Simonson, Tatum S. Altitude adaptation: A glimpse through various lenses. High Alt Med Biol 16:125-137, 2015.--Recent availability of genome-wide data from highland populations has enabled the ...identification of adaptive genomic signals. Some of the genomic signals reported thus far among Tibetan, Andean, and Ethiopian are the same, while others appear unique to each population. These genomic findings parallel observations conveyed by decades of physiological research: different continental populations, resident at high altitude for hundreds of generations, exhibit a distinct composite of traits at altitude. The most commonly reported signatures of selection emanate from genomic segments containing hypoxia-inducible factor (HIF) pathway genes. Corroborative evidence for adaptive significance stems from associations between putatively adaptive gene copies and sea-level ranges of hemoglobin concentration in Tibetan and Amhara Ethiopians, birth weights and metabolic factors in Andeans and Tibetans, maternal uterine artery diameter in Andeans, and protection from chronic mountain sickness in Andean males at altitude. While limited reports provide mechanistic insights thus far, efforts to identify and link precise genetic variants to molecular, physiological, and developmental functions are underway, and progress on the genomics front continues to provide unprecedented movement towards these goals. This combination of multiple perspectives is necessary to maximize our understanding of orchestrated biological and evolutionary processes in native highland populations, which will advance our understanding of both adaptive and non-adaptive responses to hypoxia.
Genetic Evidence for High-Altitude Adaptation in Tibet Simonson, Tatum S; Yang, Yingzhong; Huff, Chad D ...
Science (American Association for the Advancement of Science),
07/2010, Letnik:
329, Številka:
5987
Journal Article
Recenzirano
Tibetans have lived at very high altitudes for thousands of years, and they have a distinctive suite of physiological traits that enable them to tolerate environmental hypoxia. These phenotypes are ...clearly the result of adaptation to this environment, but their genetic basis remains unknown. We report genome-wide scans that reveal positive selection in several regions that contain genes whose products are likely involved in high-altitude adaptation. Positively selected haplotypes of EGLN1 and PPARA were significantly associated with the decreased hemoglobin phenotype that is unique to this highland population. Identification of these genes provides support for previously hypothesized mechanisms of high-altitude adaptation and illuminates the complexity of hypoxia-response pathways in humans.
Over millions of years, vertebrate species populated vast environments spanning the globe. Among the most challenging habitats encountered were those with limited availability of oxygen, yet many ...animal and human populations inhabit and perform life cycle functions and/or daily activities in varying degrees of hypoxia today. Of particular interest are species that inhabit high-altitude niches, which experience chronic hypobaric hypoxia throughout their lives. Physiological and molecular aspects of adaptation to hypoxia have long been the focus of high-altitude populations and, within the past decade, genomic information has become increasingly accessible. These data provide an opportunity to search for common genetic signatures of selection across uniquely informative populations and thereby augment our understanding of the mechanisms underlying adaptations to hypoxia. In this review, we synthesize the available genomic findings across hypoxia-tolerant species to provide a comprehensive view of putatively hypoxia-adaptive genes and pathways. In many cases, adaptive signatures across species converge on the same genetic pathways or on genes themselves i.e., the hypoxia inducible factor (HIF) pathway). However, specific variants thought to underlie function are distinct between species and populations, and, in most cases, the precise functional role of these genomic differences remains unknown. Efforts to standardize these findings and explore relationships between genotype and phenotype will provide important clues into the evolutionary and mechanistic bases of physiological adaptations to environmental hypoxia.
The indigenous people of the Tibetan Plateau have been the subject of much recent interest because of their unique genetic adaptations to high altitude. Recent studies have demonstrated that the ...Tibetan EPAS1 haplotype is involved in high altitude-adaptation and originated in an archaic Denisovan-related population. We sequenced the whole-genomes of 27 Tibetans and conducted analyses to infer a detailed history of demography and natural selection of this population. We detected evidence of population structure between the ancestral Han and Tibetan subpopulations as early as 44 to 58 thousand years ago, but with high rates of gene flow until approximately 9 thousand years ago. The CMS test ranked EPAS1 and EGLN1 as the top two positive selection candidates, and in addition identified PTGIS, VDR, and KCTD12 as new candidate genes. The advantageous Tibetan EPAS1 haplotype shared many variants with the Denisovan genome, with an ancient gene tree divergence between the Tibetan and Denisovan haplotypes of about 1 million years ago. With the exception of EPAS1, we observed no evidence of positive selection on Denisovan-like haplotypes.
