Populations of the Caucasus as an object for studying the process of adaptation to conditions of high-altitude hypoxia

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BACKGROUND

High-altitude hypoxia is manifested by decreased partial pressure of oxygen in the inhaled air that occurs at high altitudes and causes serious physiological effects on the human body. It is caused by the exponential decrease in barometric pressure with altitude gain, which is characterized by a decrease in pressure by an average of 1 mmHg/10.5 m of altitude gain [1]. Along with a lack of oxygen, aggravating factors in high-altitude conditions include ultraviolet radiation, body dehydration, cooling, physical fatigue, and sudden temperature changes during the day. These factors can cause the development of acute mountain sickness and life-threatening high-altitude cerebral and pulmonary edema [2, 3]. Moreover, hypoxia is a risk factor of various widespread human diseases including coronary heart disease, stroke, anemia, chronic obstructive pulmonary disease, and pulmonary hypertension [4].

There are various classifications of high-mountain regions; however, the most commonly accepted altitude gradations are 1500–3500, 3500–5500, and >5,500 m above sea level [5]. Each of these levels is characterized by certain body responses that lead to physiological adaptation or acclimatization.

Approximately 400 million people worldwide live at altitudes >1500 m above sea level, and over 100 million lowland residents annually visit areas above 2500 m[*]. Additionally, approximately 82 million people live permanently at altitudes above 2500 m [6]. There are several high-mountain regions where people have lived for millennia, including the Ethiopian Plateau, Tibetan Plateau, and Andes. However, until recently, evidence of settlement of the high-mountain regions of the Old World before the Holocene is unclear. [7]. The latest research data indicate that people of the modern anthropological type began to populate the highland regions in the early Paleolithic period [8]. According to modern research, the earliest traces of Homo sapiens penetration (30,000–40,000 years ago) into the highlands are found in Tibet [8]. Furthermore, settlement in the highland regions of South America occurred about 11,500 years ago [9].

To date, the Caucasus is the least studied mountain region. This is surprising as this country has been known since ancient times. Ancient acquaintance with the Caucasus, which is a predominantly mountainous region located between the Black and Caspian Seas on the border of Europe and Asia, occurred long before the Common Era [10]. During the ancient times, it induced legendary and cosmogonic fantasies in the minds of people. In Greek mythology, the Caucasus became the most popular place, associated with the myths of Prometheus, Jason, and Theseus, among others, and Aeschylus (525–456 BC) stated that the Caucasus Mountains, similar to Atlantes, support the sky and serve as a home for the gods [11]. In biblical times, the Caucasus Mountains attracted attention and contributed to myths associated with Noah’s Ark, and there are records of the Renaissance that in 1395, Tamerlane climbed Elbrus (the highest peak in the Caucasus and Europe) for jihad [12].

The length of the Main Caucasian Ridge is >1100 km, and its area is approximately 400,000 km². According to various estimates, there are approximately 50 indigenous people in this region, with a total population of approximately 30 million individuals. The highest mountain part of the Caucasus is its central part, located between the stratified volcanoes Elbrus and Kazbek, and all the 5000-meter peaks of Russia and Europe are located in this part of the Caucasus [13]. The Balkars and Karachays, which are Turkic-speaking populations belonging to the Caucasian anthropological type, represent the indigenous population of this region [14]. Based on craniological, somatological, odontological, and dermatoglyphic study results, a conclusion was generated on the aboriginal (Caucasian) origin of the Balkars and Karachays and their relationship with representatives of neighboring people and the insignificant role of the Central Asian component in their ethnogenesis [14–16]. The 2022 census showed that the population of the Balkars in Russia was 125,000 people, and that of the Karachays was 226,3000 people [17]. Forming a single linguistic and cultural population, the Karachays and Balkars are the constituent people of the Kabardino-Balkarian and Karachay-Cherkess Republics. Before the policy of unifying peasant farms began in the 1930s, Balkars and Karachays inhabited >80 mountain villages at altitudes from 1000 m to over 2000 m above sea level [18] (Table 1).

