The Genetics of Living at Altitude

tibet himalayan village

Genetic differences have been found to explain the hypoxia (oxygen starvation) physiological adaptations in Tibetans and Andeans necessary for surviving at high altitude.

For proof of how we adapt to our environment one can look at the Tibetans and the altitude adaptations they have developed. The Tibetan Plateau has an average elevation over 5000 meters (16,400 ft.) and covers an area almost half the size of the continental United States. Tibetans have been estimated to been residing at these extreme altitudes for at least 5000 years and possibly as long as 21,000 years. Tibetans exhibit a suite of physiological adaptations at altitude: decreased arterial oxygen content, increased resting ventilation, lack of hypoxic pulmonary vasoconstriction and reduced hemoglobin concentration.

Interestingly, these physiological traits are not all exhibited in the Andeans of South America who live at similar high altitude conditions. A study by Cynthia M. Beall compared the physiological mechanisms Tibetan and Andean natives have developed to deal with the hypoxia (oxygen starvation) experienced at high-altitude (Two routes to functional adaptation: Tibetan and Andean high-altitude natives, 2007, Cynthia M. Beall).  

There are several points on the path from atmospheric air to venous blood (called the oxygen transport cascade) to make up for differences in oxygen concentration seen at high-altitude and sea level. The figure below shows these points.

The oxygen transport cascade at sea level (solid line) and at the high altitude of 4,540 m (dashed line) illustrates the oxygen levels at the major stages of oxygen delivery and suggests potential points of functional adaptation.

Tibetans show ventilation rates similar to sea-level populations in response to hypoxic conditions. Andeans have a decreased hypoxic ventilation response. Despite the higher levels of ventilation seen by Tibetans, the oxygen concentration in the blood at high elevations is lower in Tibetans than Andeans. This is because hemoglobin (the protein that transports oxygen in the blood) concentration is higher in the Andeans. However, high hemoglobin concentrations are not necessarily advantageous because it alters the viscosity of the blood and may cause chronic mountain sickness. Tibetans have also been found to have higher blood flow to the brain during exercise.

Tibetans have higher blood flow to compensate of their low levels of oxygen in the blood. In addition, Tibetans have a higher rate of oxygen diffusion as their capillarity density is much higher than Andeans at similar elevation.  Mitochondrial density decreases at altitude for normal populations (the reason is unknown). Tibetans have decreased mitochondrial density at sea-level as well as at elevation suggesting a purely genetic trigger for mitochondrial density in Tibetans. The differences in mitochondrial and capillarity density is shown in the figure below.

High-altitude native Tibetans have higher capillary density than their Andean counterparts or populations at low altitude; Tibetan and Andean highlanders both have lower mitochondrial volume than low-altitude populations.

To explain the physiological adaptations Tatum Simonson, PhD led a team to Tibet  to look at the genetics of native Tibetans (Genetic Evidence for High Altitude Adaptation in Tibet, 2010. Tatum S. Simonson, et al.). The research team identified SNPs (single nucleotide polymorphisms) unique to Tibetans. A SNP is a single nucleotide difference in the DNA code that is unique to, or more frequent in, certain populations. Generally, SNPs occur in noncoding sections of the DNA gene so that the associated protein's function is not affected. SNPs propagate and reach a peak at about 10,000 years in a population before disappearing due to random mutation.  

Tatum and her team found 10 genes that were both unique to Tibetans as identified with SNPs and labeled as associated with hypoxia resistance. Several of these genes, PPARA and EGLN1, are associated with the regulation of hemoglobin concentration.

In summary, Tibetans and Andeans have developed physiological adaptations to the hypoxia conditions associated with living at high altitude. A genomics analysis of Tibetans has found several genes of interest related to hypoxia and hemoglobin concentration. This research is important because understanding the genetics behind hypoxia adaptation may help develop a cure to alleviate chronic mountain sickness.

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