

PROVIDER: S-EPMC5512539 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia.

D'Alessandro Angelo A Nemkov Travis T Sun Kaiqi K Liu Hong H Song Anren A Monte Andrew A AA Subudhi Andrew W AW Lovering Andrew T AT Dvorkin Daniel D Julian Colleen G CG Kevil Christopher G CG Kolluru Gopi K GK Shiva Sruti S Gladwin Mark T MT Xia Yang Y Hansen Kirk C KC Roach Robert C RC

Journal of proteome research 20160927 10

Red blood cells (RBCs) are key players in systemic oxygen transport. RBCs respond to in vitro hypoxia through the so-called oxygen-dependent metabolic regulation, which involves the competitive binding of deoxyhemoglobin and glycolytic enzymes to the N-terminal cytosolic domain of band 3. This mechanism promotes the accumulation of 2,3-DPG, stabilizing the deoxygenated state of hemoglobin, and cytosol acidification, triggering oxygen off-loading through the Bohr effect. Despite in vitro studies, ...[more]

PMID: 27646145

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Project description:High altitudes (>8,000 ft or 2,500 m) provide an experiment of nature for measuring adaptation and the physiological processes involved. Studies conducted over the past ~25 years in Andeans, Tibetans, and, less often, Ethiopians show varied but distinct O2 transport traits from those of acclimatized newcomers, providing indirect evidence for genetic adaptation to high altitude. Short-term (acclimatization, developmental) and long-term (genetic) responses to high altitude exhibit a temporal gradient such that, although all influence O2 content, the latter also improve O2 delivery and metabolism. Much has been learned concerning the underlying physiological processes, but additional studies are needed on the regulation of blood flow and O2 utilization. Direct evidence of genetic adaptation comes from single-nucleotide polymorphism (SNP)-based genome scans and whole genome sequencing studies that have identified gene regions acted upon by natural selection. Efforts have begun to understand the connections between the two with Andean studies on the genetic factors raising uterine blood flow, fetal growth, and susceptibility to Chronic Mountain Sickness and Tibetan studies on genes serving to lower hemoglobin and pulmonary arterial pressure. Critical for future studies will be the selection of phenotypes with demonstrable effects on reproductive success, the calculation of actual fitness costs, and greater inclusion of women among the subjects being studied. The well-characterized nature of the O2 transport system, the presence of multiple long-resident populations, and relevance for understanding hypoxic disorders in all persons underscore the importance of understanding how evolutionary adaptation to high altitude has occurred.NEW & NOTEWORTHY Variation in O2 transport characteristics among Andean, Tibetan, and, when available, Ethiopian high-altitude residents supports the existence of genetic adaptations that improve the distribution of blood flow to vital organs and the efficiency of O2 utilization. Genome scans and whole genome sequencing studies implicate a broad range of gene regions. Future studies are needed using phenotypes of clear relevance for reproductive success for determining the mechanisms by which naturally selected genes are acting.

Project description:Since their arrival in the Tibetan Plateau during the Neolithic Age, Tibetans have been well-adapted to extreme environmental conditions and possess genetic variation that reflect their living environment and migratory history. To investigate the origin of Tibetans and the genetic basis of adaptation in a rigorous environment, we genotyped 30 Tibetan individuals with more than one million SNP markers. Our findings suggested that Tibetans, together with the Yi people, were descendants of Tibeto-Burmans who diverged from ancient settlers of East Asia. The valleys of the Hengduan Mountain range may be a major migration route. We also identified a set of positively-selected genes that belong to functional classes of the embryonic, female gonad, and blood vessel developments, as well as response to hypoxia. Most of these genes were highly correlated with population-specific and beneficial phenotypes, such as high infant survival rate and the absence of chronic mountain sickness. Genetic features of Tibetans have been broadly investigated, but the properties of copy number variation (CNV) have not been well examined. To get a preliminary view of CNV in Tibetans, we scanned 29 Tibetan genomes with the Illumina Human-1 M high-resolution genotyping microarray and identified 139 putative copy number variable regions (CNVRs), consisting of 70 deletions, 61 duplications, and 8 multi-allelic loci. Thirty-four of the 139 CNVRs showed differential allele frequencies versus other East-Asian populations, with P values ,0.0001. These results indicated a distinct pattern of CNVR allele frequency distribution in Tibetans. The Tibetan CNVRs are enriched for genes in the disease class of human reproduction (such as genes from the DAZ, BPY2, CDY, and HLA-DQ and -DR gene clusters) and biological process categories of ‘‘response to DNA damage stimulus’’ and ‘‘DNA repair’’ (such as RAD51, RAD52, and MRE11A). These genes are related to the adaptive traits of high infant birth weight and darker skin tone of Tibetans, and may be attributed to recent local adaptation. Our results provide a different view of genetic diversity in Tibetans and new insights into their high-altitude adaptation.

Dataset Information

AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia.

Publications

AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia.

Similar Datasets

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