 

Table. Some villages and their altitudes above sea level Таблица. Некоторые аулы и высоты их расположения над уровнем моря [18]
Name of settlement	Altitude above sea level, m	Name of settlement	Altitude above sea level, m
Terskol	2150	Yozen	1800
Itkol	2030	Zhapyr-Tala	1780
Baidaevo	1940	Elbrus	1780
Duut	1870	Gubasanty	1770
Achi	1845	Dumala	1735
Tegenekli	1840	Kholam	1700
Shiki	1830	Kala	1700

 

Thus, the populations of the Caucasus are an interesting focus for studying the methods of adaptation to high-altitude conditions. This becomes even more attractive considering the fact that from the Balkars and Karachays (the highest-altitude populations of the Caucasus) alone, during the period from the end of the 19th to the beginning of the 20th century, about 70 guides and climbers emerged, participating in ascents with groups of famous climbers such as Douglas Freshfield, Hermann Woolley, and Moritz Dechy [19]. Currently, various high-altitude search and rescue teams of the Russian Emergencies Ministry are mainly staffed by Balkars and Karachays.

GENETIC AND EPIGENETIC FACTORS

People have adapted to conditions of constant oxygen deficiency at high altitudes in several places, and recent genome-wide studies have shown the genetic basis for this adaptation [4, 20, 21]. The most significant genes in this context are EGLN1, EXOC8, and SPRTN. The EGLN1 gene encodes the oxygen-sensitive enzyme prolyl hydroxylase 2 (PHD2) and is located in a region with one of the strongest selection signals in Tibetans, which proves convergent evolution in Tibetans and Andean people [22, 23]. A cluster of 13 SNPs (Single Nucleotide Polymorphism) located in the conservative intron of the EGLN1 gene is of particular interest, which demonstrates high differentiation in the Dagestani Kubachin population and, possibly exhibits genetic pathways of adaptation of the Caucasian people to high altitude [24].

The functional role of polymorphic variants (e.g., rs186996510 and rs12097901) localized in the first exon of the EGLN1 gene was demonstrated previously, and their adaptive significance for Tibetans was proven. Moreover, the minor allele C of rs186996510 of the EGLN1 gene, which is detected with high frequency in the inhabitants of the Tibetan Plateau, was not revealed among Andean mountain population representatives [21]. The hypothesis of adaptation in the highland Quechua population, which indicates the presence of genetic variants that provide an advantage in hypoxic conditions, was confirmed in a study of the polymorphic loci rs2491403, rs479200, and rs1769793 of the EGLN1 gene [20].

The most convincing association was detected in the polymorphic locus rs1769793, which remained significant even after Bonferroni correction for multiple testing (p = 0.00625; α = 0.05) [20]. Additionally, the polymorphic loci rs2437150 of the SPRTN gene and rs2064766 of the EXOC8 gene are significant (p < 0.05) [20]. The SPRTN gene is a nuclear metalloprotease involved in DNA repair, and mutations in this gene in humans are associated with genomic instability [25]. Therefore, this gene is crucial for general DNA replication and in the regulation of the replication-associated G2/M checkpoint [25]. Further, EXOC8 is a component of the exocyst complex involved in targeting secretory vesicles [26].

Notably, variants of vascular system genes such as ACE, CYP11B2, and NOS3 are critical in altering the activity of circulating angiotensin II, which significantly affects the physiological parameters of the body in oxygen-depleted conditions. A study of the indigenous population of the Himalayas revealed that the rs1799998 and rs4539 variants of the CYP11B2 gene are in complete linkage disequilibrium, and a combination of homozygous wild-type genotypes between the 344T/C, Iw/Ic, and A5160C variants, containing all six wild-type alleles, were overrepresented in the indigenous people of the Himalayas [27, 28].

Furthermore, the rs1799983 and rs7830 variants of the NOS3 gene were actively studied in the context of the genetic adaptation of populations to high-altitude hypoxia. It was revealed that the combination of wild types is significantly higher in the Sherpa population [29, 30].

An increase in hematocrit (the volume percentage of red blood cells in the blood) and/or hemoglobin concentration in the peripheral blood causes polycythemia. A study reported that variants of the EPHA2 and AGT genes correlate with susceptibility to high-altitude polycythemia in ethnic Chinese and Tibetan populations [31]. Moreover, if variants rs2291804, rs2291805, rs3768294, rs3754334, rs6603856, rs6669624, rs11260742, rs13375644, and 10907223 of the EPHA2 gene and rs699, rs4762, and rs5051 of the AGT gene showed an association with reduced susceptibility to polycythemia in ethnic Chinese, then rs2478523 of the AGT gene showed an increased risk of polycythemia in the Tibetan population [31]. Furthermore, the occurrence and development of chronic obstructive pulmonary disease is regulated by environmental and genetic factors, and under hypoxia occurring in mountain conditions, erythropoietin can satisfy the body’s need for oxygen, promoting red blood cell production [32–34]. This was demonstrated using the example of rs1617640 of the EPO gene and rs1042713 of the ADRB2 gene [35, 36].

