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date: 05 July 2022

Adaptations to High-Altitude Hypoxiafree

Adaptations to High-Altitude Hypoxiafree

  • Cynthia M. BeallCynthia M. BeallCase Western Reserve University
  •  and Kingman P. StrohlKingman P. StrohlCase Western Reserve University

Summary

Biological anthropologists aim to explain the hows and whys of human biological variation using the concepts of evolution and adaptation. High-altitude environments provide informative natural laboratories with the unique stress of hypobaric hypoxia, which is less than usual oxygen in the ambient air arising from lower barometric pressure. Indigenous populations have adapted biologically to their extreme environment with acclimatization, developmental adaptation, and genetic adaptation. People have used the East African and Tibetan Plateaus above 3,000 m for at least 30,000 years and the Andean Plateau for at least 12,000 years. Ancient DNA shows evidence that the ancestors of modern highlanders have used all three high-altitude areas for at least 3,000 years. It is necessary to examine the differences in biological processes involved in oxygen exchange, transport, and use among these populations. Such an approach compares oxygen delivery traits reported for East African Amhara, Tibetans, and Andean highlanders with one another and with short-term visitors and long-term upward migrants in the early or later stages of acclimatization to hypoxia. Tibetan and Andean highlanders provide most of the data and differ quantitatively in biological characteristics. The best supported difference is the unelevated hemoglobin concentration of Tibetans and Amhara compared with Andean highlanders as well as short- and long-term upward migrants. Moreover, among Tibetans, several features of oxygen transfer and oxygen delivery resemble those of short-term acclimatization, while several features of Andean highlanders resemble the long-term responses. Genes and molecules of the oxygen homeostasis pathways contribute to some of the differences.

Subjects

  • Biological Anthropology

Introduction

Biological anthropologists aim to explain the hows and whys of human variation using the concepts of evolution and adaptation. Extreme environments and their indigenous populations provide the opportunity to observe the elements of evolution and adaptation: environmental stress, traits with heritable bases, some biological characteristics and their genetic basis, and underlying genotypes having higher survival and reproductive success than others. The outcomes are populations with distinctive biological features and gene pools reflecting those processes. The study of high-altitude populations exemplifies the anthropological approach to understanding modern human biological variation.

Additional environmental stresses at high altitudes include cold, dryness, slow growth of plants and animals, and high solar radiation. The unique stress, however, is hypobaric hypoxia, which is less than usual oxygen in the ambient air arising from lower barometric pressure (fig. 1).

Figure 1. Stress of hypobaric hypoxia. The decline with altitude in the partial pressure of inspired oxygen, expressed as a percentage of the amount at sea level. Oxygen is 21 percent of the air at all altitudes; barometric pressure falls with increasing altitude because there is less air and lower weight of the air above.

(Illustration from Beall [2014]. Used with permission.)

The first anthropological work at high altitudes included cold and nutritional stresses while later efforts focused on hypoxia. The particular interest in hypoxia comes from its uniqueness and the lack of traditional technology to buffer people as it could buffer from environmental stresses such as cold. All people at a given altitude experience the same quantifiable stress. Most anthropological, medical, and physiological work attributed to hypoxia the distinctive biological characteristics of residents.

Figure 2. Map of continents by altitude. Roughly 83 million people live above 2,500 m around the world on four continents. That population estimate used GIS and census data as of 2014 and is substantially lower than the often-quoted 140 million published in 1998 using estimates for total population and land above 2,500 m. People live above 5,000 m in Asia, above 4,000 m in Asia and South America, and above 3,000 m on all four continents. The widest cross-population comparisons occur between 3,000 and 4,000 m, while the widest range of altitudes occur in Asia. Details about the population estimated are available.

(Illustration from Beall [2014]. Used with permission.)

Figure 2 maps the continents by altitude. Studies before the 1970s took place mainly on the Andean plateau of South America. The term “Andean man” came to denote successful adaptation. However, subsequent research on the Central Asian and East African plateaus found that people live successfully at high altitudes but with different biological characteristics. Explaining how highlanders on the various plateaus differ from lowlanders and figuring out how that came about—evolution and genetic adaptation or other modes of adaptation—remains an important area of investigation.

The Prehistory of Indigenous High-Altitude Populations

Some 83 million people on four continents live above 2,500 m, an altitude often used as a threshold for studying biological responses to hypoxia. Populations with millennia of residence at high altitudes live in East Africa, Central Asia, and South America (fig. 2). Information on the prehistory of human use of the high-altitude environments provides evidence on the time available for evolution and adaptation. The population size estimates come from global information systems (GIS) and census data as of 2014, when they totaled roughly 83 million people. That estimate is substantially lower than the often quoted 140 million people published in 1998 using estimates from the predigital era provided by national censuses and atlases to estimate people and land above 2,500 m (Moore et al. 1998).

On the East African Plateau, a rock shelter at 3,500 m in southern Ethiopia dates to 47,000–31,000 years bp (before the present) when the area was cold and glaciated. Hunters and gatherers occupied that residential site, eating local game and using tools made from a nearby source at 4,200 m. We do not know whether the people settled there or used the site regularly or occasionally (Aldenderfer 2019; Ossendorf et al. 2019). Neighboring lowland sites imply ease of movement up and down the altitude gradient. DNA isolated from the skeleton of an individual who lived in an Ethiopian cave 4500 years bp at ~2,000 m had genetic features related to altitude adaptation in Ethiopian highlanders today (Callaway 2015; Gallego Llorente et al. 2015).

People used the Tibetan Plateau before and throughout glaciation. A mandible found in a cave at 3,280 m on the northeast edge of the plateau in mainland China dates to 160,000 years bp (Chen et al. 2019). However, the find may not be relevant to understanding the early use of the plateau because it is not clear how or when it got there, and the dating is indirect. More than 100,000 years later, evidence for seasonal access to the northeastern edges of the plateau occurred 15,000–13,000 years bp. People passed through these areas before then on their way to some of the earliest sites. A central plateau site at 4,600 m in the Tibet Autonomous Region was used 45,000–30,000 years bp during glaciation, perhaps as a toolmaking site for hunting expeditions (Zhang et al. 2018). This central location suggests those early hunters could survive and work for weeks or months on the plateau. The permanent occupation of the central plateau occurred between 12,000 and 7400 years bp (Meyer et al. 2017). Sites on the margins of the plateau likely had easy access to lower-altitude resources, while those on the central plateau did not. Scientists analyzed proteins adhering to the 160,000-year-old mandible to infer the genetic sequences that encoded them. The individual had genetic elements common with people whose bones were found in a low-altitude cave in Siberia. That site, called Denisova Cave, was occupied from roughly 40,000 to 28,000 years bp (Chen et al. 2019). Modern Tibetans also share “Denisovan” genes (Huerta-Sanchez et al. 2014), evidence of a widespread ancestral gene pool in Central and East Asia. Ancient DNA of several individuals buried between 3150 and 2400 years bp on the southern margins of the Tibetan Plateau at sites ranging from 3,000 to 4,000 m show both East Asian ancestry and genetic continuity with modern Tibetans, including genetic variants thought to be adaptive (Jeong et al. 2016).

The earliest sites from the Andes date from 12,800 to 11,800 years bp in a cold, dry glaciated climate and include rock shelters at 3,933–4,500 m, and open-air “workshops” at 4,400–4,500 m. These sites in Peru, Bolivia, and Chile were likely temporarily occupied sites for hunting and toolmaking (Capriles et al. 2016, 2018; Haas et al. 2017; Rademaker et al. 2014) by people from nearby low-altitude sites. Recent evidence from southern Peru suggests that hunters and gatherers permanently occupied the Andean plateau at 3,810 m by at least 7000 bp if not earlier (Haas et al. 2017). Ancient DNA (aDNA) extracted from Andean individuals who lived about 7000 bp at an altitude of 3,800 m shows evidence of a close relationship with modern Andean highlanders (Lindo et al. 2018).

Commonalities among the first high-altitude sites include their use for stone tool manufacture and their occupation during periods of glaciation by hunters or gatherers who exploited ice-free areas. Those people must have had the cultural knowledge and technology to buffer themselves from the cold with clothing and fire. People have used the East African and Tibetan Plateaus above 3,000 m for at least 30,000 years and the Andean Plateau for at least 12,000 years. The aDNA data provide evidence indicating that ancestors of both modern Tibetan and Andean highlanders have used those high-altitude areas of the world for at least 3000 years. These discoveries indicate that the length of habitation at high altitude was sufficient for evolution by natural selection to occur.

Natural selection and other forces of evolution acted on the ancestors of today’s indigenous populations both before and after their upward migrations. Modern Africans exhibit the highest genetic diversity, which declines with distance from East Africa. Stresses such as new climates, diets, and diseases encountered differently during dispersal from East African to Central Asia to South America would have shaped gene pools. Random events, including mutation and fluctuations in numbers that occur uniquely in one population, would also have shaped gene pools. Consequently, the genetics of the ancestral highland populations likely varied, perhaps in ways that influenced biological systems for responses to hypoxia.

Adaptation

Phenotype-Based Models

Evolution by natural selection results in populations well-adapted to their environment. The term “adaptation to the environment” is used in many contexts, all implying the process or state of better function than an alternative. Populations adapt over a range of time and may do so on an ongoing basis, or more than once, and in more than one way. The genetic mode of adaptation denotes a trait with a heritable basis that has increased in frequency over generations owing to natural selection because the resulting form of the trait confers higher survival or reproductive success. The developmental mode refers to “an irreversible trait acquired during the process of growth and development that reflects cellular or organ system plasticity in response to early . . . exposure” (Brutsaert 2016, 102). The acclimatization mode of adaptation consists of immediate (seconds to weeks) physiological processes that reverse upon relief from the stress. Cultural adaption refers to behaviors, practice, or technologies that buffer individuals from the stress or improve the biological response. Traditional cultures could not buffer themselves from high-altitude hypoxia, therefore requiring biological modes.

To distinguish among these various modes, anthropologists Paul Baker and Geoffrey Harrison, who led the earliest anthropological studies of highlanders in Peru and Ethiopia in the 1960s, introduced the migrant model for understanding human adaptation that continues to shape research (Harrison 1966). Applying the migrant model starts by studying a pair of populations at high and low altitudes and documenting biological differences between high-altitude natives at high altitudes with low-altitude natives at low altitudes. Next, low-altitude natives visiting or relocating to high altitudes show the extent to which traits change. The lowlanders at high altitudes offer information about developmental or acclimatization responses depending on the age at and length of exposure. Little resemblance could reflect genetic adaptations by the highlanders or an acclimatization response that mimics a genetic or developmental adaptation by the lowlanders. If the highland population has traits that differ from those of the acclimatization response, then they have experienced either developmental acclimatization or genetic adaptation. High resemblance could reflect acclimatization by both populations. The extent of similarity may change over days, weeks, or months at altitude as initial responses elicit subsequent ones. Reversing the direction of migration from high to low altitude, scientists consider the extent to which the highlanders retain their distinctive biology at low altitude. Showing little evidence of change leads to the inference that developmental or genetic modes operate. If highlanders’ biology comes to resemble that of the lowlanders, it could be due to acclimatization to the removal of altitude stress. Elaborations of the migrant model include extending to multiple high-altitude populations to asking whether high-altitude populations on all continents adapt the same way (they do not). Extending the model to admixed populations such as people of Han Chinese and Tibetan descent or European and Andean descent provides another way to examine the genetic bases of adaptations.

Most studies of biological characteristics—phenotypes—use some version of the migrant model because it remains informative. Since the 1960s, we have become aware of other possible influences on the biology of highlanders (e.g., factors influencing the expression of genes). For example, the study of genomics has transformed our understanding of the genetic mode of adaptation. Despite this, we adopt the genetic–developmental–acclimatization–cultural model of adaptation while acknowledging a need for refinement.

