Tibetans are well adapted to high-altitude hypoxic conditions, and in recent 
genome-wide scans, many candidate genes have been reported involved in the 
physiological response to hypoxic conditions. However, the limited sequence 
variations analyzed in previous studies would not be sufficient to identify 
causal mutations. Here we conducted resequencing of the entire genomic region 
(59.4 kb) of the hypoxic gene EGLN1 (one of the top candidates from the 
genome-wide scans) in Tibetans and identified 185 sequence variations, including 
13 novel variations (12 substitutions and 1 insertion or deletion). There is a 
nonsynonymous mutation (rs186996510, D4E) showing surprisingly deep divergence 
between Tibetans and lowlander populations (Fst = 0.709 between Tibetans and Han 
Chinese). It is highly prevalent in Tibetans (70.9% on average) but extremely 
rare in Han Chinese, Japanese, Europeans, and Africans (0.56-2.27%), suggesting 
that it might be the causal mutation of EGLN1 contributing to high-altitude 
hypoxic adaptation. Neutrality test confirmed the signal of Darwinian positive 
selection on EGLN1 in Tibetans. Haplotype network analysis revealed a 
Tibetan-specific haplotype, which is absent in other world populations. The 
estimated selective intensity (0.029 for the C allele of rs186996510) puts EGLN1 
among the known genes that have undergone the strongest selection in human 
populations, and the onset of selection was estimated to have started at the 
early Neolithic (∼8,400 years ago). Finally, we detected a significant 
association between rs186996510 and hemoglobin levels in Tibetans, suggesting 
that EGLN1 contributes to the adaptively low hemoglobin level of Tibetans 
compared with acclimatized lowlanders at high altitude.