among the tibetans, which is the hallmark of their adaptation to hypoxia. simultaneously, two genes, egl nine homolog 1 (egln1) (which inhibits hemoglobin production under high oxygen concentration) and peroxisome proliferator-activated receptor alpha (ppara), were also identified to be positively selected in relation to decreased hemoglobin nature in the tibetans. similarly, the sherpas, known for their himalayan hardiness, exhibit similar patterns in the epas1 gene, which further fortifies that the gene is under selection for adaptation to the high-altitude life of tibetans. a study in 2014 indicates that the mutant epas1 gene could have been inherited from archaic hominins, the denisovans. epas1 and egln1 are definitely the major genes for unique adaptive traits when compared with those of the chinese and japanese. comparative genome analysis in 2014 revealed that the tibetans inherited an equal mixture of genomes from the nepalese-sherpas and hans, and they acquired the adaptive genes from the sherpa-lineage. further, the population split was estimated to occur around 20,000 to 40,000 years ago, a range of which support archaeological, mitochondria dna and y chromosome evidence for an initial colonisation of the tibetan plateau around 30,000 years ago. the genes (epas1, egln1, and ppara) function in concert with another gene named hypoxia inducible factors (hif), which in turn is a principal regulator of red blood cell production (erythropoiesis) in response to oxygen metabolism. the genes are associated not only with decreased hemoglobin levels, but also in regulating energy metabolism. epas1 is significantly associated with increased lactate concentration (the product of anaerobic glycolysis), and ppara is correlated with decrease in the activity of fatty acid oxidation. egln1 codes for an enzyme, prolyl hydroxylase 2 (phd2), involved in erythropoiesis. among the tibetans, mutation in egln1 (specifically at position 12, where cytosine is replaced with guanine; and at 380, where g is replaced with c) results in mutant phd2 (aspartic acid at position 4 becomes glutamine, and cysteine at 127 becomes serine) and this mutation inhibits erythropoiesis. the mutation is estimated to occur about 8,000 years ago. further, the tibetans are enriched for genes in the disease class of human reproduction (such as genes from the daz, bpy2, cdy, and hla-dq and hla-dr gene clusters) and biological process categories of response to dna damage stimulus and dna repair (such as rad51, rad52, and mre11a), which are related to the adaptive traits of high infant birth weight and darker skin tone and are most likely due to recent local adaptation. andeans the patterns of genetic adaptation among the andeans are largely distinct from those of the tibetan, 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. even then, the pattern of variation for this gene differs between the two populations. furthermore, there are no significant associations between epas1 or egln1 snp genotypes and hemoglobin concentration among the andeans, which has been the characteristic of the tibetans. 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). 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 7000 years, discovered selection in dst, a gene involved in cardiovascular function. 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. ethiopians the adaptive mechanism of ethiopian highlanders is quite different. this is probably because their migration to the highland was relatively early; for example, the amhara have inhabited altitudes above 2,500 meters (8,200 ft) for at least 5,000 years and altitudes around 2,000 meters (6,600 ft) to 2,400 meters (7,900 ft) for more than 70,000 years. genomic analysis of two ethnic groups, amhara and oromo, revealed that gene variations associated with hemoglobin difference among tibetans or other variants at the same gene location do not influence the adaptation in ethiopians. identification of specific genes further reveals that several candidate genes are involved in ethiopians, including cbara1, vav3, arnt2 and thrb. two of these genes (thrb and arnt2) are known to play a role in the hif-1 pathway, a pathway implicated in previous work reported in tibetan and andean studies. this supports the concept that adaptation to high altitude arose independently among different highlanders as a result of convergent evolution.