Search for genetic variations that allow populations to thrive in high-altitude environment of Caucasus highlands

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Dzhaubermezov, Natalia V. Ekomasova, Askar A. Akhmetshin, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7766645/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Jan, 2026 Read the published version in Genetica → Version 1 posted 12 You are reading this latest preprint version Abstract High-altitude hypoxia refers to the state of reduced oxygen availability experienced at high elevations, which poses significant physiological challenges. Genetic adaptations to this condition involve mutations in various genes that regulate oxygen sensing, erythropoiesis, and metabolic processes, enabling populations indigenous to high-altitude regions to maintain adequate tissue oxygenation and metabolic function under chronic hypoxic conditions. The aim of the study was to investigate the 1q42.2 region in Caucasian populations to identify alleles that may contribute to evolutionary adaptation. We studied a ~ 700 kb region within the 1q42.2 locus in Caucasus populations using the integrated selection of alleles favored by evolution (iSAFE) method. The study included 308 individuals from five ethnic groups inhabiting the high-altitude regions of the North Caucasus (Balkars, Ingush, Karachays, and Chechens) and the South Caucasus (Armenians). Whole-genome sequencing of the samples was performed on the DNBSEQ-T7 platform. The genomic region chr1:231046413–231737003 (GRCh38.p14) was selected due to its established role in high-altitude adaptation across various global populations. Analysis revealed a region encompassing five variants in the SPRTN and EGLN1 genes with the highest iSAFE scores in Balkar samples. Similarly, five high-scoring genetic variants were identified in the Karachay population within the same locus. In contrast, only one variant in the EGLN1 gene showed a maximum score in both the Ingush and Armenian groups. The study found evidence of positive selection for two SPRTN gene variants, confirmed across all studied populations except Chechens. Caucasus evolution hypoxia SPRTN EGLN1 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction High altitude areas are extreme habitats primarily due to hypobaric hypoxia conditions. High altitude sickness has a severe impact on the human body and is a direct consequence of the exponential decrease in barometric pressure with increasing altitude (Fig. 1 ). The body's response to stressful conditions is extremely diverse. These include changes in the respiratory, cardiovascular, hematological systems, and cellular adaptation (Leon-Velarde et. al. 2006; Richalet et al. 2024). Despite the negative impact of these conditions on the human body, approximately 400 million people worldwide currently live at altitudes above 1,500 m above sea level, and approximately 82 million people live permanently at altitudes above 2,500 m (Tremblay et al. 2021). It should be noted that the scientific community does not have a clear understanding of altitudes at which high-altitude conditions begin to affect humans. Thus, the rarefaction of the air begins to affect people at an altitude of about 1000 m above sea level, while the conventional high-altitude boundary adopted in the study of mountain populations is considered to be 1500–2000 m (Alekseev, 1993; Paralikar et al. 2010). It is also important that the altitude at which mountain sickness begins to manifest itself in different mountainous countries can differ significantly, and if in the Himalayas the conventional boundary is at an altitude of 5000 m, then in the Caucasus signs of mountain sickness begin to manifest themselves already at 3000 m (Fig. 1 ) (Gvozdeckij et al. 1987). It is now known that humans have adapted to the conditions of chronic oxygen deficiency at high altitudes in several locations independently, and recent genome-wide studies have revealed the genetic basis for this adaptation (Peng et al. 2017; Brutsaert et al. 2019; Heinrich et al. 2019). A detailed description of all known genes associated with successful colonization of high-altitude regions has been previously presented in review publications and we will not repeat them here (Mallet et al. 2023; Dzhaubermezov et al. 2024). However, the most significant genes in this context are EGLN1 , EXOC8 , and SPRTN , all located in the 1q42.2 locus. Studies of the genetic mechanisms of adaptation to adverse conditions were previously conducted on the populations of such high-mountain regions as the Andes, Tibet, and the Ethiopian Highlands (Brutsaert et al. 2019; Heinrich et al. 2019; Bigham et al. 2010; Pagani et al. 2012; Scheinfeldt et al. 2012; Alkorta-Aranburu et al. 2012; Bigham et al. 2013; Lessel et al. 2014; Wu et al. 2015; Getu, 2022). It should be noted that the Caucasus populations were previously characterized as the most promising for the search for genetic associations with hypobaric hypoxia (Dzhaubermezov et al. 2024). However, the genetic contribution to the formation of adaptation to high-altitude living conditions in the Caucasus has been studied very fragmentarily to date. Thus, in