Tibetan Highlanders Research Articles

Increased Levels of Interleukin‐6 (IL‐6) in Andean Males with Chronic Mountain Sickness and Sea‐Level Participants After One Day at High Altitude May Reflect Differences in IL‐6 Regulation

The gene encoding interleukin‐6 (IL‐6) shows signals of evolutionary selection in Tibetans and Andeans and could be a target of convergent adaptation to high altitude. Furthermore, IL‐6 is elevated in sea‐level residents upon acute high‐altitude exposure, is involved in both the inflammatory and hypoxia‐response pathways via HIF‐1a and NFκB regulation, and plays a role in regulating hematopoiesis. We hypothesized that high‐altitude adapted populations have variants associated with reduced IL6 expression that prevent chronic systemic inflammation in response to chronic hypoxaemia. We examined the sequence of the IL6 gene region in both Tibetans (n = 27) and and Andeans (n = 32) and measured IL‐6 protein levels in male Andean highlanders with and without Excessive Erythrocytosis (EE) (Hb ≥ 21 g/dL) in Cerro de Pasco, Peru (CDP, 4,350 m) as well as healthy male sojourners before and after travel to Barcroft Station, White Mountain Research Center (3,800 m). Plasma IL‐6 was significantly higher in Andean men with EE (healthy: 1.0 ± 0.4 pg/mL, EE: 2.5 ± 2.0 pg/mL; p = 0.02). IL‐6 levels also increased in sea‐level participants from 1.2 ± 0.6 to 2.3 ± 0.7 pg/mL (p = 0.01) after one day at altitude. Elevated IL‐6 protein in Andeans with EE could result from increased IL‐6 release from monocytes and vascular cells in response to more severe hypoxemia, the degree of inflammatory responsiveness, and/or increased blood vessel sheer stress imposed by increased blood viscosity. Elevated IL‐6 could also exacerbate CMS by further stimulating hematopoiesis. Sequence data revealed an uncommon promoter gain of function (rs1800795, c.‐237C>G, c.‐274C>G) and promoter loss of function (rs1800797, c.‐661A>G, c.‐698A>G) variant present in all 27 Tibetans as well as a shared missense variant (rs13306435, c.258T>A, c.486T>A) in 11/37 Andeans and 3/27 Tibetans; analysis of sequence data from subjects at White Mountain are underway. Since EE is uncommon in Tibetan highlanders, it is possible that these unique variants may afford protection against inflammatory responses and/or polycythemia at high altitude.Support or Funding InformationThis study was supported by an NIH NRSA Individual Postdoctoral Fellowship (Parent F32) to ECH (F32HL131218), NIH R00HL118215 and American Physiological Society Giles F. Filley Memorial Award to TSS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The UPCH team was supported by a Wellcome Trust PHTM grant (107544/Z/15/Z) to FCV.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Natural Selection on Genes Related to Cardiovascular Health in High-Altitude Adapted Andeans

The increase in red blood cell mass (polycythemia) due to the reduced oxygen availability (hypoxia) of residence at high altitude or other conditions is generally thought to be beneficial in terms of increasing tissue oxygen supply. However, the extreme polycythemia and accompanying increased mortality due to heart failure in chronic mountain sickness most likely reduces fitness. Tibetan highlanders have adapted to high altitude, possibly in part via the selection of genetic variants associated with reduced polycythemic response to hypoxia. In contrast, high-altitude-adapted Quechua- and Aymara-speaking inhabitants of the Andean Altiplano are not protected from high-altitude polycythemia in the same way, yet they exhibit other adaptive features for which the genetic underpinnings remain obscure. Here, we used whole-genome sequencing to scan high-altitude Andeans for signals of selection. The genes showing the strongest evidence of selection-including BRINP3, NOS2, and TBX5-are associated with cardiovascular development and function but are not in the response-to-hypoxia pathway. Using association mapping, we demonstrated that the haplotypes under selection are associated with phenotypic variations related to cardiovascular health. We hypothesize that selection in response to hypoxia in Andeans could have vascular effects and could serve to mitigate the deleterious effects of polycythemia rather than reduce polycythemia itself.

