Major gene for percent of oxygen saturation of arterial hemoglobin in Tibetan highlanders

This report employs a statistical genetic approach to analyze quantitative oxygen transport variables in a high-altitude (4,850–5,450 m) native Tibetan population and demonstrates the presence of a major gene influencing % O₂ saturation of arterial hemoglobin. This result suggests the hypothesis that individuals with the dominant allele for higher % O₂ saturation have a selective advantage at high altitude. Studies of the biologically distinctive Himalayan and Andean populations have greatly influenced thinking about ongoing human evolution and adaptation; this is the first statistical evidence for a major gene enhancing oxygen transport in a highaltitude native population. © 1994 wiley-Liss, Inc.     

Tibetan and Andean patterns of adaptation to high-altitude hypoxia

Understanding the workings of the evolutionary process in contemporary humans requires linking the evolutionary history of traits with their current genetics and biology. Unusual environments provide natural experimental settings to investigate evolution and adaptation. The example of high-altitude hypoxia illustrates some of the progress and many of the remaining challenges for studies of evolution in contemporary populations. Current studies exemplify the frequently encountered problem of determining whether large, consistent population differences in mean values of a trait reflect genetic differences. In this review I describe 4 quantitative traits that provide evidence that indigenous populations of the Tibetan and Andean plateaus differ in their phenotypic adaptive responses to high-altitude hypoxia. These 4 traits are resting ventilation, hypoxic ventilatory response, oxygen saturation, and hemoglobin concentration. The Tibetan means of the first 2 traits were more than 0.5 standard deviation higher than the Aymara means, whereas the Tibetan means were more than 1 standard deviation lower than the Aymara means for the last 2 traits. Quantitative genetic analyses of within-population variance revealed significant genetic variance in all 4 traits in the Tibetan population but only in hypoxic ventilatory response and hemoglobin concentration in the Aymara population. A major gene for oxygen saturation was detected among the Tibetans. These findings are interpreted as indirect evidence of population genetic differences. It appears that the biological characteristics of sea-level humans did not constrain high-altitude colonists of the 2 plateaus to a single adaptive response. Instead, microevolutionary processes may have operated differently in the geographically separated Tibetan and Andean populations exposed to the same environmental stress. Knowledge of the genetic bases of these traits will be necessary to evaluate these inferences. Future research will likely be directed toward determining whether the population means reflect differences identified at the chromosomal level. Future research will also likely consider the biological pathways and environmental influences linking genotypes to phenotypes, the costs and benefits of the Tibetan and Andean patterns of adaptation, and the question of whether the observed phenotypes are indeed adaptations that enhance Darwinian fitness.     

Identifying Signatures of Natural Selection in Tibetan and Andean Populations Using Dense Genome Scan Data

High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude.     

Genetic adaptation to high altitude in the Ethiopian highlands

Background

Genomic analysis of high-altitude populations residing in the Andes and Tibet has revealed several candidate loci for involvement in high-altitude adaptation, a subset of which have also been shown to be associated with hemoglobin levels, including EPAS1, EGLN1, and PPARA, which play a role in the HIF-1 pathway. Here, we have extended this work to high- and low-altitude populations living in Ethiopia, for which we have measured hemoglobin levels. We genotyped the Illumina 1M SNP array and employed several genome-wide scans for selection and targeted association with hemoglobin levels to identify genes that play a role in adaptation to high altitude.

Results

We have identified a set of candidate genes for positive selection in our high-altitude population sample, demonstrated significantly different hemoglobin levels between high- and low-altitude Ethiopians and have identified a subset of candidate genes for selection, several of which also show suggestive associations with hemoglobin levels.

Conclusions

We highlight several candidate genes for involvement in high-altitude adaptation in Ethiopia, including CBARA1, VAV3, ARNT2 and THRB. Although most of these genes have not been identified in previous studies of high-altitude Tibetan or Andean population samples, two of these genes (THRB and ARNT2) play a role in the HIF-1 pathway, a pathway implicated in previous work reported in Tibetan and Andean studies. These combined results suggest that adaptation to high altitude arose independently due to convergent evolution in high-altitude Amhara populations in Ethiopia.     

