148 research outputs found
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Integrative approaches to understanding human adaptation and acclimatization to high altitude
No full textHigh altitude and the hypobaric hypoxia associated with it impose significant physiological stressors on the human body. The human response to hypoxia varies between and within populations of differing genetic ancestries. This variation provides a natural experiment where potential mechanisms of hypoxia response can be investigated, especially for groups that have adapted to high altitude. This dissertation investigates the human response to hypoxia and high altitude by studying distinct populations through various biological approaches. The first chapter combines genetics, proteomics, and metabolomics data from Andean highlanders into a multi-omics analysis to predict phenotypes related to high-altitude adaptation, such as basic physiological traits, hematological traits, metabolism, and ventilation. The analysis identifies key contributors from each of the different -omics to various phenotypes. The second chapter characterizes the hypoxic ventilatory response in Tibetan women residing at high altitude and identifies an association between menopausal status and ventilation. The study further identifies genetic associations with ventilatory traits and genes under positive selection that may play a role in control of breathing. The third chapter is the results of a randomized, double-blinded, placebo-controlled study testing the effect of the probiotic SLAB51 on sea-level residents acclimatizing to high altitude. The study shows individuals that ingest the probiotic have a higher oxygen saturation and less symptoms of Acute Mountain Sickness at high altitude than those that receive a placebo. Taken together, this dissertation provides novel insights into how humans adapt and acclimatize to high altitude
Doctor of Philosophy
No full textdissertationHumans have lived at high altitude for hundreds of generations despite unavoidable challenges imposed by hypobaric hypoxia. The lower barometric pressure at high altitude reduces the number of oxygen molecules available in each breath of air, yet oxygen-dependent physiological processes must be maintained for survival. Cellular and system responses to hypoxic stress can result in altitude illness and may prove fatal in a small proportion of maladapted individuals. Native high-altitude populations, however, exhibit a unique suite of heritable traits that afford tolerance to hypoxia. Compared to lowland visitors and Andean highlanders, Tibetans exhibit lower hemoglobin (Hb) levels at high altitude, which tend to be similar to those expected under sea-level conditions. Such differences suggest this population has unique adaptations to their native environment. It has been hypothesized that genes specifically involved in the hypoxia inducible factor (HIF) pathway could underlie adaptive changes in high-altitude populations. Genome-wide analyses provide the first lines of evidence in support of genetic adaptation to high altitude. Three regions of the genome that contain genes associated with the human response to hypoxia show evidence of selection and are associated with decreased Hb levels, and two of these are also associated with metabolite levels. These phenotypic associations provide corroborative evidence for adaptive roles of genomic regions targeted by strong positive selection in Tibetans. iv While many of the same selection candidate genes are reported by studies of different Tibetan populations, some signals of selection and association are unique to particular groups. The genetic makeup of Tibetan groups located throughout the plateau is therefore important to consider in studies of high-altitude adaptation. Taken together, the data presented in this dissertation demonstrate that multiple genes are involved in Tibetan adaptation to high altitude. Some of these genes have been linked to hematological and metabolic phenotypes characterized thus far, providing further support for roles in physiological adaptation to this extreme environment. Studies aimed to identify associations between specific genetic variants, mechanisms, and phenotypes will help bridge the gap between genetic variation and organismal responses to hypoxia, and will have important implications for understanding human health and disease
Innate Immune Phenotypes During Acute High-Altitude Exposure.
