"Denisovian" genes helped Tibetans to master the highlands
Tibetans inherited a gene from Denisov people that saves from hypoxia
As it turned out, the genes of the ancient Denisov people helped Tibetans to master the highlands. Photos from the website tibetanshamantour.comThe EPAS1 gene is a transcription factor that turns on when there is a lack of oxygen.
It regulates the pressure in the vessels, the development and work of the heart muscle. Tibetans, as it turned out, have specific alleles of this gene, which, among other things, increase the amount of hemoglobin in the blood. This is an adaptation to high–altitude conditions with a reduced amount of oxygen. Such specific "Tibetan" alleles are extremely rare: from the entire world database of genomes of different peoples, they are found only in two representatives of Chinese nationalities. But the most interesting thing is that these same "Tibetan" alleles were found in a fossil sample of the Denisov man. It means that the Tibetans have preserved the legacy of the Denisov people, inherited from the offspring of mixed couples. Geneticists discuss this finding on the pages of the journal Nature (Nielsen et al. Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA).
Excavations in Denisova cave have been conducted for decades, during which time archaeologists have collected an extensive collection of tools, artifacts of ancient inhabitants or visitors of the cave. Among 80 thousand paleontological and archaeological finds, there were also significant ones – a pair of teeth, a bone from the foot and a bone of the phalanx of the little finger of the oldest people. The tooth (one or both) and the foot are probably of Neanderthal origin, but the little finger, as it turned out, belonged to a girl of an incomprehensible genus-tribe. Geneticists, who had previously spent at least a decade inventing and improving methods for decoding fossil genomes, took up the task. The bone from the little finger, as the decoding showed, did not belong to Sapiens or Neanderthals, but to special Denisov people. According to the features of their genomes, they turned out to be closer to erectus and Neanderthals than to modern humans. With the gene signature of a new member of the human race, the next stage of research of Denisov inhabitants began, which was supposed to confirm their place among other human relatives. Comparing the frequency of certain alleles, scientists determined that the Denisovans left a noticeable genetic inheritance to the South Asian peoples of Melanesia, and that its trace among the inhabitants of Europe, Africa, India, Pakistan and North American Indians is significantly lower. According to the frequency of specific nucleotide substitutions in the X and Y chromosomes, there was an idea that Denisov cavaliers successfully chose wives from the Sapiens tribe, leaving viable offspring; the opposite – Denisov women paired with sapient husbands – turned out to be not such a good option.
And now a new link has appeared in this storyline – the adaptive role of the introduced Denisov genes. Various alien alleles (often referred to simply as genes) are added to the genome as a result of crosses. So the genes of Denisovans (and Neanderthals) were added to the Sapiens genome. The future fate of new variants may be different, it depends on random drift, on the adaptive benefit of the introduced allele and on its interaction with the new genetic environment. Most often, geneticists assume random drift imposed on the migration activity of populations. But there are also cases of adaptive fixation. So, among the acquired Neanderthal alleles, there were those that strengthened the human immune defense, determined skin color, hair structure; these genes were supported by selection. Now in the arsenal of anthropologists there is another case, impeccable in its evidence and clarity, of an obvious adaptive fixation of the Denisovans gene in the genome of modern people. It was described by a team of geneticists from 20 scientific laboratories in 5 countries led by Rasmus Nielsen from the Center for Theoretical Evolutionary Genomics at the University of California, Berkeley.
We are talking about the EPAS1 gene. This is a transcription factor that turns on when oxygen levels decrease. It regulates the pressure in the vessels, the development and work of the heart muscle. Tibetans, as it turned out, have rare alleles of this gene, which, among other things, increase the amount of hemoglobin in the blood. The number of red blood cells remains the same. Carriers of the "Tibetan" variants have elevated hemoglobin levels, wherever they live. A number of specific EPAS1 nucleotide substitutions have been identified for the "Tibetan" alleles. It is clear that the "Tibetan" variants were developed as an adaptation to high-altitude conditions, where the amount of oxygen is reduced by 40% compared to the lower reaches. After all, another way of adapting to hypoxia – to increase the number of red blood cells themselves – is fraught with complications, since the risk of thrombosis greatly increases. Will these high-altitude alleles be found in other peoples?