Percent of oxygen saturation of arterial hemoglobin among Bolivian Aymara at 3,900–4,000 m

A range of variation in percent of oxygen saturation of arterial hemoglobin (SaO₂) among healthy individuals at a given high altitude indicates differences in physiological hypoxemia despite uniform ambient hypoxic stress. In populations native to the Tibetan plateau, a significant portion of the variance is attributable to additive genetic factors, and there is a major gene influencing SaO₂. To determine whether there is genetic variance in other high-altitude populations, we designed a study to test the hypothesis that additive genetic factors contribute to phenotypic variation in SaO₂ among Aymara natives of the Andean plateau, a population geographically distant from the Tibetan plateau and with a long, separate history of high-altitude residence. The average SaO₂ of 381 Aymara at 3,900–4,000 m was 92 ± 0.15% (SEM) with a range of 84–99%. The average was 2.6% higher than the average SaO₂ of a sample of Tibetans at 3,800–4,065 m measured with the same techniques. Quantitative genetic analyses of the Aymara sample detected no significant variance attributable to genetic factors. The presence of genetic variance in SaO₂ in the Tibetan sample and its absence in the Aymara sample indicate there is potential for natural selection on this trait in the Tibetan but not the Aymara population. Am J Phys Anthropol 108:41–51, 1999. © 1999 Wiley-Liss, Inc.     

Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara

Elevated hemoglobin concentrations have been reported for high-altitude sojourners and Andean high-altitude natives since early in the 20th century. Thus, reports that have appeared since the 1970s describing relatively low hemoglobin concentration among Tibetan high-altitude natives were unexpected. These suggested a hypothesis of population differences in hematological response to high-altitude hypoxia. A case of quantitatively different responses to one environmental stress would offer an opportunity to study the broad evolutionary question of the origin of adaptations. However, many factors may confound population comparisons. The present study was designed to test the null hypothesis of no difference in mean hemoglobin concentration of Tibetan and Aymara native residents at 3,800–4,065 meters by using healthy samples that were screened for iron deficiency, abnormal hemoglobins, and thalassemias, recruited and assessed using the same techniques. The hypothesis was rejected, because Tibetan males had a significantly lower mean hemoglobin concentration of 15.6 gm/dl compared with 19.2 gm/dl for Aymara males, and Tibetan females had a mean hemoglobin concentration of 14.2 gm/dl compared with 17.8 gm/dl for Aymara females. The Tibetan hemoglobin distribution closely resembled that from a comparable, sea-level sample from the United States, whereas the Aymara distribution was shifted toward 3–4 gm/dl higher values. Genetic factors accounted for a very high proportion of the phenotypic variance in hemoglobin concentration in both samples (0.86 in the Tibetan sample and 0.87 in the Aymara sample). The presence of significant genetic variance means that there is the potential for natural selection and genetic adaptation of hemoglobin concentration in Tibetan and Aymara high-altitude populations. Am J Phys Anthropol 106:385–400, 1998. © 1998 Wiley-Liss, Inc.     

Hemoglobin levels in a Himalayan high altitude population

This report presents data on hemoglobin concentrations in a sample of Himalayan high altitude natives measured at their habitual altitude of residence. In this sample of 270 healthy Tibetan adults resident at 3250–3560 m in Upper Chumik, Nepal, the mean hemoglobin concentration is 16.1 ± 1.2 gm/dl among adult males, 14.4 ± 1.4 gm/dl among premenopausal and 15.0 ± 1.1 gm/dl among postmenopausal adult females. 123 of 126 (98%) males, 96 of 100 (96%) premenopausal and 36 of 44 (82%) postmenopausal females have hemoglobin concentrations within two standard deviations of the sea level mean. These data demonstrate that a healthy population may reside at high altitude without the degree of elevation in hemoglobin widely known and cited for Andean highlanders. Comparing published data on mean hemoglobin concentrations of adult Himalayan and Andean samples residing between 3200 m and 4100 m reveals that Himalayan means are systematically lower. This in turn may account for the reported population differences in the prevalence of chronic mountain sickness (Monge's disease). It is hypothesized that Himalayan and Andean highlanders represent alternative patterns of high altitude hematological adaptation.     