Endothelial PAS domain-containing protein 1 (EPAS1), also called hypoxia-inducible factor 2 alpha, is a protein encoded by the EPAS1 gene. It is located on human chromosome 2 and is expressed by endothelial cells [37]. The most specific condition associated with EPAS1 is adaptation to high-altitude environments [38]. In this regard, natural selection for EPAS1 has been demonstrated to be associated with lower hemoglobin concentrations in Tibetan highlanders, but not in Andean residents [39–41]. This difference indicates different evolutionary pathways of adaptation to altitude in residents of high-altitude regions.

The potential determinants of the relationship between the genome and hematological status of highland residents are rs11549465 of the HIF1A gene and rs1572312 of the NFIA-AS2 gene, which is confirmed by a series of studies of the hematological status and aerobic capacity of elite athletes [42–44]. Rs11549465 of the HIF1A gene is of greatest interest, owing to the fact that for the Lak population from the Northeast Caucasus, in contrast to the lowland population of the Adyghe (Northwest Caucasus), a significant increase in the ancestral allele C was revealed, which may indicate the existence of certain patterns in adaptation to hypobaric hypoxia [24].

Additionally, predisposition to idiopathic pulmonary arterial hypertension may be a limiting factor for life in highland conditions. In this context, the potential targets for the study are the rs10478694 and rs5369 variants of the EDN1 gene [45, 46]. Polymorphic variants of the EDN1 gene have been associated with cardiovascular diseases such as hypertension, coronary heart disease, angina, and acute coronary syndrome [47], which was a reason to study their possible impact on adaptation to high-altitude conditions. The rs2070699 variant of the EDN1 gene was found to be a potential risk factor for the development of acute mountain sickness [48].

As a result, of the Illumina 1M SNP analysis of the Ethiopian Highlands populations, several candidate genes (e.g., CBARA1, VAV3, ARNT2, and THRB) were identified for participation in high-altitude adaptation [49]. This was of particular interest as most of these genes had not been previously identified in Tibetan and Andean populations, and the THRB and ARNT2 genes were found to play a role in the HIF-1 (Hypoxia-Inducible Factor-1) pathway. Moreover, it was noted that the variants associated with hemoglobin variation in Tibetans did not affect this trait in Ethiopian populations [50]. This indicates the existence of other pathways for the adaptation of Ethiopian populations to high altitude [51].

However, genetics alone does not elucidate the degree of phenotype variability. Epigenome analysis is one of the methods to determine the environmental impact. Epigenetic modifications include DNA methylation, posttranslational modifications of the histone tail, and noncoding RNAs. Various genes encode proteins with HIF proline hydroxylase activity, and among them, EGLNs are the most studied; moreover, it has been shown that EGLNs act as oxygen sensors that regulate HIFα stability [52]. Additionally, EGLN1 mRNA has been shown to be induced by hypoxia in various cell types [53–55], and increased mRNA levels are associated with increased EGLN activity [56]. Further, the protein encoded by the SPRTN gene may play a role in DNA repair during replication of damaged DNA, and its deficiency in mice causes chromosomal instability and a progeroid phenotype [57].

In La Paz, Bolivia (3640 m), genome-wide differences in DNA methylation have already been reported in peripheral blood mononuclear cells from offsprings of mothers with and without hypertensive pregnancy [58]. Men with severe erythrocytosis, a preclinical form of chronic mountain sickness (CMS), exhibit epigenetic differences compared to healthy controls [59]. The association between adaptive responses and high altitude in a high-altitude Andean Quechua population and its relationship to epigenetic mechanisms has been studied [60]. DNA methylation of the EPAS1 promoter region and the LINE-1 repeat element in 572 high-altitude (4388 m) and lowland Quechua individuals was analyzed. The high-altitude sample was characterized by low EPAS1 DNA methylation and higher LINE-1 DNA methylation [60]. Further studies of the association between genome-wide analysis data and DNA methylation levels in the Quechua population showed that local genetic variations are significantly associated with DNA methylation levels for EPAS1 and SOD3 [61]. Moreover, it was found that the Tibetan variant of EPAS1 suppresses expression in the human umbilical cord and placental endothelial cells, and heterozygous EPAS1 knockout mice exhibited blunted physiological responses to chronic hypoxia [62].

