Tibetan Genetic Altitude Adaptation

Tibetans, compared with either Andeans or Hans born at altitude, have decreased arterial oxygen content, increased resting ventilation, lack of hypoxic pulmonary vasoconstriction, lower incidence of reduced birth weight, and lower mean hemoglobin (Hb) concentration. The genetic basis for the established greater tolerance to high altitude of Tibetans than Hans is now reported by two groups, published together in Science with a commentary by Gibbons (2010). Simonson et al. (2010) report genome-wide scans revealing positively selected haplotypes of EGLN1 and PPARA involved in activation of hypoxia-inducible factor (HIF) that were significantly associated with the Tibetan decreased hemoglobin phenotype. Yi et al. (2010) in association with Danish biologist Rasmus Nielsen present strong genetic candidates for very rapid adaptation of humans to altitude. They sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes. The strongest signal of natural selection came from endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1). One single-nucleotide polymorphism (SNP) at EPAS1 showed a 78% frequency difference between Tibetans and Hans. EPAS1 is also known as HIF-2a. Each member of the HIF family act on a unique set of regulatory targets. The narrower expression profile of EPAS1 includes adult and fetal lung, placenta, and vascular endothelial cells. A protein-stabilizing mutation in EPAS1 is associated with erythrocytosis suggesting a link between EPAS1 and the regulation of red blood cell production. EPAS1 may therefore represent both the fastest and the strongest instance of natural selection documented in a human population, being so advantageous that it had spread to 90% of all Tibetans in just 4000 years.

In response to these papers in Science, archeologists note that permanent settlement above 4000 m only began 4000 years ago with the domestication of the Yak (Brantingham et al., 2010). Because human tolerance to altitude varies widely, the 2750 year rapid genetic adaptation of Tibetans reported here may not have occurred after settling at high altitude, but as self-selection between migrants who flourished and those who sickened and returned to lower altitudes, e.g. in Mongolia.

Beall et al (2010) used a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han. This revealed a significant divergence across eight SNPs located near EPAS1. In 2 groups of Tibetans, they identified 31 EPAS1 SNPs in high linkage disequilibrium that correlated significantly with hemoglobin concentration. The sex-adjusted hemoglobin concentration was, on average, 0.8 g/dL lower in the major allele homozygotes compared with the heterozygotes. The alleles associating with lower hemoglobin concentrations were correlated with the signal from the GWADS study and were observed at greatly elevated frequencies in the Tibetan cohorts compared with the Han.

Buroker et al (2010) studied five genetic polymorphisms in 98 Han patients with AMS and 60 controls, and 50 Tibetan patients with CMS with 36 controls. ACE D and AGT 235M alleles were found to be significantly associated with AMS and CMS, respectively, while a significantly high incidence of the G-protein (GNB3) (-350)A allele was found in the AMS patients. ACE (I/D) was significantly associated with HR in CMS patients while the AGT M235T was significantly associated with SaO₂ in AMS patients.

Brain Structural Differences Between Sea Level and High Altitude Native Han

Comparing 28 Han college students born to 2^nd–3^rd generation migrants at 2616–4200 m altitude with sea level native Han matched controls, Zhang et al. (2010) report that birth and life long high altitude residence is associated with brain structural modifications, including the loss of regional cortical grey matter accompanied by changes in the white matter.

Possible Roles of Angiogenesis Factors in Higher Birth Weights in Andean Natives at Altitude

In a study of the mechanism whereby altitude decreases birth weight in Europeans but not Andeans, Davila et al. (2010) report that high-altitude decreases sFlt-1 levels in both Europeans and Andeans, but Andeans had lower sFlt-1, comparable PlGF, lower sFlt-1/PlGF ratios, and higher umbilical arterial (UA) blood flow throughout pregnancy relative to Europeans. In high-altitude Europeans sFlt-1/PlGF and sFlt-1 levels were negatively associated with UA diameter and birth weight, respectively. The authors suggest that these differences could potentially influence ancestry-associated differences in birth weight.

Andean–Tibetan Differences in Cerebral Blood Flow (CBF) and Hematocrit (Hct)

Jansen and Basnyat (2010), using a Medline and Embase search, examined 10 studies that investigated CBF in Andeans and Himalayans between 3,658 and 4,330 m altitude. Mean Hct was 50% in Himalayans and 54.1% in Andeans. Arterial oxygen saturation was 86.9% in Andeans and 88.4% in Himalayans. CBF was approximately 24% and 20% higher in Himalayans compared with Andeans before and after correction for differences in Hct and arterial oxygen saturation. I conclude that the lower flow in Andeans does not establish cerebral regulation differences other than due to Hct.

Mutation Associated with High Altitude Paraganglioma

The high incidence of paragangliomas of the head and neck (e.g. carotid body) in high altitude natives may be associated with germ line mutations of SDHB and related genes. Cerecer-Gil et al. (2010) identified a pathogenic missense mutation in exon 7 of SDHB and loss of the SDHB protein in two patients from a Mexican family, born and resident at altitudes of between 1560 and 2240 m, with head and neck paragangliomas, including a remarkably aggressive recurrent tumor.

Nocturnal Periodic Breathing during Acclimatization at Very High Altitude

Despite the rise of SpO₂ with acclimatization, periodic breathing cycles increased over several weeks with acclimatization and with altitude in 34 mountaineers over 19–20 days climbing to high altitude (7546 m in this study) (Bloch et al., 2010). Periodic breathing is driven by the carotid body chemoreceptors, the sensitivity of which may double over the first few weeks at altitude.

