Background:
Nepal has an incredible geographic diversity with an altitude ranging from 50m to highest peak in the world (Mt. Everest, 8848m) from sea level and is topographically divided into three regions: The Terai, the Hilly and the Himalayan regions. The Himalaya and its foothills make up the northern border of the country and represent 16% of the total land area. This is the least inhabited region of country with less than 8% of the population.
High altitude exposes several hassles e.g. low temperature, high UV radiation, low oxygen level and strong seasonal changes. The indigenous inhabitants of these regions can cope with these changes and survive well while the other population would suffer from serious health problems. Sherpa are an ethnic group residing on 3000 to 4300m high altitude on northern part of Nepal bordering with Tibet autonomous region of China.
High lander populations like Sherpa, Tibetans, Andeans and Ethiopians arean evidence for physiological and genetic changes, particularly in the regulatory systems of respiration and blood circulation when compared to the general lowland population. Among the best studied high altitudes study, molecular studies have shown modifications of hemoglobin and the increased Hb oxygen affinity.. The irreversible adaptation includes long-term physiological responses to high-altitude environments, associated with heritable behavioral and genetic changes. The physiological adaptations to high altitude among high altitude populations are higher Resting Ventilation, lower Hypoxic Ventilator Response, elevated Arterial Oxygen Saturation, Haemoglobin Concentration, Pulmonary Arterial Pressure, increased level of Nitric Oxide and elevated Birth Weight. Multiple genes may act together to adapt an individual in high altitude, several of these evolutionary genes are conserved in human and other lower species like Drosophila., all inhabitant of high altitude.
Genetic approach
The result of advantageous genetic mutation and environmental factors has assisted in adaptation of human to high-altitude environment. Several well-characterized human genes that play important roles in environmental adaptation have been identified. Studies have shown that genetic factors contribute to adaptive differences in the indigenous populations. Recently, genomic study has provided evidence that some of them are identified as genes related to hypoxia sensing andresponse such as hypoxia-inducible factor (HIF-1) pathway genes, EPAS1, EGLN1 and PPARA. Such as Single nucleotide polymorphisms (SNP) in the first intron of EGLN1 are highly differentiated.
The HIF-pathway loci which exhibit adaptivefeatures of associationswith hemoglobin have been reported but many of them are yet to be explored effusively. Adaptive genetic signals identified in more than one study of high altitude population includeHMOX2/NMRAL1, CYP17A1, HBB (the ß-globin genecluster), HFE and PKLR gene regions.
Among the top list of candidate genes, EPAS1 and EGLN1 are the two genes showing a relatively strong signature of selection. Although it is likely that other genes may also contribute to high-altitude adaptation, the combined genome-wide data from multiple studies implied that these two genes are likely the key players, which is supported by the known direct involvement of these two genes in hypoxia. The entire sequencing of EPAS1 and EGLN1 genes Tibetan people living in high altitude show 301 SNPs with respect to normal population of low altitude. This can reveal that the major candidate gene is responsible for unique feature of people living in high altitude.
Conclusions
High altitude is an appropriate setting for understanding evolution because it presents researchers with a natural design of experiment by enabling them to examine diverse altitude communities. It ia always suggest to further analyze of those genes in Nepalese population i.e., Sherpas living in high altitude that might possess unique adaption to cope with the high-altitude environment. Finding their mechanism of action may lead therapeutic approaches toward treating some of common chronic hypoxia related diseases in human being in future.
Appendixes:
EPAS1: (Endothelial PAS Domain Protein 1)
PKLR: (Pyruvate Kinase, Liver and RBC)
CYP2E1: (Cytochrome P450 Family 2 Subfamily E Member 1)
NMRAL1: (NmrALike Redox Sensor 1)
PPARA:(Peroxisome Proliferator Activated Receptor Alpha)
HMOX2/: (Hemeoxygenase 2)
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