Silent hypoxaemia in COVID‐19 patients Simonson, Tatum S.; Baker, Tracy L.; Banzett, Robert B. ...
The Journal of physiology,
02/2021, Letnik:
599, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The clinical presentation of COVID‐19 due to infection with SARS‐CoV‐2 is highly variable with the majority of patients having mild symptoms while others develop severe respiratory failure. The ...reason for this variability is unclear but is in critical need of investigation. Some COVID‐19 patients have been labelled with ‘happy hypoxia’, in which patient complaints of dyspnoea and observable signs of respiratory distress are reported to be absent. Based on ongoing debate, we highlight key respiratory and neurological components that could underlie variation in the presentation of silent hypoxaemia and define priorities for subsequent investigation.
figure legend Genesis of air hunger. In a working model of mechanisms giving rise to air hunger, brainstem respiratory centres send projections (corollary discharge) to the forebrain, giving rise to breathing discomfort in proportion to the magnitude of corollary discharge (Banzett et al., 2021 in press). These brainstem respiratory centres also send descending projections, driving respiratory motor neurons and respiratory muscle activity to generate ventilation. Inputs to the brainstem centres include chemoreceptor inputs, exercise and voluntary inputs from the motor cortex. Afferent feedback from lung stretch receptors modulates different qualities of dyspnoeic sensation. Slowly adapting lung stretch receptors are inhibitory to air hunger. Pulmonary C‐fibre receptors contribute to air hunger, but precise neural projections are not well understood. Whenever corollary discharge reaches a certain threshold, or when ventilation fails to meet demand, dyspnoea ensues. Inputs contributing to dyspnoea are indicated by blue arrows; inputs that inhibit dyspnoea are indicated with blue circles. Black arrows indicate homeostatic regulation of breathing.
Impairments in cognitive function, mood, and sleep quality occur following ascent to high altitude. Low oxygen (hypoxia) and poor sleep quality are both linked to impaired cognitive performance, but ...their independent contributions at high altitude remain unknown. Adaptive servoventilation (ASV) improves sleep quality by stabilizing breathing and preventing central apneas without supplemental oxygen. We compared the efficacy of ASV and supplemental oxygen sleep treatments for improving daytime cognitive function and mood in high-altitude visitors (N = 18) during acclimatization to 3,800 m. Each night, subjects were randomly provided with ASV, supplemental oxygen (SpO2 > 95%), or no treatment. Each morning subjects completed a series of cognitive function tests and questionnaires to assess mood and multiple aspects of cognitive performance. We found that both ASV and supplemental oxygen (O2) improved daytime feelings of confusion (ASV: p < 0.01; O2: p < 0.05) and fatigue (ASV: p < 0.01; O2: p < 0.01) but did not improve other measures of cognitive performance at high altitude. However, performance improved on the trail making tests (TMT) A and B (p < 0.001), the balloon analog risk test (p < 0.0001), and the psychomotor vigilance test (p < 0.01) over the course of three days at altitude after controlling for effects of sleep treatments. Compared to sea level, subjects reported higher levels of confusion (p < 0.01) and performed worse on the TMT A (p < 0.05) and the emotion recognition test (p < 0.05) on nights when they received no treatment at high altitude. These results suggest that stabilizing breathing (ASV) or increasing oxygenation (supplemental oxygen) during sleep can reduce feelings of fatigue and confusion, but that daytime hypoxia may play a larger role in other cognitive impairments reported at high altitude. Furthermore, this study provides evidence that some aspects of cognition (executive control, risk inhibition, sustained attention) improve with acclimatization.
Erythrocytosis, or increased production of red blood cells, is one of the most well-documented physiological traits that varies within and among in high-altitude populations. Although a modest ...increase in blood O
-carrying capacity may be beneficial for life in highland environments, erythrocytosis can also become excessive and lead to maladaptive syndromes such as chronic mountain sickness (CMS).
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