How Tibetans Successfully Adapted to High-altitude Environments Due to Genetic Changes

Humans have adjusted to their various environments over hundreds of thousands of years through a wide variety of both behavioral as well as genetic adaptations. One of the most remarkable as well as rapid examples of this is the genetic changes that led to high-altitude tolerance in populations that live in areas like Tibet in southwestern China. However, for the majority of humans, high altitude locations are extremely difficult physiologically to successfully inhabit. At 4,000 meters, every lungful of air has only about 60% of the oxygen present at sea level (Yi et al., 2010). Because of this, elevations above about 7,600 meters become lethal to low-altitude humans due to the body’s hypoxic response to this severe lack of oxygen. Hypoxia is characterized by a number of adverse symptoms, some of the more minor of which include fatigue, dizziness, breathlessness, headaches, insomnia, malaise, nausea, vomiting, body pain, loss of appetite, ear-ringing, blistering, and dilated veins. If hypoxia becomes severe enough, cerebral edema (swelling of the brain) or pulmonary edema (fluid accumulation in the lungs) may result, as well as excessive breathing causing one to burn extra energy even when resting, and finally a gradually decreasing heart rate until possible death (Penaloza & Arias-Stella, 2006). Hypoxia is one of the leading causes of death in mountaineers, making salient the extreme toll high-altitude conditions can have on the average human body (Huey et al., 2001).

However, instead of experiencing some of these potentially life-threatening symptoms in high-altitude areas, Tibetans are remarkably and expertly adapted to their otherwise inhospitable environment on “the roof of the world.” Tibetan populations achieve this with a variety of physiological differences from low-altitude humans, such as decreased levels of hemoglobin (Yi et al., 2010). Normally, the body increases levels of hemoglobin in response to lower levels of oxygen in order to increase red blood cells’ affinity for oxygen; however, this can lead to blood clots, stroke, and even death. Tibetans’ bodies are adapted to their environment so that this potentially fatal response does not occur (Gibbons, 2014). In addition, they are resistant to the normally progressive reduction in birth weight due to altitude; in fact, a progressive increase in birth weight has been observed over the past couple decades in these populations. At birth, babies experience better oxygenation as well to maximize their chances of survival (Yi et al., 2010). Tibetans also breathe more rapidly, inhale more air with each breath, and have enlarged lung volumes to maximize the amount of oxygen that gets to their cells. As a result, their capacity for exercise is increased. Scientists have even discovered that Tibetan populations have naturally higher levels of nitric oxide in their blood. This helps blood vessels dilate for enhanced circulation (Beall et al., 2012).

A number of genes have conferred this variety of physiological adaptations, one of the most positively, highly selected of which being Endothelial PAS domain-containing protein 1, or EPAS1. EPAS1 is a transcription factor involved in the body’s response to hypoxia (Yi et al., 2010). It is associated with a slower-than-normal increase in red blood cell production due to normally hypoxic conditions, which as mentioned above, prevents clots, stroke, and death. In addition, a gene called EGLN1 has also been highly positively selected for in Tibetans, helping to inhibit hemoglobin production under normal oxygen concentration. This also aids in avoiding clots and stroke. PPARA, when inhibited by HIF1a transcription factors, is a gene that prevents the typical reduction in red blood cell production in response to high altitudes, helping to maintain red blood cell levels in concert with EPAS1. Together, these three genes function within the larger hypoxia-inducible factor (HIF) pathway. This pathway generally regulates red blood cell production in response to oxygen metabolism and controls red blood cell production (Simonson et al., 2012; Cheviron & Brumfield, 2011).

A second collection of important genes in long-term altitude acclimatization that have been found near these major “candidate” genes are HBB and HBG2, SPTA1, HFE, and FANCA and PLKR. HBB and HBG2 are associated with delayed transition from fetal to adult hemoglobin, which is thought to aid Tibetans in preventing a number of potential hematological diseases due to high altitudes. SPTA1 is associated with red blood cell shape, and HFE with iron storage. Finally, FANCA and PLKR are associated with red blood cell production and maintenance, respectively (Yi et al., 2010). Because many genes that are close to each other are inherited together, identifying these nearby genes is valuable in determining how Tibetan populations have adapted to their environment genetically. Additionally, women who possess one or two alleles conferring high blood-oxygen content have also been found to be more likely to produce surviving children; these alleles have also been selected for over time (Beall et al., 2004).

From extensive genetic analysis, scientists have been able to conclude that the EPAS1 allele was acquired from archaic hominins called Denisovans about 40,000 years ago (Huerta-Sánchez et al., 2014). Denisovans are more closely related to Neanderthals than modern humans, and once ranged across Asia and up into what is known today as Siberia some 35,000 to 25,000 years ago (Gibbons, 2014; Huerta-Sánchez et al., 2014). Denisova Cave in Siberia, where many Denisovan fossils have been found, was high altitude, but not nearly as high as the Tibetan plateau. However, if Denisovans had the high-altitude version of EPAS1, scientists have concluded this could mean they also went through the more mountainous parts of China and South Asia on their way to spreading through Australia (Huerta-Sánchez et al., 2014). The Tibetan plateau was then colonized around 30,000 years ago by these ancient hominins. This founder population became the broader Han Chinese/Southeast Asian population; the high-altitude demographic of Tibetans began to diverge from the Han Chinese and Dai around 40,000 to 20,000 years ago (Jeong et al., 2014). Initially, the Tibetan population was large, but dwindled in size over time as specific subpopulations became more distinct (Yi et al., 2010). Today, 40% of ethnic Tibetans are nomadic or semi-nomadic, showing that this population has historically traveled around the area extensively and possibly indicating some modes in which ancient Tibetan populations came to inhabit this area (Pistono, n.d.).

Both archaeological and genetic investigation show us that variations in EPAS1 that confer favorable altitude acclimatization occurred less than 3,000 years ago, after the split of Tibetans from the mainland Chinese. This is possibly the fastest case of human evolution ever recorded (Yi et al., 2010). As mentioned, EPAS1 was inherited from Denisovans. EPAS1’s “highly unusual” set of DNA variations that are commonly inherited together can only convincingly be explained by mating between ancient Tibetans and Denisovan-like individuals (Huerta-Sánchez et al., 2014). Jeong et al. state that, “EGLN1 and EPAS1 genes are highly enriched for high-altitude ancestry, representing respectively the second and third strongest signals of excess high-altitude ancestry in the Tibetan genome,” describing how strong the link of inheritance is for these genes (2014). Scientists have determined through this analysis that an equal mixture of genomes were inherited from the Nepalese-Sherpas and Hans; however, many of these acquired adaptive genes are from the Sherpa lineage, despite a large amount of gene flow from low-altitude East Asians. In addition, it is very likely that these genes served some other purpose for Denisovans, who did not typically live in such high-altitude environments, and were inherited in a way that incidentally conferred such acclimatizing advantages for Tibetan populations (Jeong et al., 2014). Truly, this remarkable case of human evolution has served to help us understand a plethora of ways in which evolution in general occurs, and has allowed us to gain insight into not only the genetic history of ancient hominins, but also geographic history. Through these discoveries, we have begun to unlock the potential for many more novel findings across multiple scientific disciplines.