Gonzales and Chaupis [63] demonstrated that men with CMS from the Peruvian Central Andes had increased transcriptional activity of the SENP1 (SUMO-specific protease 1) and ANP32D genes in response to hypoxia compared to men without CMS. The SENP1 gene product increases the transcriptional activity of androgen receptors and regulates erythropoiesis, which is crucial for the stability and activity of hypoxia-inducible factor 1 (HIF-1α) [63].

The HIF gene family encodes transcription factors that respond to the prevailing oxygen level. In hypoxia, oxygen deficiency leads to ubiquitination failure of HIF-1α, which, as a result, moves into the nucleus, binds to HIF-1β, and recruits coactivator proteins to the HIF binding site. Thus, a large number of genes involved in adaptation to hypoxia are activated, including the VEGF gene and erythropoietin [64]. CMS is characterized by the expression of key enzymes of glucose metabolism, namely, increased mRNA levels of the HK2, GLU1, and GLU2 genes, which positively correlates with hemoglobin [65]. In 2021, a study of Chinese people living on the plateau revealed differential changes in 145 gene expression, including an increase in the activity of 89 genes and a decrease in 56 genes. The expression products of these genes are involved in the metabolism of hydrogen peroxide and reactive oxygen species and in inflammatory reactions [66].

PATHOPHYSIOLOGICAL AND METABOLIC CHARACTERISTICS OF HIGH-ALTITUDE RESIDENTS

Despite the transmission of genetic characteristics that facilitate survival at high altitudes, 5%–33% of highland residents show signs of CMS due to maladaptation to constant hypoxia [67]. CMS is characterized by tinnitus and headache, paresthesia, varicose veins, cyanosis, sleep disturbances, palpitations, and dyspnea [68]. Additionally, long-term hypoxia contributes to an increase in hematocrit and changes in hematological parameters [69], such as excessive erythrocytosis [68]. As a result, blood viscosity increases, promoting flow-mediated vascular dilation, which is noted in individuals living at high altitudes [70].

CMS is often associated with pulmonary hypertension and heart failure. Furthermore, cardiovascular adaptation to hypoxia represents a remarkable model of the regulation of oxygen availability at the cellular and systemic levels [71]. High-altitude pulmonary hypertension with pulmonary arteriolar remodeling and right ventricular enlargement is detected in more severe stages of CMS. The degree of ventricular hypertrophy depends on the severity of hypoxemia [72]. In healthy individuals living in regions located at an altitude of 5100 m above sea level, dilation of the right compartments of the heart and left ventricular concentric remodeling with diastolic dysfunction are observed. These changes are more pronounced in patients with moderate to severe CMS and may represent the limits of cardiac adaptability before progression to heart failure [73]. CMS patients exhibit increased morbidity and mortality and risk of stroke and migraine [74], and CMS contributes to cognitive impairment [75]. This is associated with excessive oxidative–inflammatory–nitrosative stress with increased formation of free radicals and decreased bioavailability of nitric oxide [74]. However, people living at high altitudes have a lower mortality rate from malignant neoplasms owing to the influence of physiological adaptive processes in response to hypoxia [76]. The development of CMS in highlanders is attributed to excess weight, which is associated with metabolic changes and critical ventilation impairment in obesity, which aggravate hypobaric hypoxemia at high altitudes, leading to hypoxemia [77].

Although levels of cholesterol and lipoprotein levels were higher were revealed in Andean residents than in their peers from the Amazon basin, no significant differences were noted in the risk of cardiovascular diseases [78]. Moreover, it was determined that low oxygen levels in the environment prevent the development of atherosclerosis. This is because of an increase in anti-inflammatory cytokine interleukin 10 expression [79]. Further, differences in physiological changes in highland residents of different ethnic groups and countries have been described. For example, Andean residents have a higher hemoglobin concentration than Tibetans. This is reflected in the functional characteristics of people, such that lung ventilation at rest is lower in Andean residents than in Tibetans [80].

Highlanders show increased intracellular pH in the brain due to adaptation to hypoxemia and promotion of glycolysis, DNA synthesis, and cell-cycle progression. Lower intracellular pH was detected in brain astrocytes in highlanders with CMS compared with astrocytes of highlanders without CMS [81]. Severe erythrocytosis is caused by increased transcription of the EPAS1 gene, which regulates erythroblast proliferation [82]. Testosterone, an erythropoietic hormone, is involved in the development of severe erythrocytosis in individuals with CMS. Men living at normal altitudes have higher androstenedione levels and low androstenedione/testosterone ratio compared with highlanders, indicating reduced activity of 17-beta-hydroxytestosteroid dehydrogenase in the mechanisms of adaptation to living at high altitude.