the only work devoted to this issue, 15 candidate genes for adaptation to high-altitude conditions were analysed in three populations of the northeastern Caucasus (Avars N = 16, Kubachins N = 12 and Laks N = 21) (Pagani et al. 2012). As a result of the study, the presence of positive selection signals in the HIF1A gene, whose function of improving oxygen metabolism had already been confirmed earlier, was confirmed for the Laks, and a cluster of 13 SNPs located in the conservative intronic region of the EGLN1 gene was found in the Kubachins (Pagani et al. 2012; Harun-Or-Roshid et al. 2022; Bai et al. 2022; Anastasiou et al. 2024). Thus, taking into account the data of previous studies, the 1q42.2 locus is a priority in studying the genetic mechanisms of adaptation of Caucasian populations to conditions of hypobaric hypoxia. Due to the complete lack of archaeogenetic studies of ancient populations of mountainous regions for already known genetic variants associated with adaptation to life at high altitudes, it is necessary to point out some indirect signs showing a complex process of development of adaptive traits to unfavorable conditions. The discovery of archaeological samples with the so-called cribra orbitalia (a pathological condition affecting the bones of the cranial vault) may indicate a long and complex process of adaptation of the ancient population to the highlands of the Caucasus. Thus, among the population of the Central Caucasus of the 5th-6th centuries AD living at altitudes of 1700–2500 m above sea level, cribra orbitalia occurs with a frequency of 7.4% (Biyaslan Kh. Atabiev, unpublished data). This may indicate that the population was poorly adapted to the environment and / or was in a state of nutritional stress (Stuart-Macadam, 1992; Scaffidi, 2020). It should be noted that currently there is interest not only in the population-genetic aspects of adaptation of the autochthonous mountain population to the conditions of hypobaric hypoxia, but also in the search for genes that have adaptive significance in various lowland populations. This direction will improve the understanding of the distribution of functional alleles in multiethnic groups and will allow the development of new approaches for a medical control during the adaptation of lowland residents to highland conditions. This part of personalized medicine is extremely relevant at present due to the constant growth of tourist flow to mountainous regions. Just in Russia in 2024, about 4.8 million people visited the most popular mountain resorts of the North Caucasus: the Sochi Mountain Cluster, Arkhyz, Dombay, and Elbrus region. It is important to note that these resorts are developing rapidly and new cable cars are being built that rise ever higher above sea level (Online Resource/File 1), which, coupled with the rapid melting of glaciers in the Caucasus and the increasing tourist flow, will inevitably lead to a stricter medical control (GlaMBIE Team, 2025). Materials and methods The study involved 308 presumably healthy individuals from 5 populations of the North and South Caucasus. Sample collection was carried out in accordance with the ethical standards of the Bioethics Committee developed by the WMA Declaration of Helsinki ("Ethical principles for medical research involving human subjects"). Blood sampling was performed after signing an informed consent to participate in the scientific study of those who have reached the age of 18 and filled out questionnaires indicating ancestors up to the third generation (Fig. 2 ). DNA extraction was performed from peripheral venous blood using the phenol-chloroform method (Mathew, 1985). Genomic libraries were prepared using the MGIEasy FS PCR-Free Library Prep Set. Whole-genome sequencing in 2×150 bp reads was performed on a DNBSEQ-T7 device with a target coverage of 30×. Reads were mapped to the human reference genome GRCh38 analysis set using BWA (Li, 2013). Variants were called using DeepVariant (Poplin et al. 2018). Sequencing quality indicators were calculated using the Samtools coverage tool (Danecek et al. 2021). Statistical Analysis In our case, classical association (GWAS) analysis was undesirable due to the significant level of genetic similarity between the populations of the Caucasus (Yunusbayev et al. 2012). Also, due to the fact that most of the populations, both those studied in this work and those not included in it, inhabited both high-mountain and foothill (often lowland) zones for many generations, it is extremely difficult to select a control group. Therefore, we investigated genetic variants within a ~ 700 Kbp region surrounding the rs2739515 variant of the EGLN1 gene using the integrated selection of alleles favored by evolution (iSAFE) method (Akbari et al. 2018). Visualization of the obtained data, as well as the calculation of linkage disequilibrium (LD) were performed using R. Results Caucasian populations living in high-altitude conditions for centuries represent a unique model for studying natural selection and human genetic adaptation to extreme environmental conditions. Using the integrated selection of alleles favored by evolution (iSAFE) method, a region was