Baker, Harrison, and other early biological anthropologists added to a body of knowledge about high-altitude natives of the Andean Plateau in South America. A Peruvian physician, Carlos Monge, wrote extensively about the “climatic aggression” of high altitude and the success of “Andean man” compared with the Spanish colonizers of that plateau (Monge 1978). Another Peruvian physician, Alberto Hurtado, summarized decades of work in a classic 1964 description of the state of knowledge of high-altitude human biology (Hurtado 1964). He compared Peruvians from the mining town of Morococha at 4,500 m (14,900′) and the city of Lima at 156 m (512′). Hurtado explained that highlanders differ physiologically from their counterparts at low altitudes and from acutely exposed people in ways that appear to offset the high-altitude hypoxic stress. He also described some costs of life at high altitudes. Hurtado, along with others working before the mid-1960s, sought to understand how the organs and systems functioned at high and low altitudes, mainly to improve medical diagnosis and intervention. When biological anthropologists began studying highlanders in the 1960s, they added the perspective of development, evolution, and adaptation.

Genome-Based Models

Understanding of the heritable bases of biological traits has changed rapidly in the 21st century. The migrant model, proposed when the genetic bases of many traits remained rudimentary, relied on analyses of the means of quantitative, continuously varying traits to make inferences about the genetic mode of adaptation. Scientists inferred the genetic mode of adaptation if a trait was stable in multiple environments. The publication of the complete sequence of the human genome in 2003 and the subsequent explosion of genomic sciences introduced new ways to study the genetic mode of adaptation. Measures of the four billion nucleotide base pairs, the building blocks comprising the human genome, became feasible. Nucleotide substitutions occur randomly throughout the genome. When they happen in a sperm or an egg and get transferred to children, over time some people will have the ancestral nucleotide and others will have the substitution. When two or more common variants frequently occur at a site in the genome, they are called single nucleotide polymorphisms, or SNPs (pronounced “snips”). Genomic analyses study SNPs, their frequencies, and their effects on traits (Timpson et al. 2018).

Several genomics analyses using SNPs—candidate gene, genome-wide, and signals of selection—have vastly expanded and enriched the study of indigenous highlanders.

A candidate gene study involves a gene chosen based on knowledge of its biology. It tests the hypothesis that people with specific SNP variants in the candidate gene have different mean values of a trait than people with other SNP variants. For example, a candidate gene study tested the association of SNPs across a gene called EPAS1 (endothelial PAS domain protein) gene with hemoglobin concentration in samples of Tibetan highlanders at 4,200 m and higher (Beall et al. 2010). Tibetans with the most frequent SNP variants at sites across EPAS1 had lower hemoglobin concentration than others. The most frequent trait among Tibetans rarely occurred among Han Chinese. The authors chose to analyze EPAS1 because it plays a role in oxygen sensing and signaling.

Genome-wide studies scan all the nucleotides to find patterns among SNPs, such as unusual allele frequencies that may identify candidate genes. Two genome-wide studies in 2010 identified regions of the genome with known roles in oxygen sensing and signaling. One replicated the finding that SNP sites across EPAS1 associated with lower hemoglobin concentration among Tibetan highlanders (Yi et al. 2010). Another detected two candidate genes and tested for association with hemoglobin concentration. One was EGLN1, a gene encoding an oxygen-sensing protein that is part of the same molecular pathway as EPAS1. EGLN1 and another locus called PPARA together associated with lower hemoglobin concentration among Tibetan highlanders (Simonson et al. 2010), a useful reminder that multiple genes may influence one trait. The most frequent variants among the Tibetans occurred rarely in the related lowland Han Chinese population.

EPAS1 and EGLN1 are part of an ancient oxygen homeostatic system found in all multicellular animals. The system consists of oxygen sensors, transcription factors, and their targets (Rytkönen and Storz 2010). Presently, we know most about the oxygen sensor known as the protein PHD2 (prolyl-hydroxylase 2) encoded by the locus EGLN1 and the transcription factors HIF1 and HIF2 (hypoxia-inducible factors 1 and 2). HIFs are composed of two proteins, encoded by HIF1alpha and HIF1beta in the case of HIF1, and EPAS1 and HIF1beta in the case of HIF2. The HIFs and other factors induce the transcription of hundreds of target genes in response to changes in cellular oxygen levels and do so in a cell-type specific manner (Fratantonio et al. 2018). Integrating the physiological, molecular, and genetic information remains an important goal.

Other analyses search for signals of selection, independent of measures of biological traits. Detecting signatures of selection uses statistical measures comparing SNP site allele frequencies and the patterns of differences for the population of interest relative to a reference sample or samples (Hancock and Di Rienzo 2008; Nielsen 2005).

Figure 3. Best known oxygen homeostasis pathway, including EGLN1, HIF1alpha, EPAS1, and HIF2alpha. Hypoxia-inducible factor (HIF) pathway candidate genes under selection in populations indigenous to the Tibetan, Andean, and East African Plateaus. Candidate genes in blue font show signals of selection in all three populations, those in green font show signals common to Andean and Tibetan highlanders; those in purple font are common to Tibetan and Amhara (Ethiopia), those in red font are common to Amhara and Andean highlanders. The HIF pathway encompasses hundreds of target genes. Twelve genetic loci show signals of selection common to the Tibetan and Andean populations, eight show signals common to the Tibetan and Amhara (Ethiopia) populations, and seven show signals common to the Amhara and Andean populations. (Illustration from Bigham [2016]. Used with permission.)

Bigham (fig. 3) summarized the results of studies focusing on the best known oxygen homeostasis pathway, including EGLN1, HIF1alpha, EPAS1, and HIF2alpha (Bigham 2016). The three high-altitude native populations show signals of selection not found in nearby populations. Moreover, there is little overlap among the three highland populations in the areas of the genome that appear to be under selection. Five signals appear in the figure insets for all three continental groups. Apart from EGLN1, all act on the layer of cells separating the inner arterial walls from the blood (the vascular endothelium). Many other loci show signals of selection in one or two, but not all three populations. The intercontinental variety in the signals of selection implies that there is no unique set of loci underlying all genetic adaptations to high-altitude hypoxia. Signals of selection may also reflect population-specific factors (e.g., arsenic in the soil in the Andes [Schlebusch et al. 2013]).

With these phenotypic and genomic concepts in mind, we turn to the shared or unique patterns of physiological traits found among indigenous high-altitude populations, how they differ from lowlanders, and what we understand about their origins and genetic associations.

Physiology

People and other mammals acquire, deliver, and use oxygen by engaging overlapping physiological processes connecting respiration in the lungs with mitochondrial respiration in the cells. The term “systems biology” describes analyses of large-scale phenomena such as adaptation by putting together the parts, in this case, the interacting traits that result in a successful adaptation. A combination of traits can respond to lower ambient oxygen and may differ among thriving populations.

Figure 4. Interconnected processes of oxygen transfer, oxygen transport, and oxygen use. The external environment and mitochondrial metabolism are coupled by processes in the airways and lungs via the pulmonary circulation to the heart and vasculature. These, in turn, connect via the peripheral circulation to the tissues and cells. The interconnecting gears illustrate that changing one component of the coupled system likely causes other changes. Red indicates oxygenated blood, blue indicates deoxygenated blood. This adaptation of a classic figure called “Wasserman’s gears,” after the original author, Karlman Wasserman, shows the functional interdependence of the mechanisms of oxygen transport and the pervasive role of circulation in coupling them. Variation expressed in any gear likely influences processes elsewhere.

(Illustration adapted and redrawn from Wasserman et al. [1987].)

Figure 4 illustrates the interconnected processes of oxygen transfer (airway and lungs), oxygen transport (heart and peripheral vasculature), and oxygen use (consumption in the tissues and cells). Toothed wheels (cogs) in figure 4 represent each set of processes as part of a set of gears. Some components of oxygen delivery, such as the circulation, are integral to more than one set of processes. This model shows three cogs (toothed wheels) representing physiological systems engaging with one another. Scientists refer to the set of toothed wheels as cogs in gear. Changes in one cog influence the function of others because of their interconnectedness.

Physiology connects ambient oxygen levels with cells to maintain oxygen delivery and changes with altitude. Molecular processes connect with oxygen sensing at the cellular level. The earliest people using the highland areas of the world deployed these oxygen delivery and oxygen homeostasis toolkits already in operation for hundreds of millions of years (Rytkönen and Storz 2010; Semenza 2011). People at all altitudes use this toolkit in everyday settings accompanied by hypoxia, including healthy intrauterine life, sleep, anemia, blood loss, and wound healing, as well as unusual circumstances such as exposure to high-altitude hypoxia. These considerations reasonably lead to the hypothesis that human biology has ample capacity to adapt to high-altitude hypoxia. However, acutely exposed people suffer a loss of work capacity, dulling of the senses, and occasional temporary failures such as acute mountain sickness, or potentially fatal ones such as high-altitude pulmonary edema. In contrast, the vast majority of the 83 million residents who descend from populations with millennia of high-altitude residence do not suffer from these acute maladies.

This narrative review examines phenotypic (observable biology) variation in processes involved in oxygen exchange, oxygen transport, and oxygen use among indigenous high-altitude populations with millennia of residence and exposure to the opportunity for natural selection. It considers reports of samples of ten or more people described with age (usually adults), sex, and ethnicity of study participants, specifying the birthplace and measurement location, and providing information on altitude exposure. Ten or more participants have reasonable potential to capture the normal range of variation. Some studies of acutely exposed visitors measured over days or weeks at altitude have smaller samples. We include them because they effectively illustrate trends over time. We recognize the challenges of comparing studies conducted by different investigators designed for different purposes, using different instruments, protocols, sample sizes, recruiting techniques, and inclusion criteria. We exclude numerous samples without complete description, those of high-altitude natives studied at altitudes substantially higher than their altitude of residence (e.g., Sherpa measured at Everest Base Camp at 5,300 m rather than at the typical Sherpa residential altitudes of 3,400–3,800 m), and populations whose history of residence is little known (e.g., Kyrgyz, Tigrayan, Daghestani). Because there are relatively few data describing East African Amhara populations, Tibetan and Andean populations contribute most of the evidence. Indeed, “The two major human populations that have adapted well to high altitude, the Tibetans and Andeans, have strikingly different phenotypes” (West 2012, 1229). We cover those different phenotypes and their origins and consider how the study of high-altitude populations has and continues to contribute to understanding human biological variation.

Gas Exchange

Lung Volumes

Drawing air into the lungs and the alveoli (tiny air sacs of the lungs where oxygen and carbon dioxide gas exchange occurs) brings about the first contact of ambient oxygen with the oxygen transport system. Forced vital capacity (FVC, the volume of air in a maximal inspiration and expiration) is one indicator of lung volume. For nearly a century, scientists have noted that large lung volumes relative to body size characterize Andean highlanders (Hurtado 1932; Kiyamu et al. 2012). Numerous implementations of the migrant and migrant–admixture models demonstrate the influence of developmental adaptations. For instance, Brutsaert and colleagues implemented the developmental model by comparing eight subsamples. Four had highland ancestry and four had lowland European–North American ancestry. Both ancestry groups had subgroups based on migrant status: non-migrants born and raised at the altitude of testing, migrants to the other altitude during adulthood, migrants to the other altitude during childhood, and “migrants” who were lifelong residents of the other altitude but whose parents or grandparents had migrated (Brutsaert et al. 1999). The samples assessed in their native environments differed markedly, with highlanders having about 17 percent higher FVC than lifelong lowlanders. Adult migrants to both altitudes retained the FVC characteristic of their altitude of birth and developmental period. Both ancestry groups showed developmental acclimatization of FVC to the destination altitude: larger FVC among upward migrants and lower FVC among downward migrants.