The Chinese nationalities are closest (both geographically and historically) to the Tibetans. Therefore, scientists isolated a section of DNA with the EPAS1 gene from 40 Chinese tissue samples and compared it with the corresponding sample of 40 Tibetans. The difference between the set of nucleotide substitutions of Chinese and Tibetans turned out to be huge, and there was also a motive that was not present in any (!) representative of the Chinese from the sample. This is an amazing result with such an impressive sample. Then scientists took data on this gene (more precisely, on the whole site with this gene, where specific nucleotide substitutions are collected) from world databases for representatives of different races (1000 Genomes Project and NCBI Sequence Read Archive). Here the catch was, though not zero, but insignificant: of all the available sequences, only two (representatives of the northern and southern Chinese) revealed a unique Tibetan motif. No one else had it. Although, no – it was found, and here you would need to put a big exclamation mark. The genome with a clear Tibetan painting did not belong to a modern man, but to a famous Denisovan, the one from whom only the little finger remained. Thus, modern Tibetans and ancient Denisovans had a common adaptation to high-altitude hypoxia.
Scientists have tried to understand how it happened that the Denisov variant of EPAS1 got only to Tibetans. There are three possibilities here. Firstly, it is the legacy of the common ancestor of Denisovans and Sapiens, which all Sapiens have disappeared for one reason or another. Secondly, the Denisovans interbred with the common ancestors of the Chinese and Tibetans, the Chinese, after separating from the common trunk, this gene practically disappeared, leaving only a relict trace. Thirdly, it is a random drift of genes. All these possibilities were modeled, the probabilities of frequencies of "Tibetan" alleles in various modern peoples related and distant to Tibetans were calculated. Here, data on Denisov admixture from other nationalities and the estimated time of their divergence were taken into account. Calculations have shown that the second scenario has the greatest probability, according to which Denisovans interbred with the ancestors of the Han and Tibetans and left mixed offspring, in one of the branches of which, due to the adaptive advantage, alleles of the EPAS1 gene of Denisovans remained. Let me remind you that the genetic diversity of Denisovans, as it became clear not so long ago, is very low. Probably, the polymorphism of the EPAS1 gene was quite low.
A genealogical diagram from an article in Nature illustrating gene flows from Denisovans (Denisovan) to the peoples of Tibet (TIB), Chinese (HAN), Europeans (CEU), Yoruba (YRI). The Tibetan haplotype turned out to be closer to the Denisov haplotype than the others most characteristic of modern man; also, the difference between the Tibetan and Denisov haplotypes is less than the average for other human haplotypes.Thus, we now definitely know that the Denisovans who lived in the Altai Mountains interbred with the inhabitants of the South Asian highlands.
Later, the descendants of these nationalities, bearing variants of the Denisov highland EPAS1 alleles, were divided into Chinese and Tibetans. The former have mostly lost these alleles as unnecessary, the latter, on the contrary, have been preserved as the most valuable inheritance. However, it is possible that the Chinese had a small admixture of Tibetan alleles introduced in historical times: still, the two nationalities are not completely separated from each other. So the dates of the crossing of Denisovans with the ancestors of Tibetans are very approximate, and, most likely, will be significantly refined. There is still a lot of work to be done to confirm exactly introgression, and not the parallel convergent appearance of specific motives. The probabilistic approach for evidence, as it becomes clear from recent studies, may not be entirely reliable.
For us, this case is interesting not by estimates of the time of the divergence of the two peoples, but by an illustration of the evolutionary destinies of individual genes. It is interesting and important for us to see how the evolutionary force works with genetic material and how adequately it disposes of it.
Portal "Eternal youth" http://vechnayamolodost.ru11.07.2014