Human populations originally descended from Africa. From there, several expansions into new habitats and environments resulted in cultural and genetic adaptation. One of these adaptations involved the low-oxygen habitats that occur at high altitude. Residents of the Tibetan Plateau live above 4000m with oxygen concentrations that are nearly half of that experienced by human populations at sea level. Low oxygen levels can result in oxygen deprivation that hampers physical performance and reduces newborn survival rates.
Tibetans who have long heritage on the plateau possess physiological differences from those who live at sea level. Many of these features involve the ability of their blood cells to use oxygen more efficiently at such low air pressure. It’s been hypothesized that these features are unique adaptations to their challenging habitat.
Yi et al. 2010 investigated the entire genome of Tibetan populations. They sampled 50 unrelated individuals and identified several genes that are involved in avoiding “hypoxia” (widespread deprivation of oxygen). Then, they compared the DNA sequences in Tibetan individuals to 40 individuals from China and 200 individuals from Denmark (Fig. 2). Based on these comparisons, they identified Tibet-specific alleles for the EPASItranscription factor gene, several genes associated with making different forms of hemoglobin and a gene,DISC1, associated with schizophrenia induced by low oxygen during pregnancy.
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To look for evidence of adaptation in Tibetan populations at the EPASI locus, they looked at an additional 366 individuals from different regions in Tibet. They hypothesized that individuals that had two copies of the Tibet-specific allele (E’) would be more common than any other genotype since the gene is involved in avoiding hypoxia. Indeed, they found that the E’ allele (Tibet-specific), was at higher frequency in Tibet than either China or Denmark. They also found that the E’E’ genotype was much more common in Tibetan populations.

If a single nucleotide is important in coping with hypoxia, in which codon position might you expect to find nucleotide differences? Why?

I just do not understand because I thought the 3rd codon position was best to not mess up the genetic code but then natural selection to pass down heritably is better in position 1 or 2 codon.