A migrant–admixture study design analyzed samples of Andean women born and raised at both high (4,338 m) and low (150 m) altitudes in Peru. The study quantified the percentage of each woman’s Native American Ancestry Proportion, defined as the percentage of a set of single nucleotide polymorphism (SNP) sites with an “Andean” allele (Kiyamu et al. 2012). Developmental exposure contributed to larger FVC for those exposed to hypoxia.

The relatively few data describing lung volumes among Tibetans, Sherpa, and Amhara (Ethiopia) report a trend toward larger FVC in those populations (Droma et al. 1991; Hackett et al. 1980; Harrison et al. 1969; Havryk et al. 2002). Tibetans and Han Chinese teenagers both show evidence of developmental acclimatization (Weitz et al. 2002, 2016), although adults do not, consistent with the findings from the Andes.

FVC plus residual volume (RV), air remaining in the lung after a maximal expiration, comprise total lung volume. RV allows for gas exchange between breaths. Andean and Tibetan highlanders both have higher RV than upward adult migrants of European–North American or Han Chinese descent (Droma et al. 1991; Frisancho et al. 1997; Greksa 1994). The migrant–admixture model applied to samples of Andean women born and raised at 4,338 m, and 150 m detected developmental adaptation and acclimatization in RV (Kiyamu et al. 2012). The authors hypothesized that larger RV leads to higher pulmonary gas exchange. A common theme voiced in these studies expresses the need for longitudinal data to document changes during acclimatization.

Ventilation

Ventilation, the volume of air drawn into the lungs in a given time, quantifies another component of gas exchange. Higher ventilation moves more oxygen into the lungs. The airways and lungs form the interfaces between the environment and internal processes that transport and use oxygen (fig. 5AD).

Figure 5. Ventilation. (A) High-altitude native men have elevated resting ventilation compared with those at low altitude. Each symbol represents the mean of a sample of ten or more men. Tibetans have higher ventilation than Andean highlanders. Both populations show a wide range of variation in ventilation above 3,500 m. Women show the same population contrast (not shown). The panel summarizes six studies of 437 Andean men and five studies of 214 Tibetan men living between 3,500 and 4,600 m. The median resting ventilation for Andean men in that altitude range is 9.3 L/min and the median for Tibetan men is 11.6 L/min. The respective median altitudes are 3825 m and 3658 m. The wide variation among samples in both populations shows that it is important to conduct multiple studies of a trait and studies comparing populations such as those illustrated at 3,900 m.

Source (A): Anderson et al. (1953), Banchero et al. (1966), Beall et al. (1992, 1997c), Brutsaert et al. (2000), Curran et al. (1995, 1998), Ge et al. (1994, 1995), Hackett et al. (1980), Holtby et al. (1988), Huang et al. (1984b), Hultgren et al. (1965a), Hurtado (1964), Kryger et al. (1978), Marconi et al. (2004), Regensteiner et al. (1988), Sun et al. (1990), Vargas et al. (1998), White et al. (1983), and Zhuang et al. (1993).

Figure 5(B). Ventilation measured at maximum work capacity is low at high altitude for both Tibetan and Andean men compared with those at low altitude. Each symbol represents the mean of a sample of five or more men. The explanation for the two clusters of means above 3,500 m, one above 120 L/min and the other below 100 L/min, is unknown. The panel summarizes five studies of 138 Tibetan men (median 3,800 m) and six studies of 153 Andean men at a median altitude of 3,840 m, all living between 3,500 and 4,550 m.

Source (B): Baker (1969), Brutsaert et al. (1999), Curran et al. (1998), Frisancho et al. (1973, 1995), Garrido et al. (1997), Ge et al. (1994, 1995), Horstman et al. (1980), Lahiri et al. (1976), Lawler et al. (1988), Lundby et al. (2004), Maresh et al. (1983), Mazess (1969a), Mazess (1969b), Sun et al. (1990), and Weitz (1984).

Figure 5(C). Resting ventilation increases markedly within the first 5 days of acute exposure to altitude and remains elevated or trends slightly lower within 2–3 weeks. This panel summarizes findings from sixty-two people in six studies and includes samples with fewer than ten people.

Source (C) Grover (1963), Hackett et al. (1980), Insalaco et al. (1996), Marconi et al. (2004), Moore et al. (1987), and Reeves et al. (1967).

Figure 5(D). Migrant men of European or Han Chinese ancestry residing at high altitude for a year or longer have resting ventilation in the middle range of low-altitude men at low altitude. The few samples of Han Chinese men tend to have higher ventilation than long-term migrants from other populations. This summarizes twenty-eight studies of 604 people, including those with sample sizes of five or more participants.

Source (D): Anderson et al. (1953), Bosco et al. (2003), Brutsaert et al. (2000), Dempsey et al. (1971), Fan et al. (2010), Filuk et al. (1988), Ge et al. (1994, 1995), Georgopoulos et al. (1989), Hackett et al. (1980), Holtby et al. (1988), Huang et al. (1984b, 1984c), Hultgren et al. (1965a), Kryger et al. (1978), Marconi et al. (2004), Marcus et al. (1994), Moore et al. (1987), Poulin et al. (1993), Regensteiner et al. (1988, 1990), Schoene (1982), Schoene et al. (1990b), Sun et al. (1990), Tucker et al. (1984), White et al. (1983), and Zhuang et al. (1993).

Figure 5A shows higher resting ventilation (the volume of air breathed in and out for a minute) among Tibetans compared with Andean highlanders. All eight samples of Tibetan highlanders have resting ventilations above 10 L/min compared with just three of the seven Andean samples. The median ventilation among Tibetan men in the most studied residence range of 3,500–4,600 m is 11.6 L/min as compared with 9.3 L/min among the samples of Andean men. Considering a pair of Tibetan and Andean samples at 3,900 m collected specifically for population comparison, the men and women had resting ventilation one standard deviation higher than the Andean (Beall et al. 1997b). That study attributed 31 percent of the variance in Tibetan’s resting ventilation to genetic differences, whereas Andean highlanders showed no evidence of such genetic variation in the trait (Beall et al. 1997b). The presence of genetic variation implied the potential for ongoing natural selection on resting ventilation in the Tibetan population. In contrast to higher resting ventilation among Tibetans, the populations have similar ventilation at maximum work capacity (fig. 5B).

Resting ventilation illustrates the vital point that acclimatization is a process. Among lowlanders acutely exposed to high altitude, an increase in ventilation is key to successful acclimatization (Torrance et al. 1970/1971), although it is not sustained indefinitely. Nearly all the Tibetan samples lie in the same range of variation as the lowlanders acutely exposed to high altitude (fig. 5C). Most of the Andean samples fall in the same range of variation as the lowlanders at low altitude.

The short-term acclimatization response dampens over months to years of exposure (Weil et al. 1970), as illustrated in figure 5D, where six of the eight samples of long-term upward migrants have average ventilation below 10 L/min. The few samples of Han Chinese men tend to have higher ventilation than long-term migrants from other populations. The contrast supports a hypothesis that the distinctive phenotypes in the Tibetan population represent the outcome of evolution by natural selection because the direction of difference—higher ventilation—is the opposite of that exhibited by lowlanders exposed for months or years. The qualitative similarities of Tibetans and acutely exposed individuals or Andean highlanders and chronically exposed individuals may or may not arise from the same mechanism (Storz 2010).

Studies of Andean children, adults of highland ancestry with lifelong or years of residence at low altitude, and adults of Andean–European–North American ancestry concur that the highlanders’ blunted ventilation has a genetic rather than an environmental origin (Beall et al. 1997b; Brutsaert et al. 2004; Vargas et al. 1998). For example, Brutsaert and colleagues quantified the proportion of highland ancestry for samples of acutely exposed lowland Peruvians with mixed Spanish and Andean Native American heritage. They found that the higher the proportion of Native American ancestry, the lower the ventilation. If long-term acclimatization were the explanation, then the degree of admixture would not have been influential. Brutsaert and colleagues concluded that the blunted ventilatory response of Andean highlanders had “both a genetic basis and an evolutionary origin” (Brutsaert et al. 2005, R225).

Taken together, the studies of resting ventilation show considerable variation in average values within the Tibetan and Andean populations along with a pattern of generally higher ventilation among Tibetans than among Andean highlanders. A hypothesis to explain these contrasts reasons that the two populations may have experienced different evolutionary histories. One history resulted in the Tibetans resembling the early acclimatization response and the other resulted in Andean highlanders resembling the late acclimatization response. Currently, any genetic bases for resting ventilation remain unknown. Figures 5AC show considerable variation among samples within populations and indicate the need for work to discover why: for instance, do different measurement techniques or other confounding factors account for the finding?

Control of breathing refers to the mechanisms regulating ventilation. Peripheral chemoreceptors (oxygen-sensing cells) in the carotid body and aorta control breathing (Kumar and Prabhakar 2007; Milsom and Burleson 2007; Powell 2007). Insights into the control of breathing come from experiments exacerbating hypoxia. The hypoxic ventilatory reflex (HVR) is the reflexive increase in ventilation upon experiencing acute exposure to hypoxia at altitude, during acute exposure (fig. 5C), or in the course of an experiment. Tibetan highlanders show the brisk HVR of individuals tested with hypoxia at low altitude. “Andeans, in contrast, show low resting ventilation and a low or ‘blunted’ hvr, with little evidence that these traits are acquired via lifelong exposure” (Brutsaert 2007, 51). Andean highlanders have roughly one standard deviation lower HVR (Beall et al. 1997b; Curran et al. 1995). Andean high-altitude natives have blunted HVR when tested across a range of altitudes (Brutsaert et al. 2005; Vargas et al. 1998). Years of low-altitude residence do not reverse the blunting (Gamboa et al. 2003; Rivera-Ch et al. 2003; Vargas et al. 1998). The blunted response resembles that of long-term upward migrants.

. . . [C]hronic exposure to hypoxia during adulthood in man [sic] results in marked attenuation of the ventilatory response to hypoxia at rest and this is a function of the length of exposure to hypoxia. . . This suggests that the alterations in ventilatory control at altitude are due to failure of peripheral chemoreceptor function.

(Weil et al. 1971a, 186)

Long-term upward migrants of European and Han Chinese descent have attenuated HVR (Brutsaert 2007; Curran et al. 1997; Sun et al. 1990; Terblanche et al. 2005; Zhuang et al. 1993). Men residing at 3,658 m with Tibetan mothers and Han Chinese fathers have blunted HVR, similar to long-term resident upward migrants (Curran et al. 1997).

One reason for the relatively brisk HVR of Tibetans (i.e., similar to unexposed lowlanders) may be high levels of circulating S-nitrosated proteins (SNOs) that can signal hypoxia to the peripheral chemoreceptor in the carotid body (Erzurum et al. 2007; Gaston et al. 2006; Lipton et al. 2001). SNO proteins can release the attached nitric oxide groups as molecules of the vasodilator molecular NO (nitric oxide). Another reason may be loci under selection that associate with the HVR response. Population differences in the control of breathing require further research.

Gilbert-Kawai and colleagues summarized the costs or benefits of sustaining the brisk ventilation of Tibetans or the blunted ventilation of Andean highlander as follows:

The optimum HVR is probably that seen in acclimatized lowlanders and Himalayan highlanders; however, there are distinct advantages to both a “brisk” and a “blunted” response. A brisk response results in hyperventilation and improved oxygen and has been suggested to relate to performance at high altitude. . . . This, however, comes at the cost of increased energy expenditure and a reduction in PaCO2, (CO2 tension in the arteries) which may impair cerebral function by reducing cerebral blood flow. . . . Conversely, a blunted or low HVR conserves energy but results in lower P02 and therefore increases the risk of hypoxia related pathology.