Effects of dietary nitrate on respiratory physiology at high altitude - Results from the Xtreme Alps study

Nitric oxide (NO) production plays a central role in conferring tolerance to hypoxia. Tibetan highlanders, successful high-altitude dwellers for millennia, have higher circulating nitrate and exhaled NO (ENO) levels than native lowlanders. Since nitrate itself can reduce the oxygen cost of exercise in normoxia it may confer additional benefits at high altitude. Xtreme Alps was a double-blinded randomised placebo-controlled trial to investigate how dietary nitrate supplementation affects physiological responses to hypoxia in 28 healthy adult volunteers resident at 4559 m for 1 week; 14 receiving a beetroot-based high-nitrate supplement and 14 receiving a low-nitrate ‘placebo’ of matching appearance/taste. ENO, vital signs and acute mountain sickness (AMS) severity were recorded at sea level (SL) and daily at altitude. Moreover, standard spirometric values were recorded, and saliva and exhaled breath condensate (EBC) collected. There was no significant difference in resting cardiorespiratory variables, peripheral oxygen saturation or AMS score with nitrate supplementation at SL or altitude. Median ENO levels increased from 1.5/3.0 mPa at SL, to 3.5/7.4 mPa after 5 days at altitude (D5) in the low and high-nitrate groups, respectively (p = 0.02). EBC nitrite also rose significantly with dietary nitrate (p = 0.004), 1.7–5.1 μM at SL and 1.6–6.3 μM at D5, and this rise appeared to be associated with increased levels of ENO. However, no significant changes occurred to levels of EBC nitrate or nitrosation products (RXNO). Median salivary nitrite/nitrate concentrations increased from 56.5/786 μM to 333/5,194 μM with nitrate supplementation at SL, and changed to 85.6/641 μM and 341/4,553 μM on D5. Salivary RXNO rose markedly with treatment at SL from 0.55 μM to 5.70 μM. At D5 placebo salivary RXNO had increased to 1.90 μM whilst treatment RXNO decreased to 3.26 μM. There was no association with changes in any observation variables or AMS score. In conclusion, dietary nitrate supplementation is well tolerated at altitude and significantly increases pulmonary NO availability and both salivary and EBC NO metabolite concentrations. Surprisingly, this is not associated with changes in hemodynamics, oxygen saturation or AMS development.

Gain-of-function EGLN1 prolyl hydroxylase (PHD2 D4E:C127S) in combination with EPAS1 (HIF-2α) polymorphism lowers hemoglobin concentration in Tibetan highlanders.

Most Tibetans are protected from polycythemia while living in high altitude. An EGLN1 co-adapted haplotype, EGLN1 c.12C>G, c.380G>C is uniquely Tibetan. The Tibetan EPAS1 haplotype has introgressed from the Denisovan genome. While EGLN1 and EPAS1 genotypes lower Hb, this study indicates additional Hb modifiers.

Living the high life

Helen Albert speaks to biological anthropologist Professor Cynthia Beall about her research into human evolutionary adaptation to high altitude and the important role of oxygen transport genes in Tibetan highlanders.

Ancestral Origins and Genetic History of Tibetan Highlanders

The origin of Tibetans remains one of the most contentious puzzles in history, anthropology, and genetics. Analyses of deeply sequenced (30×-60×) genomes of 38 Tibetan highlanders and 39 Han Chinese lowlanders, together with available data on archaic and modern humans, allow us to comprehensively characterize the ancestral makeup of Tibetans and uncover their origins. Non-modern human sequences compose ∼6% of the Tibetan gene pool and form unique haplotypes in some genomic regions, where Denisovan-like, Neanderthal-like, ancient-Siberian-like, and unknown ancestries are entangled and elevated. The shared ancestry of Tibetan-enriched sequences dates back to ∼62,000-38,000 years ago, predating the Last Glacial Maximum (LGM) and representing early colonization of the plateau. Nonetheless, most of the Tibetan gene pool is of modern human origin and diverged from that of Han Chinese ∼15,000 to ∼9,000 years ago, which can be largely attributed to post-LGM arrivals. Analysis of ∼200 contemporary populations showed that Tibetans share ancestry with populations from East Asia (∼82%), Central Asia and Siberia (∼11%), South Asia (∼6%), and western Eurasia and Oceania (∼1%). Our results support that Tibetans arose from a mixture of multiple ancestral gene pools but that their origins are much more complicated and ancient than previously suspected. We provide compelling evidence of the co-existence of Paleolithic and Neolithic ancestries in the Tibetan gene pool, indicating a genetic continuity between pre-historical highland-foragers and present-day Tibetans. In particular, highly differentiated sequences harbored in highlanders' genomes were most likely inherited from pre-LGM settlers of multiple ancestral origins (SUNDer) and maintained in high frequency by natural selection.

