Abstract
This special topic issue on the genetic changes in the high altitude native Tibetan population punctuates an extraordinary year of scientific discoveries reported in seven publications (Aggarwal et al., 2010; Beall et al., 2010; Bigham et al., 2010; Peng Y., et al. 2010; Simonson et al., 2010; Xu et al., 2010; Yi et al., 2010). These articles identify among Tibetans distinctively high allele frequencies at single-nucleotide polymorphism (SNP) loci in genes involved in oxygen homeostasis. These are the genes for the oxygen sensor EGLN1 (also known as PHD2, prolyl hydroxylase 2) and the transcription factor EPAS1 (also known as HIF2A, hypoxia inducible factor 2A). Interestingly, target genes of the EPAS1 transcription factor, such as those involved in hemoglobin synthesis, do not consistently show such patterns. EGLN1 or EPAS1 variants most frequent among Tibetans were associated with lower hemoglobin concentration in the three publications testing that association. The consensus among these publications is noteworthy, because genomics findings have been difficult to replicate in many other situations.
Decades of puzzling over the origins of the distinctive high altitude Tibetan phenotype began with reports of the unexpectedly low hemoglobin concentration of high altitude Sherpas and their Tibetan relatives (Beall and Reichsman, 1984). After discounting likely confounding factors such as iron-deficiency anemia, the search for explanations for the dampened erythropoietic response turned to (1) other, possibly compensatory, traits such as the percent oxygen saturation of hemoglobin and (2) the possibility of a genetic basis for a unique Tibetan suite of traits offsetting the stress of chronic, lifelong hypoxia.
Multiple approaches testing the genetic hypothesis illustrate the development of research designs. The earliest compared mean values of traits such as hemoglobin concentration of Tibetans with those of Andean highlanders and of upward migrants. Next, quantitative genetics and segregation analysis of large samples of biological relatives confirmed a genetic basis for person-to-person variability in hemoglobin concentration among Tibetan highlanders. Finally, the genomics age that began just 10 years ago in 2001 accelerated discovery by developing new techniques for generating and testing hypotheses about the association of genotypes with biological traits. The techniques enabled the current batch of reports associating variation in certain SNP alleles with variation in hemoglobin concentration.
These findings can advance the knowledge of human biology, medicine, and evolution. It will be important to identify the responsible genetic variant and the mechanisms whereby a transcription factor with dozens of target genes affects some traits, but not others. With respect to human biology, research on the consequences for healthy individuals of genetic variation in EGLN1 and EPAS1 can shed light on the biological pathways leading to vital cardiopulmonary traits. With the power to genotype individuals, scientists can compare genotype–trait associations in other highland populations and in newcomers to altitude and lowland populations. This should reveal how the body works to maintain healthy life at high altitude. With respect to medicine, there is keen interest in oxygen homeostasis biology in the course of diseases associated with hypoxia at all altitudes, such as congestive heart failure, asthma, and cancer. Such knowledge should lead to new prevention and intervention strategies.
With respect to evolutionary processes, we can ask why natural selection acted on regulatory, rather than structural, genes and why it resulted in a particular set of adaptations in one population exposed to high altitude hypoxia, but not others. We can ask why the acclimatization responses characteristic of lowland populations have apparently been selected against in the Tibetan population. Evolutionary biologist Jay Storz and colleagues (2010) suggest that if the acclimatization response has long-term high costs, for example, polycythemia and the risk of thrombosis, then natural selection may favor "cryptic adaptive evolution." That is, phenotypes evolve that resemble those of unstressed populations, although with different genetic underpinnings. If this is what occurred in the Tibetan population, then what occurred among Andean highlanders?
The community of high altitude scientists is noteworthy for a long history of comparative, integrative, and translational work. We can confidently anticipate that these new findings and questions will be incorporated rapidly into research and practice.