identified for the Balkar population that includes 6 genetic variants of the SPRTN and EGLN1 genes, as well as one variant in the regulatory region (Fig. 3 ). The SPRTN gene is the DNA-Dependent Metalloprotease SPRTN , which mediates the proteolytic cleavage of covalent DNA-protein crosslinks during DNA synthesis, thereby playing a key role in maintaining genomic integrity. It should be noted that the rs2437150 variant of this gene has previously been noted to be significant in adaptation to high-altitude conditions in Quechua and Tibetan populations (Brutsaert et al. 2019; Bigham et al. 2010; Guo et al. 2020; Liu et al. 2020; Moksnes et al. 2022; Zheng et al. 2023; Tang et al. 2024). However, rs2250749 and rs2250734 have not been previously described in this context, which suggests the existence of both universal and unique adaptation strategies to high-altitude conditions in populations of various high-mountain regions of the world. The EGLN1 (Egl-9 Family Hypoxia Inducible Factor 1) gene is a cellular oxygen sensor that catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins under normoxic conditions. In addition to the three markers with the highest score that we identified, another variant (rs2486741) of this gene was previously noted as significant in adaptation to high-altitude conditions in mountain populations of Dagestan and in Tibetans (Pagani et al. 2012; Guo et al. 2020; Li et al. 2013). In the Karachay population, 5 positions in a given region with the highest iSAFE score were identified. Unlike the Balkars, among the markers with the highest score there were no variants previously associated with life in high-altitude conditions. In addition to EGLN1 , variants in the following genes were selected. DISC1 (Disrupted In Schizophrenia 1 Protein) is involved in the regulation of multiple aspects of embryonic and adult neurogenesis. It is involved in the proliferation of neuronal precursors in the ventral/subventricular zone during the embryonic brain development and in the adult dentate gyrus of the hippocampus. Gene ID ENSG00000287856 denotes a novel gene that is still undergoing analysis and fine mapping. At the time of this study, HGNC haven’t yet assigned a preferred symbol for it. The GWAS catalog lists genetic variants of this gene as associated with the number of red blood cells in the blood, changes in hemoglobin levels, hematocrit, and mean corpuscular hemoglobin concentration (Cerezo et al. 2025; Danjou et al. 2015; Hodonsky et al. 2020; Chen et al. 2020). The product of this gene (hypoxia-inducible factor-proline dioxygenase) allows the cell to physiologically respond to low oxygen concentrations, which is critically important during prolonged exposure to high altitude conditions (Smith et al. 2008). The product of this gene—ENSP00000499467—shows close functional connections according to STRING 12.0 with the proteins EPAS1, HIF1A, HIF3A, NPAS3, NPAS1, which emphasizes the leading role of this locus in the process of evolutionary adaptation of the Caucasus population to constant conditions of hypoxia (Fig. 4 ) (Szklarczyk et al. 2023). In addition to new genetic variants not previously described in this context, SNPs previously associated with life under hypobaric hypoxia in Dagestan populations and Tibetans (rs2437150 and rs2486741) were confirmed with a significant (but not the maximum) level in the Karachay population, as well as in Balkar samples. Table 1 (also extended data in the Supplementary Note/Files 2, 3) shows the genetic variants with the highest iSAFE value in Balkars and Karachays. Variant rs2247124 is of probably regulatory nature due to intersection with a prominent cluster of ChIP-seq peaks of various transcriptional factors, according to the ENCODE V4 (Table 1 ) (ENCODE Project Consortium, 2012). Table 1 Genetic variants with the highest iSAFE value in Balkar and Karachay populations. rs ID Gene Balkars rs2250749 SPRTN rs2250734 SPRTN rs2437150 SPRTN rs2247124 intergenic (2.9 Kbp downstream of SPRTN , 5.7 Kbp downstream of EGLN1 ) rs2486732 EGLN1 rs2491410 EGLN1 rs1416914 EGLN1 Karachays rs183616633 EGLN1 new ENSG00000287856 new TSNAX-DISC1 rs148596923 DISC1 rs187890664 DISC1 For the genetic variants with the highest iSAFE value, linkage disequilibrium (LD) analysis revealed r2 = 1 (Fig. 3 ). In other studied populations, as well as in the 1000 Genomes Project data, the LD r2 was below 1, which may indicate the evolutionary significance of this region in each of the populations considered. Unlike previous populations, there was only one variant with the maximum iSAFE value in the EGLN1 gene (rs2739508) for Ingush samples (Fig. 5 ). It is also new and has not been previously cited in any population or clinical context. However, it is necessary to point out the fact that both variants previously described by other authors and variants discovered in this study were identified with slightly lower iSAFE values (Online Resource/File 4). For genetic variants with iSAFE values slightly below the maximum (0.173), the linkage disequilibrium (LD) analysis revealed r2 = 1 (Fig. 5 ). In other populations, both those studied by us and those published earlier, LD r2 was less than 