(Gilbert-Kawai et al. 2014, 389–390)

These observations reinforce the cogs-in-a-gear model of oxygen delivery shown in figure 4 by emphasizing that changes in one part influence others.

Pulmonary Vascular Responses to Hypoxia

Hypoxia constricts the pulmonary vasculature at the level of the arterioles (small blood vessels leading to the capillaries where O2 and CO2 are exchanged). In localized hypoxia, such as during lung infection, the constriction directs blood from poorly oxygenated arterioles toward better-oxygenated ones and maintains oxygen delivery. In the case of hypoxia throughout the lung, such as high altitude, the reflex causes widely distributed vasoconstriction that raises pulmonary blood pressure within minutes. The high resting ventilation and brisk HVR of Tibetans lead to expecting more oxygen in the lungs and thus less vasoconstriction. However, the evidence is mixed. Hypoxic pulmonary vasoconstriction is measured as mean pulmonary artery pressure using the invasive method of cardiac catheterization or estimated as systolic pulmonary artery pressure using the non-invasive method of echosonography.

Figure 6. Pulmonary vascular responses to hypoxia. (A) Mean pulmonary artery pressure obtained using cardiac catheterization of samples of Tibetan and Andean highlanders and acclimatized Andean, European, and Han Chinese men shows a wider range of variation at high altitude than at low. The panel summarizes two studies of twenty-seven Tibetan people living between 3,500 and 4,550 m (median 3,804 m) and eight studies of 109 Andean highlanders at a median altitude of 4,303 m and includes samples of three or more participants. Just one sample mean, of Tibetan men, lies in the low-altitude range, while the other means are higher. The median mean pulmonary artery pressure for the Tibetan people is 21.6 mmHg compared with Andean samples at 23 mmHg. Not shown is a study comparing small samples of Tibetan and Han Chinese men across an altitude range from 2,200 to 4,500 m that showed individual Tibetan values consistently lower than the Han Chinese and a smaller increase with altitude (read from fig. 1 in Wu and Kayser 2006).

Sources: (A) Banchero et al. (1966), De Micheli et al. (1960), Douguet et al. (1987), Groves et al. (1993), Hartley et al. (1967), Hultgren et al. (1965a, 1965b), Lockhart (1976), Miao et al. (1994), Moret et al. (1972), Penaloza and Sime (1971), Rotta et al. (1956), Sime et al. (1971, 1974), Spielvogel et al. (1969), and Yang et al. (1985).

Figure 6(B). Systolic pulmonary artery pressure estimated non-invasively using echosonography for Tibetan and Andean highlanders show a wide range of variation above 3,500 m that lies mostly above the range of variation for lowlanders at low altitude. Each symbol represents the mean of a sample of four or more people. Tibetan and Andean values overlap below 4,000 m, and the sole Tibetan sample above 4,000 m lies at the low end of the Andean range of variation. The panel summarizes five studies of 1,099 Tibetan people living between 3,500 and 4,550 m (median 3,875 m) and ten studies of 212 Andean people at a median altitude of 4,300 m. The median systolic pulmonary artery pressure for the Tibetan people is 30.92 mmHg compared with Andean samples at 31.5 mmHg

(B) Albert and Swenson (2014), Antezana et al. (1982, 1998), Banchero et al. (1966), Berger et al. (2009), Bruno et al. (2014), De Micheli et al. (1960), Douguet et al. (1987), Dubowitz and Peacock (2007), Hoiland et al. (2015), Hoit et al. (2006, 2011), Huez et al. (2009), Hultgren et al. (1965a, 1965b), Lockhart et al. (1976), Maignan et al. (2009), Miao et al. (1994), Mishra et al. (2013), Moret et al. (1972), Negi et al. (2013), Ordonez (1969), Penaloza and Sime (1971), Rotta et al. (1956), Sime et al. (1971, 1974), Smith et al. (2006), Stuber et al. (2010), and Yang et al. (1985).

A single study of Tibetans (fig. 6A) reported a mean pulmonary artery pressure twice as high as the healthy, low-altitude range. However, a study not included in figure 6A because it had just five people reported mean pulmonary artery pressure that was “minimally” elevated. This small sample has been influential, and its findings have received support from other lines of evidence (Groves et al. 1993). Supporting evidence comes from findings that Tibetans’ pulmonary artery pressures did not fall while breathing experimentally added oxygen, suggesting that hypoxic vasoconstriction had not occurred (Frise and Robbins 2015; Groves et al. 1993). The average values of the Andean samples (fig. 6A) show pressures in the upper limits of normal and one in the range of clinical pulmonary hypertension.

Other studies report systolic pulmonary artery pressure by non-invasive echosonography. While invasive and non-invasive measures correlate, the latter may give slightly higher values (Allemann et al. 2000). A cluster of Tibetan, Andean, and Amhara samples at 3,500–4,000 m shows values above the sea level range (fig. 6B). Tibetan samples show little evidence of higher pulmonary artery pressure at a higher altitude, while Andean highlanders show such a relationship between 2,500 and 4,500 m (Wu and Kayser 2006). A meta-analysis of articles reporting pulmonary artery systolic pressure measured by echosonography since 2010 concluded that all high-altitude native populations had elevated pulmonary artery systolic pressures and that there were no population differences (Soria et al. 2016). The wide variation in average values among samples in a population suggests the need for considering potential confounding factors such as body iron stores before reaching conclusions about population differences or similarities in hypoxic pulmonary vasoconstriction. For example, the vasodilator nitric oxide in the pulmonary vasculature of Tibetans likely offsets, to a certain extent, hypoxic pulmonary vasoconstriction. One study reported an inverse association between exhaled nitric oxide and pulmonary artery systolic pressure (Beall et al. 2012). Interestingly, 10- to 12-year-old Tibetan and Andean children do not differ in pulmonary artery systolic pressure, and both have values well below those of European migrant children living at the same altitude (Stembridge et al. 2016; Stuber et al. 2008). Any elevation in pulmonary arterial pressure appears to emerge developmentally in the second decade of life (Niermeyer 2003).

Anatomical evidence supports a hypothesis of population differences in the degree of hypoxic pulmonary vasoconstriction. Among Andean highlanders, elevated pulmonary artery pressures remodel the vasculature, which results in thicker, muscularized pulmonary artery walls with narrower interior diameters. Right-ventricular hypertrophy can result from pumping blood against the higher pressures in the pulmonary artery. These anatomical changes take years of low-altitude residence to reverse (Arias-Stella and Saldana 1962; Hogan et al. 1986; Penaloza and Arias-Stella 2007; Tucker et al. 1975). In contrast, Tibetans’ pulmonary arteries and arterioles do not show these anatomical signs of remodeling (Gupta et al. 1992; Heath and Williams 1989; Sharma 1990). These findings support a hypothesis of little pulmonary artery vasoconstriction.

Lowlanders have marked hypoxic pulmonary vasoconstriction reflexes and an increase in pulmonary artery pressures within minutes of exposure (Blitzer et al. 1996; Smith et al. 2008b). Long-term upward migrants sustain the elevated pulmonary artery pressure characteristic of ongoing pulmonary vasoconstriction based on studies of Americans in Colorado and Han Chinese in the Tibet Autonomous Region (Reeves et al. 1994; Reeves and Rubin 1998; Wu and Kayser 2006).

The hypoxic pulmonary vascular response (HPVR) is a vestigial reflex from in utero life where it aids the shunting of blood away from the fetal lungs. In adult life, the same response facilitates the shunting of blood away from areas of poor ventilation and helps maintain ventilation.

(Mortimer et al. 2004, 85)

Thus, this response causes pulmonary vasoconstriction.

Inhaled nitric oxide counteracts hypoxic pulmonary vasoconstriction among acutely exposed lowlanders (Anand et al. 1998). The oxygen homeostasis pathway includes enzymes catalyzing the synthesis of nitric oxide and mutations in EPAS1 associate with pulmonary arterial hypertension (Formenti et al. 2011; Gale et al. 2008). Evidence that Tibetans show a dampened response of EPAS1 target genes is consistent with observations of high pulmonary nitric oxide (Beall 2001; Groves et al. 1993; Hoit et al. 2006; Petousi et al. 2013). These findings suggest the hypothesis that mutations in the oxygen homeostasis.pathway of the Tibetan population contribute to any Tibetan–Andean differences in pulmonary artery pressure. Evidence from large samples could address this comparative question. Andean highlanders resemble lowlanders at high altitude.

Summarizing our comparative understanding of oxygen exchange, Andean highlanders’ phenotypes for resting ventilation, hypoxic ventilatory response, and hypoxic pulmonary vasoconstriction resemble those of long-term upward migrants. In contrast, the Tibetans’ phenotypes for these traits generally resemble either unstressed lowlanders (HVR, maybe hypoxic pulmonary vasoconstriction) or the short-term acclimatization response (ventilation, maybe hypoxic pulmonary vasoconstriction). The Tibetan phenotypes do not change toward the long-term response, which implies that over generations, the survival or reproductive costs of that response outweighed the benefits in this population. Jay Storz and colleagues call this pattern “adaptive cryptic evolution” “in which phenotypic similarity between high- and low-altitude populations is attributable to directional selection on genetically based trait variation that offsets environmentally induced changes” (Storz 2010, 4129). In the Tibetan case, a dampened EPAS1/HIF2 response may contribute to offsetting environmentally induced acclimatizations in oxygen exchange.

Gas Transport from the Lungs to the Heart and Peripheral Tissues

Moving oxygen from the lungs to tissues depends on the heart and the blood vessels (fig. 4). Cardiac output (the amount of blood the heart pumps out in a minute) and heart rate measure the first steps.

Cardiac Output and Cardiac Index

Cardiac index (cardiac output divided by body surface area take account of body size) at rest has been reported more often for Andean than Tibetan highlanders and shows a wide range of variation. The cardiac index of Andean highlanders and the sole Tibetan sample overlaps the middle to upper range of low-altitude variation (fig. 7A).

Figure 7. Cardiac output and cardiac index. (A) Cardiac index (cardiac output divided by body surface area) among high-altitude native men lies in the middle to below the low-altitude range. Each symbol represents the mean of a sample of five or more people. The panel summarizes one study of five Tibetan men living between 3,500 and 4,550 m (at 3,658 m) and five studies of 102 Andean men at a median altitude of 4,458 m. The median cardiac index for the Tibetan men is 3.15 L/min/m² and for Andean men it is 3.45 L/min/m².

Sources: (A) Ge et al. (1995), Groves et al. (1993), Hartley et al. (1967), Hultgren et al. (1965a), Moret et al. (1972), Penaloza et al. (1963), Rotta et al. (1956), and Sime et al. (1971).

Figure 7(B): Cardiac output falls during the first days and weeks at altitude. Each symbol represents the mean of a sample. This panel reports on ninety-one people in five studies, some of which have samples of fewer than ten people.

Source (B): Alexander et al. (1967), Groepenhoff et al. (2012), Hirata et al. (1991), Hoon et al. (1977), and Wolfel (1991).

Samples of acutely exposed individuals roughly form two groups: those showing an early increase in cardiac output followed by a later decline at 10 days or later and those showing a decrease in cardiac output over the first month at altitude (fig. 7B). This trait needs more comparative research.

Heart Rate

Heart rate varies widely at all altitudes. The mean heart rates of the two populations overlap at rest and peak exercise. Above 3,000 m, most samples of Tibetans at rest average more than 70 bpm while most samples of Andean highlanders average less than 70 bpm (fig. 8A).