Ventilation and hypoxic ventilatory response of Tibetan and Aymara high altitude natives

Newcomers acclimatizing to high altitude and adult male Tibetan high altitude natives have increased ventilation relative to sea level natives at sea level. However, Andean and Rocky Mountain high altitude natives have an intermediate level of ventilation lower than that of newcomers and Tibetan high altitude natives although generally higher than that of sea level natives at sea level. Because the reason for the relative hypoventilation of some high altitude native populations was unknown, a study was designed to describe ventilation from adolescence through old age in samples of Tibetan and Andean high altitude natives and to estimate the relative genetic and environmental influences. This paper compares resting ventilation and hypoxic ventilatory response (HVR) of 320 Tibetans 9–82 years of age and 542 Bolivian Aymara 13–94 years of age, native residents at 3,800–4,065 m. Tibetan resting ventilation was roughly 1.5 times higher and Tibetan HVR was roughly double that of Aymara. Greater duration of hypoxia (older age) was not an important source of variation in resting ventilation or HVR in either sample. That is, contrary to previous studies, neither sample acquired hypoventilation in the age ranges under study. Within populations, greater severity of hypoxia (lower percent of oxygen saturation of arterial hemoglobin) was associated with slightly higher resting ventilation among Tibetans and lower resting ventilation and HVR among Aymara women, although the associations accounted for just 2–7% of the variation. Between populations, the Tibetan sample was more hypoxic and had higher resting ventilation and HVR. Other systematic environmental contrasts did not appear to elevate Tibetan or depress Aymara ventilation. There was more intrapopulation genetic variation in these traits in the Tibetan than the Aymara sample. Thirty-five percent of the Tibetan, but none of the Aymara, resting ventilation variance was due to genetic differences among individuals. Thirty-one percent of the Tibetan HVR, but just 21% of the Aymara, HVR variance was due to genetic differences among individuals. Thus there is greater potential for evolutionary change in these traits in the Tibetans. Presently, there are two different ventilation phenotypes among high altitude natives as compared with sea level populations at sea level: lifelong sustained high resting ventilation and a moderate HVR among Tibetans in contrast with a slightly elevated resting ventilation and a low HVR among Aymara. Am J Phys Anthropol 104:427–447, 1997. © 1997 Wiley-Liss, Inc.     

Widespread Signals of Convergent Adaptation to High Altitude in Asia and America

Living at high altitude is one of the most difficult challenges that humans had to cope with during their evolution. Whereas several genomic studies have revealed some of the genetic bases of adaptations in Tibetan, Andean, and Ethiopian populations, relatively little evidence of convergent evolution to altitude in different continents has accumulated. This lack of evidence can be due to truly different evolutionary responses, but it can also be due to the low power of former studies that have mainly focused on populations from a single geographical region or performed separate analyses on multiple pairs of populations to avoid problems linked to shared histories between some populations. We introduce here a hierarchical Bayesian method to detect local adaptation that can deal with complex demographic histories. Our method can identify selection occurring at different scales, as well as convergent adaptation in different regions. We apply our approach to the analysis of a large SNP data set from low- and high-altitude human populations from America and Asia. The simultaneous analysis of these two geographic areas allows us to identify several candidate genome regions for altitudinal selection, and we show that convergent evolution among continents has been quite common. In addition to identifying several genes and biological processes involved in high-altitude adaptation, we identify two specific biological pathways that could have evolved in both continents to counter toxic effects induced by hypoxia.     

Hemoglobin concentration of pastoral nomads permanently resident at 4,850-5,450 meters in Tibet

This paper presents data on the hemoglobin concentration of a sample of 103 pastoral nomads who are lifelong residents of Phala, at 4,850-5,450 m, on the northern plateau of the Tibet Autonomous Region of the Peoples' Republic of China. This native population resides at the highest altitude of which we are aware and is thus exposed to the most extreme chronic hypoxic stress. However, they do not exhibit the most pronounced physiological adaptations, i.e., hemoglobin concentrations exceeding those found in all other high-altitude populations. Adult male and female mean hemoglobin concentrations of 18.2 and 16.7 gm/dl, respectively, were found. These data, in conjunction with earlier studies of ethnic Tibetans living at 3,400 m, demonstrate a pattern of increasing hemoglobin concentration (erythrocytosis) at increasing altitude of residence in the Himalayas and Tibet. At the same time, however, the hemoglobin concentration is lower than that found among Andean highlanders. These new data raise the possibility of quantitative population differences in hematological adaptation to high altitude hypoxia.     

