When I think about Tibetans, what first comes to my mind is the expression of enlightenment in their faces. Maybe because to survive at 14,000 ft of elevation, one needs to have something else, which can be either lots of wisdom or an especial adaptation craved in the genes. In a recent study published in Nature, researches found that this something else that makes Tibetans so successful at colonizing high elevation areas are haplotypes donated by Denisovan hominins through DNA introgression. In a multi-national collaboration, Huerta-Sanchez and colleagues investigated the genetic variation of the gene EPAS1, linked to adaptation to low oxygen levels in high altitudes. When ordinary, non-adapted to high altitude, people are exposed to environments with low concentration of oxygen (hypoxia) the body enters in a compensatory mode. Hemoglobin levels increase, the number of red blood cells boosts, the heart starts to overwork in order to deliver oxygen to all demanding tissues, and finally, blood pressure ramps up to the risk of heart failure and damage to the peripheral circulation. All that doesn’t happen to Tibetans though. Their hemoglobin levels aren’t boosted because of the low oxygen levels, in fact they present similar adaptations of other mammalian species that live in high altitude, such as pigs and antelopes: they have thin walled pulmonary vascular structure, which translates into high gas exchange efficiency, and their blood flows at a higher velocity, meaning that tissues get their oxygen delivered even when the supply is low. All these anatomic and physiologic variations have a direct implication on reproductive success, since women that lack high-altitude adaptation usually have miscarriages due to eclampsia, or fetal heart failure. Given such a tuned phenotype-environment adaptation, one can ask how evolution of altitude adaptation in the Tibetan population took place. In order to disentangle this evolutionary history, Huerta-Sanchez and colleagues put their bet on using SNPs (see bellow) to understand the genetic variability of one gene, EPAS1, a transcription factor associated with the activation of several other genes regulated by oxygen concentration.
Data from Single Nucleotide Polymorphisms (SNPs) analysis have been contributing to understand how altitude adaptation took place. A SNP is a single nucleotide difference in a DNA sequence. These unique changes on the basic building blocks of genes can be associated to several phenotypic differences detectable between populations of the same species. Human arrival in the Tibetan plateau took place in the Last Glacial Maximum, around 25 thousand years ago. Since then, about 1,100 generations of Tibetans have been surviving under high-elevation-related hypoxia – sufficient time for fixation of alleles that confer altitude adaptation. Just looking at the gene EPAS1, Tibetans have shown to present a remarkable SNP diversity when compared to their closely related ethnic group, the Han Chinese, showing the fastest allelic change observed in any human genome to date – how impressive! But, what is the deal with populations that are not highly differentiated, but present considerable difference in the frequency at which specific mutations happen, like Tibetans and Han Chinese for EPAS1 SNPs? Huerta-Sanchez and colleagues hypothesized that the source of variation may come from donor populations. They first tried to understand how so much variation in such a short genomic region evolved, by testing two models of selection that simulate how EPAS1 haplotype diversity evolved: 1) selection under standing variation, assuming that Tibetans already had the beneficial haplotype when they colonized high altitude environments; or 2) selection under de novo mutation, which predicts that beneficial haplotype showed up and was fixed in the population after establishment in high altitudes. Surprisingly, the high haplotype diversity found in Tibetan EPAS1 couldn’t be explained by neither of the models of evolution, which supported the hypothesis that a donor population contributed to the fast EPAS1 diversification: in other words, DNA introgression lead to adaptation.
By searching for possible donor populations in several genomic databases, the authors found that Tibetans shared several haplotypes with the Denisovan individuals, popularly known as being the Neanthertal cousins. The Denisovan fossil record, even though only composed as whole by two phalanges and two teeth, have rendered amazing insights into hominin evolution since their discovery four years ago, in a cave in Siberia. What Huerta-Sanches and co-authors visualized when they looked at the haplotype networks to understand the relationships between Denisovan, Tibetan and 26 other modern human populations haplotype diversity of the EPAS1 gene was striking: the Tibetan haplotypes are closer to the Denisovan than they are from any other modern human population, a pattern only expected under introgression. Adaptation to high altitude amongst Tibetans may have been facilitated by gene flow from other hominins that may already have been adapted to those environments. This fantastic finding leads to an infinite network of questions: What is the relationship between Tibetans and other human populations adapted to high altitudes, like Basques in the Pyrenees and several ethnic groups in the Andes? How does the genetic variation of other hypoxia-related genes look like? Are Tibetans good marathonists? How culturally different were Homo sp. populations interbreeding around 30 thousand years ago, did they speak the same language, how different they looked, how long did they interbred for? Should Tibetans thank the DNA donation by creating a new holiday called National Denisovan Day? Well, I suppose this is one of the beauties of science, one question answered, so many more to go.
Thanks to Dr Hughes, who chose this paper to be discussed in the seminar lead by him about Next Generation Sequencing at the Bio Department of the University of Missouri St Louis!