No full textVargas, Abel, Veronica Penuelas, Karapet G Mkrtchyan, Kathy Pham, Shyleen Frost, Esteban A Moya, James J Yu, Tatum S Simonson, and Erica C Heinrich. Innate immune phenotypes during acute high-altitude exposure. High Alt Med Biol. 00:00-00, 2025. Introduction: High altitude is a physiologically stressful environment due to limited oxygen availability. Decades of study reveal the complex plasticity in many physiological systems that manifests at high altitude to maintain oxygen delivery. However, there are gaps in our knowledge regarding how high-altitude exposure influences immune function. Since tissue and cellular hypoxia occur during injury and infection, we hypothesized that sustained hypoxemia during high-altitude travel may impact inflammatory and immune phenotypes due to crosstalk between hypoxia and inflammatory response pathways. Methods: We recruited 17 healthy participants and examined their immune phenotypes at sea level and during 3 days at 3,800 m elevation. Specific attention was paid to neutrophil phenotypes because changes in these cells have not been reported at high altitude. Results: We found several impacts of high altitude on immune cell populations, including shifts in monocytes from classical to intermediate (p = 0.004 after 1 night at high altitude [HA1], and p \u3c 0.001 after 2 nights at high altitude [HA2]) and nonclassical subsets (p = 0.013 on HA2), and increases in total B cells (p = 0.001 on HA2, p = 0.004 [HA3]). An effect of altitude was found for neutrophil CD15 expression (p \u3c 0.001), with a trend toward increased expression over time at high altitude. Higher Acute Mountain Sickness (AMS) scores on the second day at high altitude were associated with more pronounced shifts to nonclassical monocyte populations (R2 = 0.79, p = 0.001). These data indicate that acute high-altitude travel results in a pro-inflammatory immune response, which may contribute to AMS. This response appears to blunt with acclimatization, although elevation in B cells remain by HA3
Ancestry of the Iban is predominantly Southeast Asian: Genetic evidence from autosomal, mitochondrial, and Y chromosomes
No full textExtent: 8p.Humans reached present-day Island Southeast Asia (ISEA) in one of the first major human migrations out of Africa. Population movements in the millennia following this initial settlement are thought to have greatly influenced the genetic makeup of current inhabitants, yet the extent attributed to different events is not clear. Recent studies suggest that southto-north gene flow largely influenced present-day patterns of genetic variation in Southeast Asian populations and that late Pleistocene and early Holocene migrations from Southeast Asia are responsible for a substantial proportion of ISEA ancestry.
Archaeological and linguistic evidence suggests that the ancestors of present-day inhabitants came mainly from north-tosouth migrations from Taiwan and throughout ISEA approximately 4,000 years ago. We report a large-scale genetic analysis of human variation in the Iban population from the Malaysian state of Sarawak in northwestern Borneo, located in the center of ISEA. Genome-wide single-nucleotide polymorphism (SNP) markers analyzed here suggest that the Iban exhibit greatest genetic similarity to Indonesian and mainland Southeast Asian populations. The most common non-recombining Y(NRY) and mitochondrial (mt) DNA haplogroups present in the Iban are associated with populations of Southeast Asia. We conclude that migrations from Southeast Asia made a large contribution to Iban ancestry, although evidence of potential gene flow from Taiwan is also seen in uniparentally inherited marker data.Tatum S. Simonson, Jinchuan Xing, Robert Barrett, Edward Jerah, Peter Loa, Yuhua Zhang, W. Scott Watkins, David J. Witherspoon, Chad D. Huff, Scott Woodward, Bryan Mowry, Lynn B.Jord
Notch Signaling and Cross-Talk in Hypoxia: A Candidate Pathway for High-Altitude Adaptation.
No full textHypoxia triggers complex inter- and intracellular signals that regulate tissue oxygen (O2) homeostasis, adjusting convective O2 delivery and utilization (i.e., metabolism). Human populations have been exposed to high-altitude hypoxia for thousands of years and, in doing so, have undergone natural selection of multiple gene regions supporting adaptive traits. Some of the strongest selection signals identified in highland populations emanate from hypoxia-inducible factor (HIF) pathway genes. The HIF pathway is a master regulator of the cellular hypoxic response, but it is not the only regulatory pathway under positive selection. For instance, regions linked to the highly conserved Notch signaling pathway are also top targets, and this pathway is likely to play essential roles that confer hypoxia tolerance. Here, we explored the importance of the Notch pathway in mediating the cellular hypoxic response. We assessed transcriptional regulation of the Notch pathway, including close cross-talk with HIF signaling, and its involvement in the mediation of angiogenesis, cellular metabolism, inflammation, and oxidative stress, relating these functions to generational hypoxia adaptation
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Genomic insights into TASK-1 reveal functional roles in sleep apnea
No full textKCNK3 mutations identified in sleep apnea probands affect TASK-1 X-gate function. These changes lead to an increase in potassium current and open probability, as well as impaired sensitivity to G-protein-coupled receptor inhibitors
Metabolic adaptation to high altitude
No full textAt high altitude, hypobaric hypoxia is a significant stress for humans and other animals, challenging oxygen homeostasis and therefore tissue metabolism. Genetic signals of physiological adaptation have been identified in human populations and nonhuman species with long-term residence at high altitude. In Tibetans, some genetic signals are linked to altered metabolic function, for example, variants in EPAS1 are associated with increased glycolysis, whilst variants in PPARA are associated with a decreased capacity for fatty acid oxidation. A number of other genetic signals that may impact on metabolism have been identified in Tibetans and other populations, although the downstream consequences are not well defined. Use of high-throughput technologies to comprehensively profile metabolic phenotype could advance understanding of the evolutionary processes conferring hypoxia tolerance at high altitude.</p
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