LINE-1 and EPAS1 DNA methylation associations with high-altitude exposure

Recent discoveries indicate a genetic basis for high-altitude adaptation among human groups who have resided at high altitude for millennia, including Andeans, Tibetans, and Ethiopians. Yet, genetics alone does not explain the extent of variation in altitude-adaptive phenotypes. Current and past environments may also play a role, and one way to determine the effect of the environment is through the epigenome. To characterize if Andean adaptive responses to high altitude have an epigenetic component, we analyzed DNA methylation of the promoter region of EPAS1 and LINE-1 repetitive element among 572 Quechua individuals from high- (4,388 m) and low-altitude (0 m) in Peru. Participants recruited at high altitude had lower EPAS1 DNA methylation and higher LINE-1 methylation. Altitude of birth was associated with higher LINE-1 methylation, not with EPAS1 methylation. The number of years lived at high altitude was negatively associated with EPAS1 methylation and positively associated with LINE-1 methylation. We found four one-carbon metabolism SNPs (MTHFD1 rs2236225, TYMS rs502396, FOLH1 rs202676, GLDC rs10975681) that cumulatively explained 11.29% of the variation in average LINE-1 methylation. And identified an association between LINE-1 methylation and genome-wide SNP principal component 1 that distinguishes European from Indigenous American ancestry suggesting that European admixture decreases LINE-1 methylation. Our results indicate that both current and lifetime exposure to high-altitude hypoxia have an effect on EPAS1 and LINE-1 methylation among Andean Quechua, suggesting that epigenetic modifications may play a role in high-altitude adaptation.     

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.     

GCH1 plays a role in the high-altitude adaptation of Tibetans

Tibetans are well adapted to high-altitude hypoxia.Previous genome-wide scans have reported many candidate genes for this adaptation,but only a few have been studied.Here we report on a hypoxia gene (GCH1,GTP-cyclohydrolase I),involved in maintaining nitric oxide synthetase (NOS) function and normal blood pressure,that harbors many potentially adaptive variants in Tibetans.We resequenced an 80.8 kb fragment covering the entire gene region of GCH1 in 50 unrelated Tibetans.Combined with previously published data,we demonstrated many GCH1 variants showing deep divergence between highlander Tibetans and lowlander Han Chinese.Neutrality tests confirmed a signal of positive Darwinian selection on GCH1 in Tibetans.Moreover,association analysis indicated that the Tibetan version of GCH1 was significantly associated with multiple physiological traits in Tibetans,including blood nitric oxide concentration,blood oxygen saturation,and hemoglobin concentration.Taken together,we propose that GCH1 plays a role in the genetic adaptation of Tibetans to high altitude hypoxia.     

Growth characteristics of populations of Tibetan origin in Nepal.

Previous growth studies of highland-dwelling populations in the ecologically diverse areas of Peru and Ethiopia have yielded highly varied results: the retarded growth of the Peruvian sample was attributed to the effects of hypoxia, while the increased height and weight of the highland Ethiopian sample could be traced to better health conditions in the highland village than in the lowland village studied. In an attempt to provide a basis for evaluating studies of growth at high altitude, the present study compared Sherpa children living in the Everest region of Nepal with Tibetan children living in Kathmandu. It was found that: (1) the growth of Sherpa and Tibetan children is considerably retarded compared to other high altitude populations; (2) despite conditions favorable for optimum growth among the Tibetans, their growth resembled that of the Sherpas and (3) increased chest circumference, which seems to reflect a developmental acclimatization to hypoxia among Peruvian high-altitude natives, was not seen among the Sherpas.     

Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas

Modern humans have occupied almost all possible environments globally since exiting Africa about 100,000 years ago. Both behavioral and biological adaptations have contributed to their success in surviving the rigors of climatic extremes, including cold, strong ultraviolet radiation, and high altitude. Among these environmental stresses, high-altitude hypoxia is the only condition in which traditional technology is incapable of mediating its effects. Inhabiting at >3,000-m high plateau, the Tibetan population provides a widely studied example of high-altitude adaptation. Yet, the genetic mechanisms underpinning long-term survival in this environmental extreme remain unknown. We performed an analysis of genome-wide sequence variations in Tibetans. In combination with the reported data, we identified strong signals of selective sweep in two hypoxia-related genes, EPAS1 and EGLN1. For these two genes, Tibetans show unusually high divergence from the non-Tibetan lowlanders (Han Chinese and Japanese) and possess high frequencies of many linked sequence variations as reflected by the Tibetan-specific haplotypes. Further analysis in seven Tibetan populations (1,334 individuals) indicates the prevalence of selective sweep across the Himalayan region. The observed indicators of natural selection on EPAS1 and EGLN1 suggest that during the long-term occupation of high-altitude areas, the functional sequence variations for acquiring biological adaptation to high-altitude hypoxia have been enriched in Tibetan populations.     

Evolutionary significance of selected EDAR variants in Tibetan high-altitude adaptations

Humans have been exposed to many environmental challenges since their evolutionary origins in Africa and subsequent migrations to the rest of the world. A severe environmental challenge to human migrants was hypoxia caused by low barometric oxygen pressure at high altitudes. Several genome-wide scans have elucidated the genetic basis of human high-altitude adaptations.However, the dearth of functional variant information has led to the successful association of only a few candidate genes. In the present study, we employed a candidate gene approach and re-sequenced the EDAR locus in 45 Tibetan individuals to identify mutations involved in hypoxia adaptation. We identified 10 and five quantitative trait-associated mutations for oxygen saturation (SaO_2) and blood platelet count, respectively, at the EDAR locus. Among these, rs10865026 and rs3749110 (associated with SaO_2 and platelet count, respectively) were identified as functional candidate targets. These data demonstrate that EDAR has undergone natural selection in recent human history and indicate an important role of EDAR variants in Tibetan high-altitude adaptations.     

A Novel Candidate Region for Genetic Adaptation to High Altitude in Andean Populations

Humans living at high altitude (≥2,500 meters above sea level) have acquired unique abilities to survive the associated extreme environmental conditions, including hypoxia, cold temperature, limited food availability and high levels of free radicals and oxidants. Long-term inhabitants of the most elevated regions of the world have undergone extensive physiological and/or genetic changes, particularly in the regulation of respiration and circulation, when compared to lowland populations. Genome scans have identified candidate genes involved in altitude adaption in the Tibetan Plateau and the Ethiopian highlands, in contrast to populations from the Andes, which have not been as intensively investigated. In the present study, we focused on three indigenous populations from Bolivia: two groups of Andean natives, Aymara and Quechua, and the low-altitude control group of Guarani from the Gran Chaco lowlands. Using pooled samples, we identified a number of SNPs exhibiting large allele frequency differences over 900,000 genotyped SNPs. A region in chromosome 10 (within the cytogenetic bands q22.3 and q23.1) was significantly differentiated between highland and lowland groups. We resequenced ~1.5 Mb surrounding the candidate region and identified strong signals of positive selection in the highland populations. A composite of multiple signals like test localized the signal to FAM213A and a related enhancer; the product of this gene acts as an antioxidant to lower oxidative stress and may help to maintain bone mass. The results suggest that positive selection on the enhancer might increase the expression of this antioxidant, and thereby prevent oxidative damage. In addition, the most significant signal in a relative extended haplotype homozygosity analysis was localized to the SFTPD gene, which encodes a surfactant pulmonary-associated protein involved in normal respiration and innate host defense. Our study thus identifies two novel candidate genes and associated pathways that may be involved in high-altitude adaptation in Andean populations.     

Increased vital and total lung capacities in Tibetan compared to Han residents of Lhasa (3,658 m).