Chest Sonograms Detect Subclinical High Altitude Pulmonary Edema

Chest ultrasound can detect lung “comets”, localized evidence of increased extravascular lung water. Pratali et al. (2010) now report clinically silent interstitial pulmonary edema in 18 healthy subjects on a trek in Nepal. Ultrasound lung comets were detected at 28 predefined anterior chest scanning sites in 15 of 18 subjects (83%) at 3440 m and in 18 of 18 subjects (100%) at 4790 m altitude, but none at 1350 m baseline control. Comet score correlated with SpO₂ (P < .0001) but was not correlated with the rise of pulmonary arterial systolic pressure. Group mean systolic PAP rose from 24 ± 5 mmHg at sea level to 42 ± 11 mmHg at 4790 m.

Consensus Guidelines for the Prevention and Treatment of Acute Altitude Illness

To assist practitioners caring for people planning travel to or already at high altitude, Luks et al. (2010) provided evidence-based guidelines for prevention and treatment of acute altitude illnesses, including the main prophylactic and therapeutic modalities for AMS, HACE, and HAPE, and recommendations regarding their role in disease management. The recommended dosages are given for medications most used in the prevention and treatment of altitude illnesses—acetazolamide (diamox) and dexamethasone for acute mountain sickness and high altitude cerebral edema, or nifedipine, and recently tadalafil, sildenafil or salmeterol, for high altitude pulmonary edema.

Impairment of Antioxidant Status by Altitude Training Persists After Training

Because altitude training has been found to impair antioxidant status, Pialoux et al. (2010) tested how long the deficit lasted after training. Eleven elite cross-country skiers from the French Skiing Federation were submitted to 18-day endurance training. Six trained at 1200 m but lived higher (simulated altitude rising from 2500 to 3500 m). Five controls trained and lived at 1200 m. Two weeks after ending the altitude training, the antioxidant trolox equivalent antioxidant capacity (TEAC) lipid-soluble antioxidants (alpha-tocopherol, beta-carotene and lycopene) remained subnormal only in those 6 who had lived at higher altitude.

Hypoxic Respiratory Muscle Fatigue

All skeletal muscle shows more fatigue in work during hypoxia than in normoxia. In order to quantify this effect in respiratory muscles, Verges, Bachasson and Wuyam (2010) measured fatigue of both the diaphragm and abdominal muscles after 15 min bouts of voluntary isocapnic hyperventilation at 85% of each subject's maximum. Fatigue was measured as reductions in transdiaphragmatic pressure during cervical magnetic diaphragm stimulation and abdominal pressure during thoracic magnetic stimulation.

The authors show that fatigue was about 50% greater when SpO₂ was reduced to 80% during testing, compared with either air or oxygen breathing. After 30 min recovery, although the residual fatigue had approximately half recovered, fatigue remained significantly more after hypoxic than normoxic testing.

A Mechanism Linking Hypoxia with Increased Risk of Preeclampsia

Chang et al. (2010), using isolated ovine uterine artery from pregnant ewes in chronic hypoxia (3800 m) in pregnancy, demonstrate that chronic hypoxia in pregnancy inhibits the sex steroid hormone-mediated adaptation of decreased myogenic tone by downregulating estrogen receptor-alpha expression. The authors conclude that this identifies a mechanism linking hypoxia and maladaptation of uteroplacental circulation and an increased risk of preeclampsia in pregnancy.

Long-Term Effects of Preeclampsia on Children at Altitude

Jayet et al. (2010) report that preeclampsia leaves a persistent defect in the systemic and pulmonary circulations of offspring. They assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). In offspring of mothers with preeclampsia, pulmonary artery pressure was higher, 32.1 ± 5.6 (sd) versus 25.3 ± 4.7 mmHg in controls (p < 0.001). Flow-mediated dilation was 30% less, 6.3 ± 1.2% versus 8.3 ± 1.4% in controls (p < 0.0001). Flow-mediated dilation strongly correlated with pulmonary artery pressure (p < 0.001). Siblings of offspring of mothers with preeclampsia who were born after a normal pregnancy had normal vascular function.

High Altitude Upregulates HLA-G, a Fetal Immune Protector

HLA-G is involved protecting the fetus from attack by the maternal immune system and in directing the differentiation of human dendritic cells to promote the evolution of regulatory T cells. Bourguignon et al. (2010) report that HLA-G levels were upregulated in 6 climbers and 3 Sherpas during Everest ascent, adding it to the host of mechanisms participating in adaptation to high altitudes. Hypoxia thus appears to be an important factor in the regulation of HLA-G expression.

Extreme Altitude Hypoxia Impairs Blue Vision Discrimination

During an expedition to Mt. Everest, color discrimination thresholds were measured extensively in two climbers using a quantitative, computer controlled psychophysical color vision test (modified version of the Cambridge Color Test). With increasing altitude, color discrimination thresholds were found to rise, predominantly for the tritan (blue) axes. The deficit was partly reversible during acclimatization and completely normalized upon return to low altitude. Sukhamay ‘Larry’ Lahiri, noted high altitude physiologist who died in 2009, was among the authors (Willmann et al., 2010).

Unique Cytochrome C3 Oxidase Found in Bar-Headed Geese

In bar-headed geese (Anser indicus) flying at up to 9000 m, Scott et al. (2010) report a striking alteration in the kinetics of cytochrome c oxidase, the heteromeric enzyme that catalyzes O₂ reduction in oxidative phosphorylation. The COX3 gene contained a non-synonymous substitution at a site that is otherwise conserved across vertebrates and resulted in a major functional change of amino acid class (Trp-116→Arg). This mutation was predicted by structural modeling to alter the interaction between COX3 and COX1. Compared to low-altitude geese, bar-headed geese have been shown to have larger lungs and higher capillary densities in the left ventricle of the heart, both of which should improve O₂ diffusion during hypoxia. Adaptations in mitochondrial enzyme kinetics and O₂ transport capacity may therefore contribute to the exceptional ability of bar-headed geese to fly high.