MtDNA analysis reveals enriched pathogenic mutations in Tibetan highlanders.

Tibetan highlanders, including Tibetans, Monpas, Lhobas, Dengs and Sherpas, are considered highly adaptive to severe hypoxic environments. Mitochondrial DNA (mtDNA) might be important in hypoxia adaptation given its role in coding core subunits of oxidative phosphorylation. In this study, we employed 549 complete highlander mtDNA sequences (including 432 random samples) to obtain a comprehensive view of highlander mtDNA profile. In the phylogeny of a total of 36,914 sequences, we identified 21 major haplogroups representing founding events of highlanders, most of which were coalesced in 10 kya. Through founder analysis, we proposed a three-phase model of colonizing the plateau, i.e., pre-LGM Time (30 kya, 4.68%), post-LGM Paleolithic Time (16.8 kya, 29.31%) and Neolithic Time (after 8 kya, 66.01% in total). We observed that pathogenic mutations occurred far more frequently in 22 highlander-specific lineages (five lineages carrying two pathogenic mutations and six carrying one) than in the 6,857 haplogroups of all the 36,914 sequences (P = 4.87 × 10−8). Furthermore, the number of possible pathogenic mutations carried by highlanders (in average 3.18 ± 1.27) were significantly higher than that in controls (2.82 ± 1.40) (P = 1.89 × 10−4). Considering that function-altering and pathogenic mutations are enriched in highlanders, we therefore hypothesize that they may have played a role in hypoxia adaptation.

Glucose intolerance associated with hypoxia in people living at high altitudes in the Tibetan highland

ObjectivesTo clarify the association between glucose intolerance and high altitudes (2900–4800 m) in a hypoxic environment in Tibetan highlanders and to verify the hypothesis that high altitude dwelling increases vulnerability...

Tibetan Gain-of-Function Variant of Prolyl Hydroxylase 2 (EGLN1) and Selected SNPs of HIF-2-Alpha (EPAS1) Are Associated with Lower Hemoglobin Values in Tibetans

Hypoxia is the principal driver of erythropoiesis. Tibetan highlanders are protected from polycythemia despite living at high altitude. Whole genome sequencing studies narrowed evolutionary selected Tibetan haplotypes to two loci, EGLN1 and EPAS1 (Huerta-Sanchez et al, Nature, 2014, 512:194). Our previous work identified a functional variant of the principal negative regulator of hypoxia inducible transcription factors (HIFs), prolyl hydroxylase 2 (PHD2D4E/C127S, encoded by EGLN112C>G,380G>C), that has a lower Km for oxygen, thereby explaining the lack of polycythemia, and is present in ~88% of Tibetans (Lorenzo FR et al, Nat Genet. 2014, 46:951). Additionally, a highly selected Tibetan EPAS1 (encoding HIF-2a) haplotype has introgressed from prehistoric Denisovans (Huerta-Sanchez et al, Nature, 2014, 512:194). This Tibetan EPAS1 haplotype has no exonic variants but a unique epigenetic profile when analyzed by ENCODE software.We analyzed genomes of 260 healthy adult Tibetans residing in different altitudes in China, India and the US with appropriate IRB approvals and informed consents. Since EGLN112C>G,380G>C is located in a GC rich region that is not easily detectable by NGS and Sanger sequencing, we developed a high resolution melting assay for its detection. For the EPAS1 haplotype we analyzed 10 SNPs (5 Denisovan and 5 non-Denisovan, each with unique linkage disequilibrium (LD) value) in its evolutionary selected Tibetan region and correlated them with hemoglobin levels.We found that EGLN112C>G (D4E) is always in cis (i.e complete LD) with the EGLN1380G>C (C127S) missense variant, constituting a unique Tibetan-specific positively selected haplotype. The prevalence of PHD2D4E/C127S variants increased with altitude, seen in 52 out of 55 individuals (94.5%) at altitudes above 4000 m, consistent with positive selection of PHD2D4E/C127S at high altitude. Across all altitudes, after adjusting for age, gender and MCHC, the mean hemoglobin level was lower in PHD2D4E/C127S heterozygotes (14.4 g/dl; p=0.009), and tended to be lower in homozygotes (14.7 g/dl; p=0.10) than in PHD2 wild-type subjects (15.2 g/dl). Combining the homozygotes and heterozygotes, the hemoglobin was lower (14.6 g/dl; p=0.015) compared to PHD2 wild-type subjects. This lower hemoglobin level in those with PHD2D4E/C127S variants also extended to the subset of individuals residing at low altitudes (200 m). Thus, blunting of the HIF pathway by PHD2D4E/C127S persists even at the ambient oxygen of lower altitudes, although none these low-altitude residents were found to be anemic. We then evaluated contributions of EPAS1 SNPs to hemoglobin as the response variable using linear regression controlled for age, sex, altitude and EGLN1 genotype. Five of the 10 selected EPAS1 SNPs remained significant after multiple testing corrections (FDR <0.05). At low altitude these SNPs are associated with lower hemoglobin concentration, but the, number of Tibetans with wild-type EGLN1 and EPAS1 haplotypes at higher altitude (>3,500 m; ~11,500 feet) was not sufficient for analysis.In conclusion, we show that the gain-of-function PHD2D4E/C127S is a Tibetan specific variant that forms a part of the genetic basis of high altitude adaption by lowering hemoglobin at all altitudes. Tibetans have a unique EPAS1 haplotype introgressed from prehistoric Denisovans, but no coding mutations in this EPAS1 haplotype were found. However, selected SNPs in this Tibetan EPAS1 haplotypes also contribute to their decreased hemoglobin. At the time of writing of this report we have obtained samples from additional 110 Tibetan subjects from Yushu area of Tibetan Plateau residing at altitude 3500 meters and higher (average 3700m). This will permit more rigorous analyses of combined effect of these two EGLN1 and EPAS1 positively selected Tibetan variants on hemoglobin levels at various altitudes. Our investigation of epigenetic alterations of the DNase hypersensitive regions and methylated regions of the Tibetan selected EPAS1 haplotype and the effect of this EPAS1 haplotype on transcriptome and determination of its functional relevance is in progress. DisclosuresNo relevant conflicts of interest to declare.