Figure 8. Heart rate. (A) Resting pulse varies widely at all altitudes. Tibetans tend toward higher values above 3,500 m. Each symbol represents the mean of a sample of five or more people. The panel summarizes fourteen studies of 1,751 Tibetans living between 3,500 and 4,600 m (median 3,709 m) and thirteen studies of 664 Andean highlanders at a median altitude of 3,950 m. The median resting pulse for the Tibetans is 74 f/min compared with Andean highlanders for whom it was 71 f/min.

Sources: (A) Alexander et al. (1967), Ali et al. (2012), Alkorta-Aranburu et al. (2012), Antezana et al. (1992), Bailey et al. (2013), Beall et al. (1992, 1997a, 1997c, 2012), Berg et al. (1991), Berger et al. (2009), Bosco et al. (2003), Bruno et al. (2014), Buroker et al. (2012), Chiodi (1957), Cruden (1999), Curran et al. (1995, 1998), Droma et al. (2008), Erzurum et al. (2007), Ge et al. (1994, 1995), Gonzales et al. (2011), Groepenhoff et al. (2012), Huang et al. (1992), A. Hurtado (1964), Janocha et al. (2011), Julian et al. (2013), Lewis et al. (2014), Malville et al. (2001), Marconi et al. (2004), Marcus et al. (1994), Mazess et al. (1969), Mishra et al. (2013), Moller et al. (2001), Moore et al. (2001), Oelz et al. (1986), Poulin et al. (1993), Rotta et al. (1956), Schmidt et al. (1993), Schneider et al. (2001), Sun et al. (1990), Tarazona-Santos et al. (2000), Wolfel (1991, 1998), Yang et al. (2013), and Zhuang et al. (1996).

Figure 8(B): A wide range of peak heart rates above 3,400 m is lower than the range at low altitude. Each symbol represents the mean of a sample of five or more people. The panel summarizes five studies of 136 Tibetans living between 3,500 and 4,550 m (median 3,658 m) and twelve studies of 227 Andean highlanders at a median altitude of 3,925 m. The median maximum pulse for the Tibetan men is 185 f/min compared with Andean men of 182 f/min.

Source (B): Antezana et al. (1992), Baker (1969), Brutsaert et al. (1999), Cornolo et al. (2005), Curran et al. (1998), Frisancho et al. (1973, 1995), Garrido et al. (1997), Ge et al. (1994, 1995), Hochachka et al. (1991), Hoppeler et al. (1985), Horstman et al. (1980), Huang et al. (1992), Hurtado (1964), Lahiri et al. (1976), Lawler et al. (1988), Malville et al. (2001), Maresh et al. (1983), Mazess (1969a, 1969b), Schmidt et al. (1993), Sun et al. (1990), van Hall et al. (2009), Way (1976), and Weitz (1984).

Figure 8(C): Resting pulse increases and remains elevated during the first month of acute exposure to altitude. Each symbol represents the mean of a sample. This panel reports on 104 people in ten studies, including those with small sample sizes.

Source (C): Alexander et al. (1967), Antezana et al. (1994, 1995), Cruden (1999), Groepenhoff et al. (2012), Insalaco et al. (1996), Marconi et al. (2004), Pronk et al. (2003), Reeves et al. (1967), and Wolfel (1991).

Both populations’ peak heart rates lie below those of lowlanders at low altitudes (fig. 8B). Resting heart rate increases upon acute exposure to altitude (fig. 8C), although they may not be maintained (Siebenmann and Lundby 2015). Few studies account for confounding factors such as physical fitness or activity levels. The two populations resemble one another closely in heart rate.

Hemoglobin Concentration

Hemoglobin concentration (the amount of the oxygen-carrying molecules in red blood cells in a volume of blood) was the first oxygen transport trait found to differ consistently between Tibetan and Andean highlanders and the first to be associated reproducibly with loci in the oxygen homeostasis pathway. Substantial evidence supports the conclusion that at the same altitude, and thus the same degree of ambient hypoxia, Andean highlanders have higher hematocrit or hemoglobin concentration than Tibetans. Two studies specifically asked that question. One found that at 3,700 m, Andean men had nearly one standard deviation higher hematocrit (the percent of blood volume comprised by hemoglobin-carrying red blood cells) than Tibetans (Sherpa) (52.5 percent as compared with 48.4 percent) (Winslow et al. 1989). The other reported that at 3,900–4,000 m, Andean men and women had nearly two standard deviations higher hemoglobin concentration compared with Tibetans (19.2 g/dL as compared with 15.7 for men; 17.9 g/dL as compared with 14.2 for women) (Beall et al. 1998).

Tibetan and Andean highlanders both show evidence of reversible hematological acclimatization. Tibetans acutely exposed to low altitude showed a fall of one standard deviation in hemoglobin concentration after 3 weeks (McKenzie et al. 1991). Tibetans residing at low altitudes have hemoglobin concentrations that are one standard deviation lower than those of Han Chinese (Petousi et al. 2013), which suggests a lower homeostatic point for Tibetans regardless of altitude. After Andean men descend, the fall is proportional to the length of time at low altitude: from 0.6 standard deviations over 4 days at low altitude; 1.8 standard deviations over 3–6 weeks and 3.6 standard deviations over 2 years (Faura et al. 1969; Holden et al. 1995; McKenzie et al. 1991; Sime et al. 1971). Accounting for the length of stay at low altitude, Tibetans experience smaller de-acclimatization responses consistent with their relatively unelevated hemoglobin concentrations at altitude.

Figure 9. Hemoglobin concentration. (A) Hemoglobin concentration of samples of men who were lifelong residents and members of indigenous populations at various altitudes. Each symbol represents the mean of a sample of ten or more people. Hemoglobin concentration varies widely within and among populations. Few studies consider influences other than altitude such as rural–urban residence (rural residents have lower hemoglobin concentration than urban), iron status (a few Tibetan and Andean samples and the Amhara and Oromo are described as iron sufficient), or intrapopulation variation in genetic structure (e.g., the west to east cline among Tibetans, reported by Jeong et al. 2017). This panel presents twenty-nine Andean, twenty-eight Tibetan, two Amhara (Ethiopia), and one Oromo (Ethiopia) sample. Between 3,500 m and 4,600 m altitude, the median hemoglobin concentration of 16.9 g/dL for twenty-three samples, including 736 Tibetan men, was significantly lower than the median of 18.1 g/dL for twenty-eight samples, including 2,390 Andean men. Two samples of Amhara (Ethiopia) men have unelevated hemoglobin concentration very similar to the Tibetans, while the single sample of Oromo (Ethiopia) resembles the highest of the Andean samples.

Sources (A): Adams and Shresta (1974), Adams and Strang (1975), Alkorta-Aranburu et al. (2012), Bailey et al. (2013), Banchero et al. (1966), Basu et al. (2007), Beall and Goldstein (1987, 1990), Beall and Reichsman (1984), Beall et al. (1990, 1992, 1998, 2002, 2012), Bharadwaj et al. (1973), Brutsaert et al. (1999, 2000, 2004), Buroker et al. (2012), Cosio (1972), Cotes et al. (1986), Crapo et al. (1999), Curran et al. (1998), Erzurum et al. (2007), Garruto (1976), Garruto and Dutt (1983), Garruto et al. (2003), Ge et al. (1994, 1995), Gonzales et al. (2011), Guleria et al. (1971), Hoit et al. (2006), Huang et al. (1992), Hultgren et al. (1965a), Hurtado et al. (1945), Imai et al. (1995), Jacobs et al. (2013), Jeong et al. (2014), Julian et al. (2013), Larrick and Topgyal (1985), Leon-Velarde et al. (1991, 1994), Marconi et al. (2004), Mazess (1969a, 1969b), Montero et al. (2015), Moret et al. (1972), Penaloza et al. (1963), Petousi et al. (2013), Pugh (1966), Samaja et al. (1979), Santolaya et al. (1981), Schmidt et al. (1993), Schoene et al. (1990a), Sun et al. (1990, 1996), Tarazona-Santos et al. (2000), Velasquez (1972), Vincent et al. (1978), Winslow et al. (1989), Xu et al. (2015), and Zhuang et al. (1993, 1996).

Figure 9(B): Hemoglobin concentration of samples of women who were lifelong residents and members of indigenous populations at various altitudes. Each symbol represents the mean of a sample of ten or more people. The Tibetan–Andean contrast is larger among women than men (panel 9A), perhaps because of fewer samples or perhaps because of not controlling additional confounding factors such as recent pregnancy and childbirth. The panel summarizes five studies of 724 Andean women and thirteen studies of 587 Tibetan women living between 3,500 and 4,600 m. The median hemoglobin g/dL for Andean women is 16.3 g/dL and the median for Tibetan women is 14.9 g/dL. The respective median altitudes are 3,850 and 3,800 m. Two samples of Amhara (Ethiopia) women have unelevated hemoglobin concentration, very similar to the Tibetans, while the single sample of Oromo (Ethiopia) resembles the highest of the Andean samples.

Sources (B): Adams and Shresta (1974), Adams and Strang (1975), Alkorta-Aranburu et al. (2012), Beall and Goldstein (1987, 1990), Beall and Reichsman (1984), Beall et al. (1990, 1998, 2002, 2012), Böning et al. (2004), Brutsaert et al. (2004), Buroker et al. (2012), Cotes et al. (1986), Crapo et al. (1999), Cudkowicz et al. (1972), Erzurum et al. (2007), Garruto et al. (2003), Hoit et al. (2006), Imai et al. (1995), Jeong et al. (2014), Larrick and Topgyal (1985), Moore et al. (2001), Moreno-Black et al. (1984), Santolaya et al. (1981), and Xu et al. (2015).

Figure 9(C): Hemoglobin concentration increases after acute exposure to altitude. The increase occurs from a wide range of baseline pre-exposure hemoglobin concentrations. Each symbol represents the mean of a sample of 101 people in eleven studies provided pre-exposure baseline hemoglobin measurements and measurements after days to weeks at the indicated altitudes.

Sources (C): Antezana et al. (1994, 1995), Dempsey et al. (1975), Groepenhoff et al. (2012), Jacobs et al. (2013), Marconi et al. (2004), Morpurgo et al. (1972), Pronk et al. (2003), Reeves et al. (1967), Vincent et al. (1978), and Wolfel et al. (1991).

Figures 9A and 9B summarize dozens of publications about hemoglobin concentration among highlanders by plotting the published sample averages against the altitude of residence and measurement. Figure 9A compares samples of men. Between 3,500 m and 4,600 m altitude, the samples of Tibetan men have a median hemoglobin concentration of 16.9 g/dL, which is significantly lower than the median of 17.6 g/dL for the samples of Andean men. Figure 9B confirms the finding for women. Fifteen studies of Tibetan women had a median of 14.9 g/dL compared with 16.3 g/dL for seven samples totaling 724 Andean women. Two samples of Amhara (Ethiopia) have unelevated hemoglobin concentrations similar to the Tibetans, while the single sample of Oromo (Ethiopia) resembles the highest of the Andean samples. Hemoglobin concentration shows a substantial sample-to-sample variation in hemoglobin concentration at a given altitude. Few studies consider influences other than altitude, such as iron status (Tufts et al. 1985).