MORPHOFUNCTIONAL CHARACTERISTICS OF HIGH-ALTITUDE POPULATIONS

When considering the challenges associated with the origin of second-order races, anthropological studies periodically discussed issues on the relationship between the natural–climatic and landscape features of the habitat with a complex of morphophysiological signs characteristic of certain populations, forming their uniqueness and allowing them to be identified as separate subracial categories.

Scientists agree that one of the main factors in the formation of morphophysiological signs of representatives of various adaptive types is the entire set of physical characteristics of a particular anthropogeocenosis [83]. Moreover, the discussion of adaptive types and mechanisms of their formation is inseparable from the discussion of the features of heredity and variability, which are genetically determined traits in certain human populations [84, 85].

The concept of the confinement of manifestations of human body variability to natural–climatic zones and altitudinal zonality is comprehensively formulated in studies by Alekseeva [86, 87]. In this concept, an adaptive type is understood as a reaction norm that depends on specific environmental conditions within a certain zonality and/or altitude. Consequently, adaptive types that formed in similar environmental conditions are distinguished by a similar reaction norm and, accordingly, a set of morphological traits. One or another adaptive set of traits is reflected in the variations in the size and proportions of the body, combination of body components, and physiological characteristics of the blood as an indicator of the internal environment of the body [88].

Among the four adaptive types identified by Alekseeva, namely, arctic, continental, equatorial, and high-mountain, the last one is of interest in the present study [87]. The distinctive features of people belonging to populations that are highly possible to form in high-mountain conditions are characterized by larger body sizes, owing to a more voluminous chest, large long bones, and a massive skeleton, regardless of racial and ethnic affiliation. These traits were considered to include the degree of the face flattening; however, studies of the facial skeleton did not confirm the adaptive nature of the latter trait [89].

The listed morphological features, characteristic of representatives of mountainous countries, are associated with an enlargement of blood vessels and respiratory organs that is, those changes in the physiological functions of the body that are the result of adaptation to a decrease in atmospheric pressure and a lack of oxygen. Notably, the rate of basal metabolism and oxidation-reduction processes and functioning of the adrenal glands, thyroid gland, and heart contractions slow down, whereas blood oxygenation increases because of a large amount of hemoglobin and increased erythropoiesis [86]. Moreover, researchers do not have a clear understanding of the exact altitudes above sea level the conditions for the formation of the described population features begin to be created. Thus, according to Alekseev, the air rarefaction begins to affect at an altitude of about 1000 m above sea level, whereas the conventional highland boundary adopted in the study of mountain populations is considered to be 2000 m above sea level [88].

In addition, it is crucial to note that morphologically close adaptive types can have different biochemical mechanisms of adaptation to identical conditions [90].

PHYSICO-GEOGRAPHICAL, CLIMATIC, AND ETHNOLOGICAL FEATURES OF THE CAUCASUS

The geographical, historical, ethnological, and cultural aspects of the Caucasus have aroused particular interest in the study of this region. The history of the settlement in the Caucasus and all of Europe by modern humans has many blank spots. The Caucasus was inhabited by hominids (Homo erectus georgicus) in the Lower Pleistocene approximately 1.8 million years ago [91, 92]. Thus, the Caucasus is the oldest area of settlement of representatives of the genus Homo outside Africa, which indicates favorable conditions for habitation in this territory since ancient times and the possible genetic adaptation of the autochthonous population of the region to conditions of chronic oxygen deficiency.

Determining the nature of this adaptation is complicated by the climatic conditions in which this colonization occurred. The period from 26.5 to 19,000 years ago is characterized by the maximum extent of the ice sheet on Earth (the Last Glacial Maximum) [93]. More than 60% of the territory of modern Europe was covered by ice. This served as the main factor in population dynamics 30,000–13,000 years ago [94] and could have influenced migrations in the latitudinal and altitudinal directions (in mountainous regions), which in turn could have influenced the genetic portrait of modern populations. Periods with the lowest temperatures alternated with significantly warmer time periods. Thus, approximately 14,000 years ago, a rapid Allerod warming began on Earth, which abruptly transitioned to the final stage of glaciation, the Younger Dryas (10,730–9700 BC) [95].

