High-altitude adaptation in humans

High-altitude adaptation in humans is an instance of

Around 81.6 million humans (approximately 1.1% of the world's human population) live permanently at altitudes above 2,500 meters (8,200 ft),^[4] which would seem to put these populations at risk for chronic mountain sickness (CMS).^[1] However, the high-altitude populations in South America, East Africa, and South Asia have lived there for millennia without apparent complications.^[5] This special adaptation is now recognized as an example of natural selection in action.^[6] The adaptation of the Tibetans is the fastest known example of human evolution, as it is estimated to have occurred between 1,000 BCE^[7][8][9] to 7,000 BCE.^[10][11]

One of the best-documented effects of high altitude on non-adapted women is a progressive reduction in birth weight. By contrast, the women of long-resident, high-altitude populations are known to give birth to heavier-weight infants than women of the lowland. This is particularly true among Tibetan babies, whose average birth weight is 294–650g (~470) g heavier than the surrounding Chinese population, and their blood-oxygen level is considerably higher.^[24]

Scientific investigation of high-altitude adaptation was initiated by A. Roberto Frisancho of the University of Michigan in the late 1960s among the Quechua people of Peru.^[25][26] Paul T. Baker of Penn State University’s Department of Anthropology also conducted a considerable amount of research into human adaptation to high altitudes, and mentored students who continued this research.^[27] One of these students, anthropologist Cynthia Beall of Case Western Reserve University, began conducting decades-long research on high altitude adaptation among the Tibetans in the early 1980s.^[28]

Among the different native highlander populations, the underlying physiological responses to adaptation differ. For example, among four quantitative features, such as resting ventilation, hypoxic ventilatory response, oxygen saturation, and hemoglobin concentration, the levels of variations are significantly different between the Tibetans and the Aymaras.^[29] Methylation also influences oxygenation.^[30]

In the early 20th century, researchers observed the impressive physical abilities of Tibetans during Himalayan climbing expeditions. They considered the possibility that these abilities resulted from an evolutionary genetic adaptation to high-altitude conditions.

With the proper physical preparation, individuals can develop short-term tolerance to high-altitude conditions. However, these biological changes are temporary and will reverse upon returning to lower elevations.[35] Moreover, while lowland people typically experience increased breathing for only a few days after entering high altitudes, Tibetans maintain this rapid breathing and elevated lung capacity throughout their lifetime.^[36] This enables them to inhale large amounts of air per unit of time to compensate for low oxygen levels. Additionally, Tibetans typically have significantly higher levels of nitric oxide in their blood, often double that of lowlanders. This likely contributes to enhanced blood circulation by promoting vasodilation.^[37]

Furthermore, their hemoglobin level is not significantly different (average 15.6 g/dl in males and 14.2 g/dl in females)^[38] from those of humans living at low altitude. This is evidenced by mountaineers experiencing an increase of over 2 g/dl in hemoglobin levels within two weeks at the Mt. Everest base camp.^[39] Consequently, Tibetans demonstrate the capacity to mitigate the effects of hypoxia and mountain sickness throughout their lives. Even when ascending extraordinarily high peaks such as Mount Everest, they exhibit consistent oxygen uptake, heightened ventilation, augmented hypoxic ventilatory responses, expanded lung volumes, increased diffusing capacities, stable body weight, and improved sleep quality compared to lowland populations.^[40]

In contrast to the Tibetans, Andean highlanders show different patterns of hemoglobin adaptation. Their hemoglobin concentration is higher than those of the lowlander population, which also happens to lowlanders who move to high altitudes. When they spend some weeks in the lowlands, their hemoglobin drops to the same levels as lowland humans. However, in contrast to lowland humans, they have increased oxygen levels in their hemoglobin; that is, more oxygen per blood volume. This confers an ability to carry more oxygen in each red blood cell, meaning a more effective transport of oxygen throughout their bodies.

Among the Quechua people of the

The underlying molecular evolution of high-altitude adaptation has been explored in recent years.^[23] Depending on geographical and environmental pressures, high-altitude adaptation involves different genetic patterns, some of which have evolved not long ago. For example, Tibetan adaptations became prevalent in the past 3,000 years, an example of rapid recent human evolution. At the turn of the 21st century, it was reported that the genetic makeup of the respiratory components of the Tibetan and the Ethiopian populations were significantly different.^[29]

Substantial evidence from Tibetan highlanders suggests that variation in hemoglobin and blood-oxygen levels are adaptive as Darwinian fitness. It has been documented that Tibetan women with a high likelihood of possessing one to two alleles for high blood-oxygen content (which is rare in other women) had more surviving children; the higher the oxygen capacity, the lower the infant mortality.^[52] In 2010, for the first time, the genes responsible for the unique adaptive traits were identified following genome sequencing of 50 Tibetans and 40 Han Chinese from Beijing. Initially, the strongest signal of natural selection was a transcription factor involved in response to hypoxia, called endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1). It was found that one single-nucleotide polymorphism (SNP) at EPAS1 shows a 78% frequency difference between Tibetan and mainland Chinese samples, representing the fastest genetic change observed in any human gene to date. Hence, Tibetan adaptation to high altitude is recognized as one of the fastest processes of phenotypically observable evolution in humans,^[53] which is estimated to have occurred a few thousand years ago, when the Tibetans split from the mainland Chinese population. The time of genetic divergence has been variously estimated as 2,750 (original estimate),^[9] 4,725,^[11] 8,000,^[54] or 9,000^[10] years ago.

The patterns of genetic adaptation among the Andeans are largely distinct from those of the Tibetans, with both populations showing evidence of positive natural selection in different genes or gene regions. For genes in the HIF pathway, EGLN1 is the only instance where evidence of positive selection is observed in both Tibetans and Andeans.[66] Even then, the pattern of variation for this gene differs between the two populations.^[6] Furthermore, there are no significant associations between EPAS1 or EGLN1 SNP genotypes and hemoglobin concentration among the Andeans, which is characteristic of the Tibetans.^[67]

The Andean pattern of adaptation is characterized by selection in a number of genes involved in cardiovascular development and function (such as BRINP3, EDNRA, NOS2A).^[68][69] This suggests that selection in Andeans, instead of targeting the HIF pathway like in the Tibetans, focused on adaptations of the cardiovascular system to combat chronic disease at high altitude. Analysis of ancient Andean genomes, some dating back 7,000 years, discovered selection in DST, a gene involved in cardiovascular function.^[70] The whole genome sequences of 20 Andeans (half of them having chronic mountain sickness) revealed that two genes, SENP1 (an erythropoiesis regulator) and ANP32D (an oncogene) play vital roles in their weak adaptation to hypoxia.^[71]

The adaptive mechanism of Ethiopian highlanders differs from those of the Tibetans and Andeans due to the fact that their migration to the highland was relatively early. For example, the

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