Human high-altitude adaptation: forward genetics meets the HIF pathway
Humans have adapted to the chronic hypoxia of high elevation in respective locations, and late genome-wide studies have indicated a familial basis. In some populations, genic signatures have been identified in the hypoxia-inducible factor ( HIF ) nerve pathway, which orchestrates the transcriptional response to hypoxia. In Tibetans, they have been found in the HIF2A ( EPAS1 ) gene, which encodes for HIF-2α, and the prolyl hydroxylase world protein 2 ( PHD2, besides known as EGLN1 ) gene, which encodes for one of its key regulators, PHD2. High-altitude adaptation may be due to multiple genes that act in concert with one another. Unraveling their mechanism of legal action can offer newfangled curative approaches toward treating common human diseases characterized by chronic hypoxia.
Hypoxia is a cardinal feature of many far-flung homo diseases, including ischemic heart disease, stroke, anemia, chronic clogging pneumonic disease, and pneumonic high blood pressure, among others. In fact, following respective diseased states, it can be seen in basically any tissue of the body. If one were matter to in experimentally devising a scheme for allowing an organism to survive under chronic hypoxia, one would perform the obvious ahead genetic sieve ; namely, subject the organism to chronic hypoxia and then, after many generations, identify the phenotypical features and, ultimately, the implicit in genetic changes. Such an approach, given its indifferent nature, could offer new insights and potentially novel curative targets for promoting optimum organism and tissue responses to chronic hypoxia .
In this respect, the homo species has undergo a dramatic experiment of nature. At varying times in human demographic history, humans colonized multiple high-level locales, including the Tibetan Plateau, the Andean Altiplano, and the Semien Plateau of Ethiopia ( Fig. 1 ; Beall 2013 ). nowadays, > 140 million humans live at high altitude, defined as > 2500 meter, as this is the natural elevation at which most people display a fall in oxygen impregnation of hemoglobin ( Niermeyer et alabama. 2001 ). Both the barometric press and the absolute concentration of oxygen worsen as a serve of natural elevation. For exercise, at 4000 m, an elevation distinctive of the Tibetan Plateau, the oxygen assiduity is only 60 % of that available at sea horizontal surface. For well over a hundred, the alone cortege of physiologic adaptations to chronic hypoxia observed among long-run resident populations has been well documented ( for follow-up, see Hornbein and Schoene 2001 ). Studies conducted over the past ten a well as more late genomic studies support a genic footing for these adaptations ( Simonson et alabama. 2012 ; Scheinfeldt and Tishkoff 2013 ). interestingly, the patterns of genetic changes differ among the three populations. Intriguingly, genetic signatures in genes of the hypoxia-inducible agent ( HIF ) pathway, the central pathway that transduces changes in oxygen tension to changes in gene expression, have been identified ( Kaelin and Ratcliffe 2008 ; Lendahl et aluminum. 2009 ; Majmundar et aluminum. 2010 ; Semenza 2012 ). This suggests that in autochthonal high-level populations, survival for adaptation to chronic hypoxia ( as opposed to cold, increased UV irradiation, or some other environmental stress experienced at high altitude ) is a key component of their recent human evolution .
View larger interpretation :
figure 1 .
The geography of human adaptation to high elevation. geographic locations where humans have adapted to life at high gear altitude are in aristocratic and include ( from left to right ) the Andean Altiplano, the Semien Plateau, and the Tibetan Plateau. Adapted from Bigham ( 2008 ) .
This review discusses findings on human adaptation to high elevation, with a detail focus on Tibetans, for whom the strongest case has been made for familial changes in the HIF nerve pathway being linked to adaptation. In nonhuman species, studies have examined how Drosophila has adapted to experimental hypoxia ( Zhou et alabama. 2008, 2011 ). extra studies have focused on understanding physiologic adaptations to hypoxia in a variety of organisms, ranging from Andean hummingbirds to deer mouse ( Natarajan et aluminum. 2013 ; Projecto-Garcia et aluminum. 2013 ). early studies, including ones on snow leopards, yaks, Tibetan wilderness boars, Tibetan macaques, naked mole rats, and Tibetan antelopes, have undertaken genomic examination of these species in order to gain insight into their adaptation ( Kim et alabama. 2011 ; Qiu et aluminum. 2012 ; Cho et aluminum. 2013 ; Ge et alabama. 2013 ; Li et alabama. 2013 ; Fan et alabama. 2014 ). much of this inquiry has been discussed in a total of excellent holocene reviews ( Storz et alabama. 2010, 2013 ; Zhou and Haddad 2013 ) and is not discussed far here.
former part next section
It should be apparent from this discussion that the mechanisms of high-level adaptation in unlike human populations are distinct and undoubtedly complex. furthermore, mounting evidence suggests that the ascertained physiological adaptations are controlled by interactions among multiple genes, specially those that are separate of the HIF pathway. The Tibetan population shows the strongest support that multiple genes in the HIF nerve pathway have been reconfigured in reply to chronic hypoxia. This interaction of genes determining high-altitude-adaptive phenotypes may be contrasted with other long-familiar examples of late human evolution in which choice appears to have acted on single genes. Examples of this would include the selection of a Lactase ( LCT ) gene variant to allow lactase continuity in european populations and the survival of an EDAR random variable to produce a configuration of findings related to ectodermal development in asian populations ( Kamberov et alabama. 2013 ; Scheinfeldt and Tishkoff 2013 ). high-level adaptation may be more like skin color decision, in which multiple interact locus determine phenotype ( Sturm 2009 ) .
The continued study of high-level adaptation may provide the footing for new therapies for diseases characterized by ischemia and chronic hypoxia. In the Tibetan population, the changes in the PHD2 and HIF2A genes were selected over the course of thousands of years, providing proof of principle of their efficacy. however, challenges remain if we are to extrapolate the high-level findings to low-level, hypoxic disease states. For exemplar, it may be necessity to target both PHD2 and HIF-2α in order to phenocopy Tibetan adaptation. This is within the region of possibility, since there are many examples of drug combinations that concurrently target enzymes/proteins in the lapp pathway to achieve a beneficial effect ( for example, amoxicillin/clavulinic acerb ). furthermore, while it is likely that choice of HIF nerve pathway genes in Tibetans is chiefly a contemplation of adaptation to chronic hypoxia, familial changes in this population american samoa well as other high-level groups may reflect adaptation to other environmental stresses present at high altitude, such as moo temperature and increased UV exposure .
human high-level adaptation has drawn the care of molecular biologists, anthropologists, geneticists, and physiologists alike. It is an excellent natural experiment design in which to study the evolutionary process. By understanding how exchangeable environmental pressures can result in either the same or different genic adaptations, we will be well situated to understand the molecular basis for convergent human adaptations. Continued discipline is paramount in order to elucidate genotype–phenotype correlations and provide molecular explanations for high-level adaptation. We are at an early stage of this inquiry, and much remains to be learned from these noteworthy experiments of nature .
previous section following section
work in F.S.L. ’ randomness testing ground has been supported by National Institutes of Health grants R21-HL120751, R01-CA153347, and R01-GM090301. solve in A.W.B. ’ s testing ground has been supported by National Science Foundation grant BCS-1132310 and The University of Michigan .
This article is distributed entirely by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date ( see hypertext transfer protocol : //genesdev.cshlp.org/site/misc/terms.xhtml ). After six months, it is available under a creative Commons License ( Attribution-NonCommercial 4.0 International ), as described at hypertext transfer protocol : //creativecommons.org/licenses/by-nc/4.0/ .