Polymorphisms in two genes central to the oxygen homeostasis pathway associated with variation in hemoglobin concentration among Tibetans. The EGLN1 locus codes for the oxygen sensor protein PHD2 and the EPAS1 locus codes for the alpha subunit of the hypoxia-inducible factor 2 (HIF2) transcription factor that induces dozens of downstream target genes contributing to the homeostatic response, including those involved in the formation of red blood cells and hemoglobin synthesis (Semenza 2009a). SNP site polymorphisms in EGLN1 and EPAS1 associated statistically with a dampened erythropoietic response measured as the relatively low hemoglobin concentration of Tibetans. Two nonsynonymous variants (encoding different amino acids) in EGLN1 associated with hemoglobin concentration in some studies (Peng et al. 2011; Simonson et al. 2010; Xiang et al. 2013, males only), but not others (Bhandari et al. 2017; Jeong et al. 2014; Yang et al. 2017). EPAS1 variants have been associated with hemoglobin concentration in six studies of Tibetans from different geographic areas (Beall et al. 2010; Bhandari et al. 2017; Jeong et al. 2014; Tashi et al. 2017; Yang et al. 2017), with effect sizes ranging from 0.3 to 0.9 g/dL/allele. In a sample of Tibetans, homozygotes for the derived major (most frequent) allele average 0.6 to 1.8 g/dL lower hemoglobin concentration than homozygotes for the minor allele. Study samples ranged in size from 70 to 3,008. Mongolian, Andean, or East African samples did not show these associations (Alkorta-Aranburu et al. 2012; Bigham et al. 2013; Huerta-Sanchez et al. 2013; Scheinfeldt et al. 2012; Xing et al. 2013). Hemoglobin concentration associations with EGLN1 and EPAS1 among Tibetans are the best documented and replicated examples of associating genetic variation with physiological variation among highlanders. EGLN1 and EPAS1 play essential roles in the Tibetan pattern of adaptation. The major EPAS1 alleles among Tibetans have associated with unelevated hemoglobin concentration, hematocrit (Basang et al. 2015; Beall et al. 2010; Peng et al. 2011, 2017; Xiang et al. 2013; Yi et al. 2010), higher serum transferrin (Tashi et al. 2017) and serum lactate (Ge et al. 2012, 2015; Horscroft et al. 2017; Sun et al. 2017), and lower levels of HIF2 and HIF2 target gene mRNA expression (Frise and Robbins 2015; Petousi et al. 2013; Smith et al. 2008a, 2009; Tashi et al. 2017). The major alleles at EPAS1 protect against excessively high hemoglobin concentration, chronic mountain sickness, and low birthweight (Buroker et al. 2012; Xu et al. 2014), as well as perhaps stroke, pulmonary hypertension, and heart disease (Aryal et al. 2017; Cowburn et al. 2016; Zhao et al. 2010). The signals of selection at EGLN1 and EPAS1 reported by numerous studies attest to the success of that evolutionary strategy (Beall et al. 2010; Bhandari et al. 2017; Bigham et al. 2010; Jeong et al. 2014, 2017; Peng et al. 2011, 2017; Simonson et al. 2010, 2012; Tashi et al. 2017; Xiang et al. 2013; Yang et al. 2017; Yi et al. 2010).

Several lines of evidence concur that natural selection acted on these two loci. The genomic studies detecting signals of natural selection reported that the result was an increase in the frequency of response dampening alleles. The EGLN1 and EPAS1 alleles associating with lower hemoglobin concentration have elevated frequencies among Tibetans (Bigham et al. 2010; Buroker et al. 2012; Hanaoka et al. 2012; Lorenzo et al. 2014; Peng et al. 2011; Simonson et al. 2015; Wang et al. 2011; Xu et al. 2011; Yang et al. 2013). EGLN1 and EPAS1 alleles associating with lower hemoglobin concentration increase in frequency with altitude in a pattern roughly paralleling the increasing severity of hypoxia (Bigham et al. 2010; Hackinger et al. 2016; Hanaoka et al. 2012; Peng et al. 2011; Wang et al. 2011; Xu et al. 2011). These findings strongly support a hypothesis that Tibetans’ relatively low average hemoglobin concentrations or closely correlated traits are adaptations reflecting a distinctive gene pool shaped by natural selection. Whether hemoglobin concentration itself is the target of selection or correlates with a different trait under selection is not known (Storz 2010). The genetic and biochemical pathways connecting these loci with hemoglobin concentration and other traits require further study.

Within samples of Tibetans, those with unelevated hemoglobin concentration show evidence of better function. Tibetan men at 4,200 m with unelevated hemoglobin concentration had higher work capacity (Simonson et al. 2015). Tibetan women at 3,000–4,000 m with unelevated hemoglobin concentration had a higher probability that a pregnancy became a livebirth than those with elevated hemoglobin concentration (Cho et al. 2017). Andean women with unelevated hemoglobin concentrations enjoyed better fetal and maternal outcomes of pregnancy regardless of the altitude of residence (Gonzales et al. 2009, 2012a, 2012b), raising the question of why elevated levels persist among Andean highlanders.

Lowlanders’ hemoglobin response to acute hypoxia gives perspective on the Tibetan–Andean–Amhara comparison. Any differences between the acute response of lowlanders and the highlanders’ response may indicate that selection has occurred to change the shared acclimatization response. Hemoglobin concentration increases within days of acute exposure to high altitude and remains elevated (fig. 9C). Long-term upward migrants sustain the elevated hemoglobin concentration, and so do Andean highlanders. This evidence further supports the hypothesis that natural selection acted to dampen the acclimatization response among Tibetans, but not Andean highlanders. This increase in hemoglobin concentration upon acute exposure to altitude arises from HIF2 (EPAS1 encodes the beta subunit of this protein) induction of genes that lead to the production of more hemoglobin-filled red blood cells (Semenza 2009b).

These findings suggest that natural selection dampened the hematological acclimatization response among Tibetans, while Andean highlanders sustained the acclimatization response. We do not know if the same loci account for the same phenotype among lowlanders at altitude and Andean highlanders.

Percent of Oxygen Saturation of Hemoglobin

Oxygen is transported in the vasculature by hemoglobin in red blood cells, as measured by the percentage of oxygen saturation of hemoglobin. A higher percentage of oxygen saturation of hemoglobin could offset the comparatively low hemoglobin concentration of Tibetans compared with Andean highlanders. That is probably not the case, although opinions differ (Gilbert-Kawai et al. 2014; Jansen and Basnyat 2011).

Figure 10. Percent of oxygen saturation of hemoglobin. (A) Percentage of oxygen saturation of hemoglobin is progressively lower at higher altitudes among samples of high-altitude lifelong residents. Each symbol represents the mean of a sample of ten or more people. The range of variation among samples is larger at high altitudes. Tibetans trend toward lower values. The panel summarizes sixteen studies of 1,790 Andean highlanders and twenty-three studies of 3,096 Tibetans living between 3,500 and 4,600 m. The median oxygen saturation for Andean highlanders in that altitude range is 90 percent and that for Tibetans is 89 percent. The respective median altitudes are 3,950 m and 3,800 m.

Sources (A): Ali et al. (2012), Alkorta-Aranburu et al. (2012), Antezana et al. (1992), Bailey et al. (2013), Bailey et al. (2014), Banchero et al. (1966), Beall (2000), Beall and Goldstein (1990), Beall et al. (1992, 1994, 1997b, 1997c, 1998, 1999, 2002, 2012), Berg et al. (1991), Böning et al. (2004), Bruno et al. (2014), Buroker et al. (2012), Chronos et al. (1988), Colice et al. (1993), Curran et al. (1995, 1998), Decker et al. (1991), Droma et al. (2008), Erzurum et al. (2007), Ge et al. (1995, 2002), Gonzales et al. (2011), Groepenhoff et al. (2012), Hoit et al. (2006), Huang et al. (1992), Hultgren et al. (1965a), Jacobs et al. (2013), Jansen et al. (1999, 2007), Jefferson et al. (2002), Julian et al. (2013), Leon-Velarde et al. (1991, 1994), Lewis et al. (2014), Littner et al. (1984), Lozano et al. (1992), Marconi et al. (2004), Marcus et al. (1994), Martin et al. (1989), Mishra et al. (2013), Moller et al. (2001), Moore et al. (2001), Reuland et al. (1991), Sanguinetti et al. (1990), Sun et al. (1990, 1996), Tucker et al. (1984), Villafuerte et al. (2014), Weil et al. (1968), White et al. (1983), Xu et al. (2015), Yang et al. (2013), and Zhuang et al. (1993, 1996).

Figure 10(B): Percentage of oxygen saturation at maximal work capacity is lower among samples of Tibetan men than Andean. Each symbol represents the mean of a sample of five or more people. The panel summarizes four studies of eighty-eight Tibetan men living between 3,500 and 4,550 m (median 3,658 m) and three studies of ninety-one Andean people at a median altitude of 3,750 m. The median maximum oxygen saturation for the Tibetan men is 83.7 percent compared with Andean samples 90.55 percent.

Sources (B): Antezana et al. (1992), Curran et al. (1998), Frisancho et al. (1995), Ge et al. (1995), Horstman et al. (1980), Huang et al. (1992), Lawler et al. (1988), Lundby et al. (2004), Simonson et al. (2014), and Sun et al. (1990).

Figure 10(C): Percentage of oxygen saturation of hemoglobin falls abruptly upon acute exposure and recovers minimally, but does not return to baseline levels, over days to weeks at altitude. Each symbol represents the mean of a sample. This panel reports on eighty-two people in nine studies including those with fewer than ten participants.

Sources (C): Antezana et al. (1994, 1995), Groepenhoff et al. (2012), Insalaco et al. (1996), Jacobs et al. (2013), Marconi et al. (2004), Pronk et al. (2003), White et al. (1987), and Wolfel et al. (1991).

Figures 10AC show a slightly lower percentage of oxygen saturation of hemoglobin among Tibetans than Andean highlanders at the same altitudes. Percentage of oxygen saturation of hemoglobin falls with higher altitudes in both populations (fig. 10A). Saturations of Andean and Tibetan samples overlap considerably in the most common residence range of 3,500–4,600 m (fig. 10B). Tibetan and Andean samples from thirty-nine studies of nearly 5,000 people yield medians of 89 percent and 90 percent of oxygen saturation of hemoglobin, respectively. Those small differences are within the measurement error of most devices. The single comparative study found that Tibetans had a more substantial 2.6 percent lower oxygen saturation than Andean highlanders at 3,900–4,000 m (Beall et al. 1997a). At maximal exercise, Tibetans consistently tolerated 4–7 percent lower saturations than Andean highlanders (fig. 10C) based on studies of nearly 180 men. East African Amhara have the highest saturation, while East African Oromo have the lowest saturations at the altitudes of measurement; however, there are few studies from these populations.

Two lines of evidence hint that the percentage of oxygen saturation of hemoglobin results from a somewhat different set of factors among Tibetans. One is the evidence of significant genetic contributions to variation in saturation among Tibetan, but not Andean highlanders (Beall et al. 1994, 1997a). The other is the report that women at 4,200 m, estimated to have an inferred dominant, autosomal trait for 5–8 percent higher oxygen saturation, had more than twice as many surviving offspring (Beall et al. 2004).

However, candidate gene and genome-wide association (GWAS) studies have not consistently detected associations with saturation among highland populations. Two candidate gene studies rejected the hypothesis of an association of EPAS1 SNPs with oxygen saturation among healthy Tibetans (Simonson et al. 2010; Yi et al. 2010). People of Andean ancestry, whether born at high or low altitudes, with a particular angiotensin-converting enzyme (ACE) (involved in regulating blood pressure and physical performance) genotype, maintained higher saturation during rest and exercise compared to the alternative genotypes (Bigham et al. 2010). However, ACE allele frequencies did not correlate with altitude in Latin American populations, as would be expected if hypoxia had acted as a selective factor (Rupert et al. 1999). GWAS of Amhara (with millennia of high-altitude residence) and Oromo (with 500 years of high-altitude residence) samples in East Africa did not detect associations with oxygen saturation (Alkorta-Aranburu et al. 2012; Scheinfeldt et al. 2012).