In connection with such abrupt climate changes, refugia are of particular interest to scientists. A refugium is a surface area where species can survive an unfavorable period of geological time. Data indicate that postglacial warming released human populations from various climatic refugia with subsequent settlement of large territories [96]. In this context, the Caucasus is considered as a possible intermediate zone for the settlement of Eastern Europe and as a refugium, where the population became a source for the repopulation of both Eastern Europe and Southwest Asia after the Last Glacial Maximum [97, 98]. Although this territory was favorable for the preservation of the human population as a species, paleoclimatological data indicate harsher climatic conditions in the region compared to the modern state. For example, the snow cover line was 600–850 m below the contemporary level [99].

Considering that the Caucasus is located on the border between Europe and Western Asia, this territory was densely populated throughout the historical period. This is confirmed by the diversity of historical and archeological cultures that inhabited the region under study in different periods [10, 100, 101]. The influence of the Near Asian community on the population of the Caucasus can be traced back to the Early Bronze Age (3 millennium BC) and is associated with the Maikop and Kura–Araxes archeological cultures [102, 103]. In parallel with the Maikop culture, archeologists distinguish the development of the catacomb cultural and historical community (25–20 centuries BC). Their burials can be found in the basins of the Baksan, Chegem, and Kuban rivers that is, in modern Kabardino-Balkarian and Karachay-Cherkess Republics [100, 104, 105]. The Maikop culture was replaced by the settled population of the North Caucasian cultural and historical community (beginning of the 3 millennium BC–beginning of the 2 millennium BC) and then by the Kuban and Koban cultural and historical communities (13–3 centuries BC) [102, 106].

In the 8–7 centuries BC, the nomadic tribes of the Cimmerians [107], displaced by the Scythians from Asia Minor, appeared in the Black Sea region, and later the Scythians, who were eventually conquered by the Sarmatians. The link between the populations of the North Caucasus and nomadic tribes of the Alans, who appeared in the Ciscaucasia in the first century AD, requires a separate study. The influence of the Turkic-speaking populations of the Huns, Bulgars, and Khazars, who dominated the region from the 4th to the 10th centuries AD, on the population of the Caucasus should be comprehensively studied [108]. Moreover, the history of the eastern part of the North Caucasus cannot be studied in isolation from the Arab–Khazar wars, which had a significant impact on the entire region [109]. The 13th century is characterized by the transition of the territory under the control of the Tatar-Mongols [110].

The most high-mountain part of the Caucasus is its central region; hence, the ethnogenesis of the Balkars and Karachays should be evaluated. To date, several studies have been conducted on the anthropological characteristics of the Karachays and Balkars [14, 16, 111], resulting in a conclusion regarding their aboriginal origin (Caucasian) and kinship with representatives of neighboring people [15]. The modern population participated in the studies, and remains from medieval burials were investigated.

Studies conducted using various marker systems (i.e., mitochondrial DNA, Y chromosome, and autosomal markers) revealed the genetic homogeneity of the ethnically and linguistically diverse population of the North Caucasus and its predominant Middle Eastern origin with little external influence [97, 112, 113]. Moreover, the discovered East Eurasian lines of mtDNA and Y-chromosome haplogroups, in the absence of Mongoloid signs, indicate an ancient admixture and/or a founder effect against the background of a successful reproductive history of the carriers of these haplogroups [112–114].

CONCLUSION

Despite the increasing knowledge of the physiological, genetic, and epigenetic bases of high-altitude adaptation over the past decade, the ability to adapt to high-altitude conditions and its risk factors remain unclear. This is crucial because not all high-altitude regions worldwide have been studied to the necessary extent to date. The mountainous territories of Russia appear to be the most promising for researchers. In this regard, the Caucasus is of the greatest interest, because for many millennia, this region has been a place of active contact and formation of various people and cultural communities, which led to settlement in the highest mountain areas of this region. This review summarizes the contributions of genetic, epigenetic, and metabolic nature to the process of adaptation of populations to high-altitude conditions and characterizes the people of the Central Caucasus as the focus for further comprehensive study in this context.