Larger chest dimensions and lung volumes have been reported for Andean high-altitude natives compared with sea-level residents and implicated in raising lung diffusing capacity. Studies conducted in Nepal suggested that lifelong Himalayan residents did not have enlarged chest dimensions. To determine if high-altitude Himalayans (Tibetans) had larger lung volumes than acclimatized newcomers (Han "Chinese"), we studied 38 Tibetan and 43 Han residents of Lhasa, Tibet Autonomous Region, China (elevation 3,658 m) matched for age, height, weight, and smoking history. The Tibetan compared with the Han subjects had a larger total lung capacity [6.80 +/- 0.19 (mean +/- SEM) vs 6.24 +/- 0.18 l BTPS, P less than 0.05], vital capacity (5.00 +/- 0.08 vs 4.51 +/- 0.10 1 BTPS, P less than 0.05), and tended to have a greater residual volume (1.86 +/- 0.12 vs 1.56 +/- 0.09 1 BTPS, P less than 0.06). Chest circumference was greater in the Tibetan than the Han subjects (85 +/- 1 vs 82 +/- 1 cm, P less than 0.05) and correlated with vital capacity in each group as well as in the two groups combined (r = 0.69, P less than 0.05). Han who had migrated to high altitude as children (less than or equal to 5 years old, n = 6) compared to Han adult migrants (greater than or equal to 18 years old, n = 26) were shorter but had similar lung volumes and capacities when normalized for body size. The Tibetans' vital capacity and total lung capacity in relation to body size were similar to values reported previously for lifelong residents of high altitude in South and North America. Thus, Tibetans, like North and South American high-altitude residents, have larger lung volumes. This may be important for raising lung diffusing capacity and preserving arterial oxygen saturation during exercise.     

Lung volume, chest size, and hematological variation in low-, medium-, and high-altitude central Asian populations

To evaluate adaptive responses to high-altitude environment, we examined three groups of healthy adult males from Central Asia: 94 high-altitude (HA) Kirghiz subjects (3,200 m above sea level); 114 middle-altitude (MA) Kazakh subjects (2,100 m), and 90 low-altitude (LA) Kirghiz subjects (900 m). Data on chest size (chest perimeter and chest diameter), lung volume (forced expiratory volume (FEV) and forced expiratory volume in 1 sec (FEV1)), and hematological parameters (hemoglobin, erythrocytes, hematocrit, and SaO(2)) are discussed. The results show that 1) chest shape is less flat in the samples living at higher altitude. In the HA sample, chest perimeter is lower but chest excursion is high. 2) In the highlanders, forced vital capacity (FVC) and FEV1 are no higher than in the other samples, even when corrected for stature and body weight. The negative correlation between FVC-FEV1 and age decreases with increasing altitude. 3) The HA and MA samples have higher values of hemoglobin, erythrocytes, and hematocrit. The HA sample has lower SaO(2) and higher arterial oxygen content than the LA sample. No association between hematocrit and age was detected in the four samples. The results indicate that the high-altitude Kirghiz present features of developmental acclimatization to hypobaric hypoxia which are also strongly influenced by other major high-altitude environmental stresses.     

Mitochondrial nt3010G-nt3970C haplotype is implicated in high-altitude adaptation of Tibetans

Tibetans are well adapted to living and thriving in high-altitude environments. Mitochondria are central links to oxygen consumption, and variations in mitochondrial DNA (mtDNA) could play a role in high-altitude adaptation. Alleles at several polymorphic sites in mtDNA define common haplotypes, or haplogroups, including some that have been implicated in the risk of developing certain diseases. However, few reports have determined whether relationships exist between haplogroups and high-altitude adaptation in the Tibetan population. The D4 haplogroup is a major haplogroup of the Han Chinese. In the present study, genotypes of 12 polymorphisms were determined in members of a Tibetan population (n = 72), low altitude-Han (la-Han, n = 144), and high altitude-Han (ha-Han, n = 227) populations using polymerase chain reaction-restriction fragment length polymorphism and polymerase chain reaction-ligase detection reaction assays. The mitochondrial haplogroup D4 was negatively associated with high-altitude adaptation in Tibetans (P = 0.001 vs. la-Han, OR = 0.166, 95% CI = 0.048-0.567; P = 0.009 vs. ha-Han OR = 0.232, 95% CI = 0.069-0.778). The frequency of the nt3010G-nt3970C haplotype was significantly higher in Tibetans than in la-Han (P = 0.000) and ha-Han (P = 0.001) subjects. Findings in the present study suggest that unique mitochondrial variations determine a genetic background that is associated with high-altitude adaptation in the Tibetan population.