During acute exposure to hypoxia, the percentage of oxygen saturation of hemoglobin plunges immediately and then recovers slightly and remains well below pre-exposure levels (fig. 10C). Reeves and colleagues (1993) reported within-sample variation in the percentage of oxygen saturation of hemoglobin ranging from a high of 92 percent to a low of 72 percent on the first day of exposure to 4,300 m. Such variation, if heritable, is necessary for natural selection to occur. Taken together, the evidence for population differences in oxygen saturation is not strong. The wide range of variation within populations suggests the influence of confounding factors.

Oxygen Affinity of Hemoglobin

A strong comparative study of twenty-nine Andean and thirty Tibetan men at 3,700 m found no difference when directly measuring oxygen affinity of hemoglobin after taking into account the levels of two covariates that modify oxygen affinity (Winslow et al. 1981). A study of twenty-one Tibetans at 4,200 m calculated a higher oxygen affinity while another study of twenty Tibetans at 4,320 m found no change in measured oxygen affinity (Simonson et al. 2014; Tashi et al. 2014). Theoretically, only severe hypoxia above 5,000–5,400 m altitudes would favor a higher affinity among humans (Storz 2016). Figure 2 shows that relatively few highlanders reside at that altitude, which suggests that higher oxygen affinity would not have evolved in people.

Blood Flow

Elevated blood flow could offset the relatively low hemoglobin concentration of Tibetans.

Cerebral Blood Flow

The velocity of blood flow through cerebral arteries measures cerebral blood flow. Tibetan and Sherpa middle cerebral artery blood flow did not vary across an altitude range from 1,330 m to 4,243 m (Jansen et al. 2007). The rates of 59–64 cm/sec were about 20 percent higher than those of 49–52 cm/sec reported for Andean highlanders and the sole report of 49 cm/sec for Amhara (Ethiopia) at similar altitudes (Appenzeller et al. 2006; Claydon et al. 2008). Internal carotid artery blood flow shows the same pattern with fewer samples: two Tibetan samples at 3,658 m had nearly 40 percent higher internal carotid artery blood flow than a single Andean sample (Bailliart et al. 1990; Liu et al. 2016). Features of the biology of Tibetan highlanders that lead to the expectation of higher cerebral blood flow include lower hemoglobin and hematocrit, higher brain glucose metabolism, and higher nitric oxide levels (Jansen and Basnyat 2011; Yoon et al. 2012). These influences outweigh the low paCO2 of Tibetans (owing to the high ventilation), which usually associates with lower cerebral blood flow. Comparative studies including all these variables have not been done. In addition to high cerebral resting flow, Tibetans substantially increase cerebral blood flow during exercise while upward migrant Han Chinese do not (Huang et al. 1992).

Among lowlanders, a two-phase acclimatization response to acute hypoxia entails a significant increase in cerebral blood followed by a return to normal within the first week at altitude. The elevated cerebral blood flow with ventilatory acclimatization sustain brain oxygen delivery during acclimatization (Wolff et al. 2002; Xu and Lamanna 2006). In this context, then, the Andean highlanders resemble well-acclimatized lowlanders whose levels returned to normal low-altitude levels while Tibetan highlanders appear to sustain the immediate response.

Forearm and Upper Arm Blood Flow

Resting forearm or upper arm blood flow measures the basal tone of the arterial system. The increase in blood flow after exercise or a sudden increase in local blood volume, known as flow-mediated vasodilation, reflects the function of the endothelium (cellular lining) of the blood vessels. Tibetans at 4,200 m had two to three times higher resting and postexercise forearm blood flow and oxygen delivery than a control sample at low altitude in the United States, a contrast attributed to the high levels of circulating vasodilators among the Tibetans (Erzurum et al. 2007). In contrast, Andean women at 4,370 m compared with those at 150 m had a 40 percent lower resting upper arm (brachial arterial) blood flow at rest measured by ultrasound (Kametas et al. 2002). The different techniques and the different lowland control groups of those two studies limit the Tibetan–Andean comparison.

Conflicting descriptions of the effects of acute exposure on forearm blood flow measured by strain-gauge plethysmography further muddy interpretations. One study found that men acutely exposed to 3,636 m experienced a 20 percent fall in forearm blood flow sustained over a week of exposure (Roy et al. 1968). Two other studies, one of men and one of women acutely exposed to 4,300 m, showed increased blood flow at day 3 and then a return to pre-exposure baselines by day 10 (Weil et al. 1971b; Zamudio et al. 2001). The limited evidence from highlanders and the conflicting evidence from acutely exposed lowlanders prevent any conclusions about population differences.

Uterine Artery Blood Flow

“The 20-fold pregnancy rise in uterine artery (UtA) blood flow is among the greatest physiological changes experienced during the human lifespan” (Browne et al. 2015, 1). Uterine artery blood flow velocity correlates directly with birthweight at altitude (Moore 2017). Near-term Tibetan women showed a 6.4-fold higher uterine blood flow velocity compared with non-pregnant women (Moore et al. 2001). Near-term Andean women showed a 3.6-fold change among Andean women (Julian et al. 2009b). Both Tibetan and Andean highlanders have a larger increase in blood flow velocity to the uteroplacental unit than their upward migrant Han Chinese or European counterparts. For example, near-term pregnant Tibetan women had 20 percent higher blood flow to the uterine artery than Han Chinese women at 3,658 m, which more than offset the 12 percent lower arterial oxygen content of the Tibetans (Moore 1990). Andean near-term women had nearly double the blood flow to the uterine artery of European women at 4,100–4,300 m (Browne et al. 2015; Julian et al. 2011; Wilson et al. 2007). Both Asian high-altitude samples at 3,558 m had higher uterine artery blood flow velocities (49–59 cm/sec) than the European and Andean women (30–36 cm/sec) when they were near-term at 3,600 m. The four samples had similar flows when not pregnant. Different measurement instruments and calculations prevent assuredly concluding that Tibetans have higher blood flow than Andean highlanders near term.

Vasodilators and Vasoconstrictors

Blood flow is proportional to the fourth power of the radius of the vessel (Poiseuille’s equation). Molecular and autonomic nervous system processes influence the balance of vasoconstrictors and vasodilators in the vascular endothelium and smooth muscle and contribute to vessel radius and blood flow. The most often reported vasodilator among highlanders is nitric oxide (NO) or its metabolites (e.g., NO2 [nitrite], NO3 [nitrate]) measured in exhaled breath, plasma, serum, or urine. The most often reported vasoconstrictor is endothelin-1 measured in plasma or serum. Genes involved in the pathways producing these molecules include NOS1 (nitric oxide synthase 1), NOS2 (inducible nitric oxide synthase 2), and EDN (endothelin), which are HIF target genes.

Nitric Oxide in the Pulmonary and Systemic Circulation

The vasodilator nitric oxide (NO) influences blood flow and oxygen delivery. At 4,000 m, Tibetans have exhaled higher concentrations of NO than Andean highlanders (Erzurum et al. 2007; Hoit et al. 2011). Interestingly, 20 min of added oxygen raised exhaled NO among Tibetan, but not Andean highlanders, which suggests that levels are regulated differently in the two populations. Residential altitudes above 4,200 m depress exhaled NO among Tibetans (Beall et al. 2012), which is further evidence that levels are sensitive to oxygen.

NO exerts effects locally. Among Tibetans at 4,200 m, higher vital capacity nitric oxide is associated with lower pulmonary artery pressure but not forearm blood flow. In contrast, plasma measurements of nitric oxide are associated with higher forearm blood flow (Beall et al. 2012). The high exhaled nitric oxide levels likely contribute to offsetting hypoxic pulmonary vasoconstriction. Urinary nitric oxide levels did not associate with pulmonary artery pressure among Amhara in Ethiopia (Hoit et al. 2011), perhaps because that measure estimates whole body production rather than local availability. At the same time, the Amhara highlanders with millennia of high-altitude residence had higher urinary NO levels than Oromo with centuries of such residence, implying relatively more emphasis on vascular adaptation among Amhara (Cheong et al. 2017).

The mechanisms underlying Tibetans’ high levels of nitric oxid remain unclear. Dietary sources have been excluded (Erzurum et al. 2007). Genomic studies detect signs of selection at NOS2 (inducible nitric oxide synthase) in both Andean and Tibetan highlanders, although associations with phenotypes have not been reported. However, unreplicated studies showed signals of selection at two candidate loci, EP300 and GCH, that associate with blood (whole blood, serum, or plasma not specified) levels of nitric oxide. Nonetheless, the adaptive alleles associated with lower nitric oxide levels (Guo et al. 2017; Zheng et al. 2017).

Acutely exposed lowlanders show a transitory early decline in exhaled NO that returns to slightly above baseline within a week. More extensive studies with more prolonged exposure to altitude are necessary because we do not know the time course or trajectory of long-term (months to years) acclimatization of nitric oxide metabolism (Beall et al. 2012). Tibetans exceed low altitude levels, and Andean highlanders meet them.

Endothelin

Endothelin (EDN) is a potent vasoconstrictor. Insufficient information prevents drawing confident conclusions about population similarities or differences in endothelin levels. For example, two samples of Tibetans (including Ladakhis) show a fourfold range of variation from 2 to 8 pg/mL while the single sample of Andean highlanders had less than 2 pg/L concentrations (Painschab et al. 2015; Rajput et al. 2006; Yang et al. 2016). EDN variants associated with varying levels of endothelin in the Tibetan sample; that finding has not been replicated (Rajput et al. 2006).

Endothelin increases upon acute exposure. For instance, trekkers’ endothelin concentration increased from 3.7 to 9.1 and 11.2 pg/mL over 13 days ascending from 1,300 m to 3,400 m and then 5,050 m (Janocha et al. 2011). Non-pregnant women at 3,100 m and 1,500 m in the United States both had endothelin values less than 2 pg/mL (Julian et al. 2008), suggesting that the rise with acute exposure is transient. Further studies may evaluate whether highland populations have similarly elevated endothelin concentrations.

A study of pregnant women in Colorado illustrates the usefulness of evaluating both vasoconstrictors and vasodilators. Higher ratios of plasma endothelin to NOx (nitrite and nitrate) associated with lower birthweights supported other data emphasizing the crucial role of blood flow during pregnancy (Julian et al. 2008). Pregnant women at 3,100 m had twice the endothelin levels as those at 1,500 m, and levels remained the same throughout pregnancy. In contrast and consistent with other studies, the women at 3,100 m had roughly the same concentrations of total nitrite and nitrate, whether they were pregnant or not.

Gas Use: Oxygen Consumption

Basal

Despite the quantitative and qualitative contrasts in oxygen transfer and oxygen transport, Tibetan and Andean highlanders both have minimum levels of oxygen consumption, basal metabolic rates (BMRs), consistent with WHO predictions based on age, sex, and body size. However, only five studies of about one-hundred people, including forty in a single study of Tibetans at 4,850–5,450 m, contribute to knowledge about this phenotype (Beall et al. 1996; Gill and Pugh 1964; Kashiwazaki et al. 1995; Yamauchi and Ohtsuka 2000). Acutely exposed lowlanders show a ~17–27 percent increase in BMR during the first weeks at high altitude, which declines toward their low-altitude baseline. (fig. 11).

Figure 11. Basal metabolic rate (BMR). BMR rises and falls during the first weeks at altitude. This summarizes the results of three studies, including eleven men and eighteen women.

Data courtesy of Butterfield et al. (1992), Grover (1963), and Mawson et al. (2000).