ADDITIONAL INFO

Authors’ contribution. All authors made a substantial contribution to the conception of the study, acquisition, analysis, interpretation of data for the work, drafting and revising the article, final approval of the version to be published and agree to be accountable for all aspects of the study. Personal contribution of each author: M.A. Dzhaubermezov — collecting a collection of biomaterials, writing the text; N.V. Ekomasova — study concept and design, text writing; R.N. Mustafin — writing the text; O.S. Chagarov — collection of biomaterials; Yu.Yu. Fedorova — study concept and design; A.Kh. Nurgalieva — text writing, literature review; L.R. Gabidullina — literature review; D.S. Prokofieva — attracting funding; E.K. Khusnutdinova— making final edits.

Funding source. The work was supported by the State Assignment of the Ministry of Science and Higher Education of the Russian Federation No. 075–03–2024–123/1. This work was supported by the program for supporting bioresource collections (Collection of Human Biological Materials, Institute of Biochemistry and Genetics, Ufa Federal Research Center, Russian Academy of Sciences) and grant of the Ministry of Education and Science of the Republic of Bashkortostan No. 1 dated August 14, 2023 on the topic “Prospects of using population genetic features of mtDNA as diagnostic markers of gastric cancer” in terms of statistical data processing.

Competing interests. The authors declare that they have no competing interests.

Ethics approval. Sampling was carried out in accordance with the ethical standards of the Bioethics Committee, developed by the WMA Declaration of Helsinki “Ethical Principles for the Conduct of Medical Research Involving Human Subjects”. All subjects filled out a questionnaire taking into account nationality up to three generations, year of birth. All respondents signed an informed voluntary consent to participate in the study. The work was approved by the Local Ethics Committee of the Institute of Biochemistry and Genetics of the Ufa Federal Research Center Russian Academy of Sciences (protocol No. 14 of September 15, 2016).

 

[*] Cohen JE, Small C. Hypsographic demography: the distribution of human population by altitude. Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14009-14014. doi: 10.1073/pnas.95.24.14009.

About the authors

Murat A. Dzhaubermezov

Ufa University of Science and Technology; Institute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of Sciences

Author for correspondence.
Email: murat-kbr@mail.ru
ORCID iD: 0000-0003-1570-3174
SPIN-code: 1066-3369
Scopus Author ID: 57196059060

Cand. Sci. (Biology)

Russian Federation, Ufa; Ufa

Natalia V. Ekomasova

Ufa University of Science and Technology; Institute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of Sciences

Email: trofimova_nata_@mail.ru
ORCID iD: 0000-0003-3996-5734
SPIN-code: 6528-4117

Cand. Sci. (Biology)

Russian Federation, Ufa; Ufa

Rustam N. Mustafin

Bashkir State Medical University

Email: ruji79@mail.ru
ORCID iD: 0000-0002-4091-382X
SPIN-code: 4810-2535
Scopus Author ID: 56603137500
ResearcherId: S-2194-2018

Cand. Sci. (Biology)

Russian Federation, Ufa

Ongar S. Chagarov

Moscow State University named after M.V. Lomonosov

Email: chagarov89@gmail.com
ORCID iD: 0000-0002-1857-4163
SPIN-code: 1455-0797
Russian Federation, Moscow

Yuliya Y. Fedorova

Ufa University of Science and Technology

Email: fedorova-y@yandex.ru
ORCID iD: 0000-0002-9344-828X
SPIN-code: 5497-0441

Cand. Sci. (Biology)

Russian Federation, Ufa

Liliya R. Gabidullina

Ufa University of Science and Technology

Email: liliya.gab@gmail.com
ORCID iD: 0009-0007-1575-2642
SPIN-code: 2799-0206
Russian Federation, Ufa

Alfiya K. Nurgalieva

Ufa University of Science and Technology

Email: alfiyakh83@gmail.com
ORCID iD: 0000-0001-6077-9237
SPIN-code: 9658-8010

Cand. Sci. (Biology)

Russian Federation, Ufa

Darya S. Prokofyeva

Ufa University of Science and Technology

Email: dager-glaid@yandex.ru
ORCID iD: 0000-0003-0229-3188
SPIN-code: 7918-4737
Scopus Author ID: 57207892550

Cand. Sci. (Biology)

Russian Federation, Ufa

Elza K. Khusnutdinovna

Ufa University of Science and Technology; Institute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of Sciences

Email: elzakh@mail.ru
ORCID iD: 0000-0003-2987-3334
SPIN-code: 7408-9797
ResearcherId: A-4810-2013

Dr. Sci. (Biology)

Russian Federation, Ufa; Ufa

References

Supplementary files