Oxygen transport adaptations to exercise in native highland populations.

Oxygen transport adaptations to exercise in native highland populations.

Sea-level haemoglobin concentration is associated with greater exercise capacity in Tibetan males at 4200m.

What is the topic of this review? Recent developments link relatively lower hemoglobin concentration in Tibetans at high altitude to exercise capacity and components of oxygen transport. What advances does it highlight? Haemoglobin concentration (ranging from 15.2 to 22.9gdl(-1) ) in Tibetan males was negatively associated with peak oxygen (O2 ) uptake per kilogram, cardiac output and muscle O2 diffusion conductance. Most variance in the peak O2 uptake per kilogram of Tibetan males was attributed to cardiac output, muscle diffusional conductance and arterial partial pressure of CO2 . The mechanisms underlying these differences in oxygen transport in Tibetans require additional analyses. Despite residence at >4000m above sea level, many Tibetan highlanders, unlike Andean counterparts and lowlanders at altitude, exhibit haemoglobin concentration ([Hb]) within the typical sea-level range. Genetic adaptations in Tibetans are associated with this relatively low [Hb], yet the functional relevance of the lower [Hb] remains unknown. To address this, we examined each major step of the oxygen transport cascade [ventilation (VE), cardiac output (QT) and diffusional conductance in lung (DL) and muscle (DM)] in Tibetan males at maximal exercise on a cycle ergometer. Ranging from 15.2 to 22.9gdl(-1) , [Hb] was negatively associated with peak O2 uptake per kilogram (r=-0.45, P<0.05) and both cardiac output (QT/kg: r=-0.54, P<0.02) and muscle O2 diffusion conductance (DM/kg: r=-0.44, P<0.05) but not ventilation, arterial partial pressure of O2 or pulmonary diffusing capacity. Most variance in peak O2 uptake per kilogram was attributed to QT, DM and arterial partial pressure of CO2 (r(2) =0.90). In summary, lack of polycythaemia in Tibetans is associated with increased exercise capacity, which is explained by elevated cardiac, muscle and, to a small extent, ventilatory responses rather than pulmonary gas exchange. Whether lower [Hb] is the cause or result of these changes in O2 transport or is causally unrelated will require additional study.

Mitochondrial function at extreme high altitude.