A correlation study concluded that the increased BMR during the first days of exposure explained the increase in ventilation (Huang et al. 1984). The increase in ventilation, heart rate, and the transcription of the many genes associated with the response to acute hypoxia all may contribute to elevating metabolism.

Maximal

Tibetan and Andean highlanders have similar ranges of maximal oxygen uptake; both have higher values than lowlanders living at the same altitudes (fig. 12A).

Figure 12. Maximal oxygen uptake. (A) Peak oxygen consumption among highland men is low in the normal range of variation at low altitude. Each symbol represents the mean of a sample of five or more people. This panel summarizes five studies of 136 Tibetans living between 3,500 and 4,550 m (median 3,658 m) and thirteen studies of 273 Andean highlanders at a median altitude of 3,850 m. The median maximum oxygen consumption for the Tibetans is 51.2 mL/kg/min compared with Andean samples with a median of 46.7 mL/kg/min.

Sources (A): Antezana et al. (1992), Brutsaert et al. (1999, 2000, 2004), Buskirk et al. (1967), Cerretelli et al. (1984), Cornolo et al. (2005), Curran et al. (1998), Dempsey et al. (1975), Desplanches et al. (2014), Donoso (1977), Frisancho et al. (1973, 1995), Garrido et al. (1997), Ge et al. (1994, 1995), Hochachka et al. (1991), Hoppeler et al. (1973, 1985, 1990), Horstman et al. (1980), Huang et al. (1992), Kayser et al. (1991), Lahiri et al. (1976), Lawler et al. (1988), Lundby et al. (2004), Mackenzie et al. (2008), Mazess (1969a, 1969b), Mazess and Larsen (1972), Mazzeo et al. (1991, 1994, 1995), Powers et al. (1984), Robach et al. (2004, 2007), Sun et al. (1990), van Hall et al. (2009), Way (1976), Weitz (1984), and Wolfel (1991).

Figure 12(B). Peak oxygen consumption falls after acute exposure to high altitude for up to 20 days. Each symbol represents the mean of a sample, including those with small sample sizes. This summarizes the results of forty-two people in five studies.

Sources (B): Braun et al. (2000), Dempsey et al. (1975), Horstman et al. (1980), Reeves et al. (1967), and Wolfel (1991).

Figure 12(C). Peak oxygen consumption after acute exposure to altitude remains below low altitude baseline for up to 70 days. This summarizes the results of thirty-eight people in four studies, including those with sample sizes less than ten.

Sources (C): Buskirk et al. (1967), Levett et al. (2012), van Hall et al. (2009), and West et al. (1983).

The median maximum oxygen consumption for the Tibetan samples is 51.2 mL/kg/min compared with Andean samples of 46.69 mL/kg/min. This figure contrasts with an earlier review that included fewer Tibetan samples (Brutsaert 2016). An EGLN1 allele occurring commonly only among Andean highlanders associated with about 11 percent higher maximum oxygen consumption than alternative alleles, an association detected in two independent samples (Brutsaert et al. 2019). Different regions of the EGLN1 locus associate with phenotypes in Tibetan and Andean samples (Heinrich et al. 2019).

Acutely exposed lowlanders show an abrupt fall in maximum oxygen consumption that may rebound slightly over weeks to months at altitude (fig. 12B). The decline is larger for trained than untrained lowlanders (Kollias et al. 1968). Unfortunately, data on trained highlanders are not available. Well-acclimatized European or Han Chinese lowlanders achieve lower maximum oxygen consumption than highlanders (Brutsaert 2016; Marconi et al. 2006). As a result, lowlanders’ activities are more stressful physiologically because they occur at higher work intensity measured as a proportion of their maximum oxygen consumption.

Considering levels of minimum and peak oxygen consumption, both Andean and Tibetan patterns of oxygen delivery successfully result in normal-for-low-altitude oxygen consumption across the entire spectrum of metabolism from minimal to maximal. In contrast, acclimatized lowlanders have a narrower spectrum between their raised BMRs and reduced peak consumptions (fig. 12C).

Andean and Tibetan highlanders may achieve similar Andean and Tibetan levels of oxygen consumption slightly differently. Limited evidence from a paired population comparison suggests that the two populations use somewhat different metabolic responses to oxygen limitation. It reported on the heart and brain glucose metabolism of six Andean and six Tibetan (Sherpa) highlanders studied immediately upon arrival at low altitude and after 3 weeks. The study design presumed they remained acclimatized upon arrival and became de-acclimatized to hypoxia during the 3 weeks at low altitude. In normoxia, the heart muscle preferentially metabolizes free fatty acids that have a higher ATP (the molecule that delivers energy for biochemical processes) yield per unit of carbon than glucose. However, the ATP yield per unit of oxygen is from 50 to 60 percent higher when metabolizing glucose (Hochachka et al. 1996; Holden et al. 1995; McKenzie et al. 1991). When oxygen is limited, as it is at altitude, the yield relative to oxygen may be more critical. Measures of cardiac glucose uptake rates showed population differences. The Andean highlanders arrived at low altitudes showing a cardiac glucose uptake triple that of the Tibetans (Sherpa) upon their arrival and 70 percent higher than a control group of lowlanders. The Andean highlanders’ elevated glucose uptake fell by about one-third over the 3 weeks of de-acclimatization.

In contrast, the Tibetans (Sherpa) arrived at low altitudes with cardiac glucose uptake slightly lower than the low-altitude native controls that rose by more than twofold over 3 weeks of de-acclimatization. That is, Quechua arrived with an elevated cardiac glucose uptake rate that fell during de-acclimatization. In contrast, Tibetans arrived with low-altitude values of glucose uptake rates that rose over the same time. Both populations showed plasticity in cardiac metabolism; however, baselines and directions of change differed.

Brain metabolism, in contrast with the heart, relies on glucose and thus does not have the latitude to switch fuels. Andean highlanders arrived at low altitudes with brain glucose uptake about 20 percent lower than the lowland controls that they sustained. In contrast, the Tibetan (Sherpa) brain glucose metabolism did not differ from that of the lowland controls throughout their stay at low altitude (Hochachka et al. 1996). The authors interpreted the Andean brain hypometabolism as an adaptive response.

Birthweight as an Integrative Measure of Adaptation

Birthweight is an integrative measure of maternal, paternal, and fetal genotypic and phenotypic contributions to high-altitude adaptation (Julian et al. 2009a). Tibetan and Andean highlanders show similar declines in average birthweight with altitude (fig. 13).

Figure 13. Birthweight of Tibetan and Andean highlanders and upward migrant European and Han Chinese residents. The top panel shows that Tibetan and Andean newborns have a smaller decrease in birthweight than that of Europeans and markedly smaller than that of Han Chinese. The bottom panel illustrates the general trend toward lower birthweight at high altitudes, with plots of average birthweights from various studies.

(Illustration from Moore et al. [2004]. Used with permission.)

Moreover, both show less decline in average birthweight than residents of lowland ancestry at similar altitudes. One study reported an association of unspecified size between SNPs in an EPAS1 promoter region and in a target gene called LOX among newborns at 3,800 m in the Tibet Autonomous Region. Figure 5 of that study suggests that the effect size for the least frequent genotype was several hundred grams heavier for newborns (Xu et al. 2014).

Functional studies revealed that the SNP site alleles that associated with heavier newborns are also associated with higher expression of EPAS1 and its target. That finding is inconsistent with the contrasting finding that the most common EPAS1 SNP site alleles associated with evidence of lower expression of EPAS1 (Petousi et al. 2013), yet this is puzzling because of the less frequent alleles associated with heavier babies who presumably have better survival. Birthweights associated with SNPs in PRKAA1 and EDNRA among Andean but not European babies at the same altitude (Bigham et al. 2014). The PRKAA1 allele associating with heavier newborns was more frequent among the Andean women and associated with 258 g heavier newborns. Neither study has been replicated so far. Ancestral genetic background influences birthweight among Andean highlanders. Babies with two Andean parents weighed more than those with one Andean and one European. Babies with Andean fathers also weighed more (Bennett et al. 2008).

Overview

Biological variation is ubiquitous. It occurs within samples, among samples, and in research protocols as a result of confounding factors, as well as between populations. Differences in study design and measurement techniques further complicate interpreting apparent population differences. Our approach of comparing indigenous highlanders with acutely exposed lowlanders showed the need for information on acute exposure measured on fine time scales for several weeks or—even more informative—several months. We gave more weight to specifically designed population comparisons based on the results of paired samples from studies that control for methodology and recruitment criteria. At the same time, these paired comparisons typically sample from a single location. The variation among samples at similar altitudes indicates that local factors contribute to sample differences. Future studies would ideally be paired comparisons and involve two or more sites.

Factors in addition to hypoxia activate the oxygen homeostasis pathway. The clearest example is iron deficiency, which reduces the degradation of the HIFs and could increase the acute responses to high altitude. Environmental influences on iron status could dampen or prolong a hypoxic response (Frise and Robbins 2015; Prabhakar and Semenza 2012). For instance, reducing circulating iron by chelation increases the hypoxic pulmonary vasoconstriction response while iron supplementation dampens that response.

Taking those considerations into account, we can cautiously summarize as follows. The Tibetan pattern of oxygen transfer to the lungs differs from the usual course of acclimatization by retaining features of the short-term (weeks) phase and not progressing to the long-term (months to years) response. Tibetans retain brisk ventilation and hypoxic ventilatory reflex (HVR) and probably reduced pulmonary diffusing capacity, similar to short-term acclimatization. The Andean pattern of oxygen transfer resembles long-term acclimatization in levels of resting ventilation, HVR, hypoxic pulmonary vasoconstriction reflex, and hemoglobin concentration.

The Tibetan pattern of oxygen transport from lungs to heart and tissues also differs from the usual course of acclimatization. Tibetans sustain a dampened response in hemoglobin concentration, an elevated resting heart rate, significantly reduced oxygen saturation at rest, and elevated cerebral blood flow characteristic of short-term acclimatization. Andean highlanders resemble long-term acclimatized individuals in their heart rate, maximal heart rate, percentage of oxygen saturation, hemoglobin concentration, and cerebral and forearm blood flow. However, Tibetan values exceed those of acclimatized lowlanders for traits including the percentage of oxygen saturation at maximal work, uterine blood flow during pregnancy, and nitric oxide metabolism. Andean highlanders also exceed those of acclimatized lowlanders for traits including the percentage of oxygen saturation at maximal work and uterine blood flow during pregnancy.

The population differences in oxygen transfer and oxygen transport support a hypothesis expressed elsewhere (Storz et al. 2010) describing the Tibetan suite of traits as one of cryptic adaptive evolution. The hypothesis reasons that natural selection acted against costly long-term acclimatization responses with the result that Tibetans depart less from the unstressed characteristics of lowlanders.

In contrast, the Tibetan and Andean patterns of oxygen use measured as basal and maximal metabolic rates differ little and resemble those of unstressed lowlanders at low altitude. Likewise, birthweights are similar for the two highland populations and are heavier than those of acclimatized lowlanders. The similarities in these two integrative measures of overall oxygen transport, minimal and maximal oxygen consumption and birthweight, along with their long-term persistence likely reflect two different successful adaptations, one Andean and one Tibetan.

Further Reading

  • Beall, Cynthia M. 2013. “Human Adaptability Studies at High Altitude: Research Designs and Major Concepts During Fifty Years of Discovery.” American Journal of Human Biology 25: 141–147.
  • Moore, L. G. 2017. “Measuring High-Altitude Adaptation.” Journal of Applied Physiology 123 (5): 1371–1385.
  • Storz, J. F., and Z. A. Cheviron. 2021. “Physiological Genomics of Adaptation to High-Altitude Hypoxia.” Annual Review of Animal Biosciences 9: 149–171.

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