At high altitude, barometric pressure falls and with it inspired P(O2), potentially compromising O2 delivery to the tissues. With sufficient acclimatisation, the erythropoietic response increases red cell mass such that arterial O2 content (C(aO2)) is restored; however arterial P(O2)(P(aO2)) remains low, and the diffusion of O2 from capillary to mitochondrion is impaired. Mitochondrial respiration and aerobic capacity are thus limited, whilst reactive oxygen species (ROS) production increases. Restoration of P(aO2) with supplementary O2 does not fully restore aerobic capacity in acclimatised individuals, possibly indicating a peripheral impairment. With prolonged exposure to extreme high altitude (>5500 m), muscle mitochondrial volume density falls, with a particular loss of the subsarcolemmal population. It is not clear whether this represents acclimatisation or deterioration, but it does appear to be regulated, with levels of the mitochondrial biogenesis factor PGC-1α falling, and shows similarities to adapted Tibetan highlanders. Qualitative changes in mitochondrial function also occur, and do so at more moderate high altitudes with shorter periods of exposure. Electron transport chain complexes are downregulated, possibly mitigating the increase in ROS production. Fatty acid oxidation capacity is decreased and there may be improvements in biochemical coupling at the mitochondrial inner membrane that enhance O2 efficiency. Creatine kinase expression falls, possibly impairing high-energy phosphate transfer from the mitochondria to myofibrils. In climbers returning from the summit of Everest, cardiac energetic reserve (phosphocreatine/ATP) falls, but skeletal muscle energetics are well preserved, possibly supporting the notion that mitochondrial remodelling is a core feature of acclimatisation to extreme high altitude.

Adaptation to High Altitude: Phenotypes and Genotypes

Populations residing for millennia on the high-altitude plateaus of the world started natural experiments that we can evaluate to address questions about the processes of evolution and adaptation. A 2001 assessment in this journal summarized abundant evidence that Tibetan and Andean high-altitude natives had different phenotypes, and the article made a case for the hypothesis that different genetic bases underlie traits in the two populations. Since then, knowledge of the prehistory of high-altitude populations has grown, information about East African highlanders has become available, genomic science has grown exponentially, and the genetic and molecular bases of oxygen homeostasis have been clarified. Those scientific advances have transformed the study of high-altitude populations. The present review aims to summarize recent advances in understanding with an emphasis on the genetic bases of adaptive phenotypes, particularly hemoglobin concentration among Tibetan highlanders. EGLN1 and EPAS1 encode two crucial proteins contributing to oxygen homeostasis, the oxygen sensor PHD2 and the transcription factor subunit HIF-2α, respectively; they show signals of natural selection such as marked allele frequency differentiation between Tibetans and lowland populations. EPAS1 genotypes associated in several studies with the dampened hemoglobin phenotype that is characteristic of Tibetans at high altitude but did not associate with the dampened response among Amhara from Ethiopia or the vigorous elevation of hemoglobin concentration among Andean highlanders. Future work will likely develop understanding of the integrative biology leading from genotype to phenotype to population in all highland areas.

Whole-genome sequencing of six dog breeds from continuous altitudes reveals adaptation to high-altitude hypoxia

The hypoxic environment imposes severe selective pressure on species living at high altitude. To understand the genetic bases of adaptation to high altitude in dogs, we performed whole-genome sequencing of 60 dogs including five breeds living at continuous altitudes along the Tibetan Plateau from 800 to 5100 m as well as one European breed. More than 150× sequencing coverage for each breed provides us with a comprehensive assessment of the genetic polymorphisms of the dogs, including Tibetan Mastiffs. Comparison of the breeds from different altitudes reveals strong signals of population differentiation at the locus of hypoxia-related genes including endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) and beta hemoglobin cluster. Notably, four novel nonsynonymous mutations specific to high-altitude dogs are identified at EPAS1, one of which occurred at a quite conserved site in the PAS domain. The association testing between EPAS1 genotypes and blood-related phenotypes on additional high-altitude dogs reveals that the homozygous mutation is associated with decreased blood flow resistance, which may help to improve hemorheologic fitness. Interestingly, EPAS1 was also identified as a selective target in Tibetan highlanders, though no amino acid changes were found. Thus, our results not only indicate parallel evolution of humans and dogs in adaptation to high-altitude hypoxia, but also provide a new opportunity to study the role of EPAS1 in the adaptive processes.

High altitude genetic adaptation in Tibetans: No role of increased hemoglobin–oxygen affinity

High altitude exerts selective evolutionary pressure primarily due to its hypoxic environment, resulting in multiple adaptive responses. High hemoglobin-oxygen affinity is postulated to be one such adaptive change, which has been reported in Sherpas of the Himalayas. Tibetans have lived on the Qinghai-Tibetan plateau for thousands of years and have developed unique phenotypes, such as protection from polycythemia which has been linked to PDH2 mutation, resulting in the downregulation of the HIF pathway. In order to see if Tibetans also developed high hemoglobin-oxygen affinity as a part of their genetic adaptation, we conducted this study assessing hemoglobin-oxygen affinity and their fetal hemoglobin levels in Tibetan subjects from 3 different altitudes. We found normal hemoglobin-oxygen affinity in all subjects, fetal hemoglobin levels were normal in all except one and no hemoglobin variants in any of the subjects. We conclude that increased hemoglobin-oxygen affinity or increased fetal hemoglobin are not adaptive phenotypes of the Tibetan highlanders.

Human adaptation to the hypoxia of high altitude: the Tibetan paradigm from the pregenomic to the postgenomic era

The Tibetan Plateau is one of the highest regions on Earth. Tibetan highlanders are adapted to life and reproduction in a hypoxic environment and possess a suite of distinctive physiological traits. Recent studies have identified genomic loci that have undergone natural selection in Tibetans. Two of these loci, EGLN1 and EPAS1, encode major components of the hypoxia-inducible factor transcriptional system, which has a central role in oxygen sensing and coordinating an organism's response to hypoxia, as evidenced by studies in humans and mice. An association between genetic variants within these genes and hemoglobin concentration in Tibetans at high altitude was demonstrated in some of the studies (8, 80, 96). Nevertheless, the functional variants within these genes and the underlying mechanisms of action are still not known. Furthermore, there are a number of other possible phenotypic traits, besides hemoglobin concentration, upon which natural selection may have acted. Integration of studies at the genomic level with functional molecular studies and studies in systems physiology has the potential to provide further understanding of human evolution in response to high-altitude hypoxia. The Tibetan paradigm provides further insight on the role of the hypoxia-inducible factor system in humans in relation to oxygen homeostasis.

Genomic Analysis of Natural Selection and Phenotypic Variation in High-Altitude Mongolians

Deedu (DU) Mongolians, who migrated from the Mongolian steppes to the Qinghai-Tibetan Plateau approximately 500 years ago, are challenged by environmental conditions similar to native Tibetan highlanders. Identification of adaptive genetic factors in this population could provide insight into coordinated physiological responses to this environment. Here we examine genomic and phenotypic variation in this unique population and present the first complete analysis of a Mongolian whole-genome sequence. High-density SNP array data demonstrate that DU Mongolians share genetic ancestry with other Mongolian as well as Tibetan populations, specifically in genomic regions related with adaptation to high altitude. Several selection candidate genes identified in DU Mongolians are shared with other Asian groups (e.g., EDAR), neighboring Tibetan populations (including high-altitude candidates EPAS1, PKLR, and CYP2E1), as well as genes previously hypothesized to be associated with metabolic adaptation (e.g., PPARG). Hemoglobin concentration, a trait associated with high-altitude adaptation in Tibetans, is at an intermediate level in DU Mongolians compared to Tibetans and Han Chinese at comparable altitude. Whole-genome sequence from a DU Mongolian (Tianjiao1) shows that about 2% of the genomic variants, including more than 300 protein-coding changes, are specific to this individual. Our analyses of DU Mongolians and the first Mongolian genome provide valuable insight into genetic adaptation to extreme environments.

Pulmonary hypertension and the right ventricle in hypoxia

Hypoxia causes pulmonary vasoconstriction. Regional hypoxic vasoconstriction improves the matching of perfusion to alveolar ventilation. Global hypoxic vasoconstriction increases right ventricular afterload. The hypoxic pulmonary pressor response is universal in mammals and in birds, but with considerable interspecies and interindividual variability. Chronic hypoxia induces pulmonary hypertension in proportion to initial vasoconstriction. Prolonged hypoxic exposure is also associated with an increase in red blood cell mass, which aggravates pulmonary hypertension by an increase in blood viscosity. Hypoxic pulmonary hypertension in humans is usually mild to moderate, but pulmonary vascular pressure-flow relationships are steep, which corresponds to a substantial afterload on the right ventricle during exercise. A partial recovery of 10-25% of the hypoxia-induced decrease in maximal oxygen uptake has been reported with intake-specific pulmonary vasodilating interventions. Hypoxia has been reported to decrease myocardial fibre contractility in vitro. However, the acutely hypoxic right ventricle remains able to preserve the coupling of its contractility to increased afterload in intact animals. Echocardiographic studies of the right ventricle in healthy hypoxic human subjects show altered diastolic function, but systolic function that is preserved or even increased acutely and slightly depressed chronically. These findings are more pronounced in patients with chronic mountain sickness. Their clinical significance remains incompletely understood. Almost no imaging studies of right ventricular function have been reported in a minority of subjects who develop severe pulmonary hypertension and clinical right ventricular failure in hypoxia. No imaging studies of right ventricular function during hypoxic exercise in normal subjects are yet available. Thus, while it is plausible that the right ventricle limits exercise capacity in hypoxia, this still needs to be firmly established.

Human adaptability studies at high altitude: Research designs and major concepts during fifty years of discovery

This report presents a perspective on the broad research trends in the biology of human populations at high-altitude and their contributions to the improved understanding of evolution and adaptation. A focus is on the research that has occurred over the past 50 years of anthropological fieldwork on the Andean, Tibetan, and, to a lesser extent, the East African plateaus. With an emphasis on fieldwork studies, this report presents and illustrates major concepts and research designs in published high-altitude studies. Early use of a single population-multiple stress research design focused on Andean Quechua, sometimes in comparison with European or admixed Andean-European samples. That design identified physical and sociocultural environmental factors including cold and under nutrition as well as high-altitude hypobaric hypoxia. Researchers accumulated evidence supporting the hypothesis of four modes of adaptation to a complex Andean highland environment: cultural, acclimatization, developmental, and genetic. The discovery that Andean biological patterns were not replicated among Tibetan highlanders stimulated research on the extent and origins of the contrasts. It also shifted emphasis to a multiple population - single stress study design. The discovery of oxygen-homeostasis-associated genetic loci and traits in all multicellular animals has transformed high-altitude research. Paradoxically, genomic analyses identifying the pertinent biological pathways are likely to return interest to environmental factors other than hypoxia. Details of the proximate mechanisms, the biochemical, and physiological processes underlying the three modes of biological adaptation are accumulating. Better understanding of oxygen-homeostasis processes leads to questions about crossadaptation with other environmental factors. The particulars of the ultimate mechanisms, the evolutionary, and microevolutionary history underlying the population differences are also emerging. For example, similar hemoglobin phenotypes among Tibetan and Ethiopian Amhara highlanders associate with different genetic loci and the variants at those loci are present in most populations regardless of altitude. Continuing fieldwork is urgent because modernization and migration are changing the traditional ways of life and patterns of exposure to the environment among highlanders everywhere.

The Genetic Architecture of Adaptations to High Altitude in Ethiopia

Although hypoxia is a major stress on physiological processes, several human populations have survived for millennia at high altitudes, suggesting that they have adapted to hypoxic conditions. This hypothesis was recently corroborated by studies of Tibetan highlanders, which showed that polymorphisms in candidate genes show signatures of natural selection as well as well-replicated association signals for variation in hemoglobin levels. We extended genomic analysis to two Ethiopian ethnic groups: Amhara and Oromo. For each ethnic group, we sampled low and high altitude residents, thus allowing genetic and phenotypic comparisons across altitudes and across ethnic groups. Genome-wide SNP genotype data were collected in these samples by using Illumina arrays. We find that variants associated with hemoglobin variation among Tibetans or other variants at the same loci do not influence the trait in Ethiopians. However, in the Amhara, SNP rs10803083 is associated with hemoglobin levels at genome-wide levels of significance. No significant genotype association was observed for oxygen saturation levels in either ethnic group. Approaches based on allele frequency divergence did not detect outliers in candidate hypoxia genes, but the most differentiated variants between high- and lowlanders have a clear role in pathogen defense. Interestingly, a significant excess of allele frequency divergence was consistently detected for genes involved in cell cycle control and DNA damage and repair, thus pointing to new pathways for high altitude adaptations. Finally, a comparison of CpG methylation levels between high- and lowlanders found several significant signals at individual genes in the Oromo.