1. Chechens are related to the Ingush people. Only one intergenic variant was found in Chechen samples, not characteristic of any other of the populations considered (rs147029201). Its iSAFE value turned out to be borderline, amounting to only 0.104 (Fig. 5 ). The functional significance of this variant is also unknown (Online Resource/File 5). Among the populations of the South Caucasus, Armenians are of great interest due to their small territorial distance from other ethnic groups of the Caucasus, as well as their geographical and historical rapprochement with the populations of Western Asia. However, the fact of the geographical distance of Armenians did not affect the nature of the selection of alleles favored by evolution. Thus, the variant in the EGLN1 gene (rs480902) was identified with the highest iSAFE score, previously described in this context for the populations of Dagestan, Tibet, and the Andes, and confirmed by us for the Ingush population (Brutsaert et al. 2019; Pagani et al. 2012; Shen et al. 2020; Yasukochi et al. 2020). Most of other genetic variants confirmed in Armenians were either previously described in the scientific literature or identified in this study (Fig. 6 . Online Resource/File 6). For genetic variants with iSAFE values slightly below the maximum (0.172), the linkage disequilibrium (LD) analysis revealed r2 = 1 (Fig. 6 ). Again, in other populations, both those studied by us and those published earlier, the LD r2 was less than 1. Discussion In the course of this study, we have found the evidence of positive selection for 2 variants of the SPRTN gene (rs2437150, rs4486439), which were confirmed for all analyzed populations except for Chechens. Of particular interest is the fact that one of them was previously noted as significant in adaptation to high-altitude conditions in the Quechua and Tibetan populations, which may indicate similar processes of adaptation to identical environmental conditions in the populations of Tibet, the Andes, and the Caucasus. However, most of identified genetic variants have not been previously identified in this context and in this regard, of particular interest is the cluster of 8 SNPs located in the conservative intronic region of the ENSG00000287856 gene. It may also indicate the existence of other ways of adaptation to high altitudes in the peoples of the Caucasus. The study of the processes of adaptation to high-altitude conditions in the populations of the Caucasus should be continued, and this especially concerns the Chechens, who demonstrate results that differ from those of other studied populations. To date, EGLN1 (Egl-9 Family Hypoxia Inducible Factor 1) is one of the most studied genes associated with adaptation to life at high altitude. It is the most important component of the hypoxia response pathway. Adaptive variants of this gene are associated, among other things, with lower hemoglobin concentrations. As it turned out, this region also demonstrates one of the strongest signals of selection in the Caucasus populations. Without listing the large number of variants that are common to two or more ethnic groups (all of which are listed in Online Resource/File 7), we provide a list of genetic variants with high iSAFE values ​​that have been confirmed in several of the populations we studied (Table 2 ). Thus, in addition to the widely known variants, another 8 SNPs were identified in this gene for the studied populations. These variants may be of great importance in adaptation to high-altitude conditions in the populations of Caucasus. Table 2 Markers preferred for natural selection in the Caucasus populations. Position (GRCh38.р14) rs ID Gene Previous references 1:231352778 rs2437150 SPRTN Bigham et al., 2010; Brutsaertet et al., 2019; Guo et al., 2020; Liu et al., 2020; Moksnes et al., 2022; Zheng et al., 2023; Tang et al., 2024 1:231341724 rs4486439 SPRTN Has not previously been associated with human adaptation to high altitudes 1:231350017 rs2250749 SPRTN Has not previously been associated with human adaptation to high altitudes 1:231350212 rs2250734 SPRTN Has not previously been associated with human adaptation to high altitudes 1:231471136 rs2790860 ENSG00000287856 Has not previously been associated with human adaptation to high altitudes 1:231474293 rs1769798 ENSG00000287856 Has not previously been associated with human adaptation to high altitudes 1:231453252 rs1765814 ENSG00000287856 Has not previously been associated with human adaptation to high altitudes 1:231515529 rs1765795 ENSG00000287856 Has not previously been associated with human adaptation to high altitudes 1:231487727 rs1765797 ENSG00000287856 Has not previously been associated with human adaptation to high altitudes 1:231497405 rs1765787 ENSG00000287856 Has not previously been associated with human adaptation to high altitudes 1:231498611 rs1765786 ENSG00000287856 Has not previously been associated with human adaptation to high altitudes 1:231499512 rs1765785 ENSG00000287856 Has not previously been associated with human adaptation to high altitudes 1:231327455 rs7546511 intergenic variant Has not previously been associated with human adaptation to high altitudes 1:231355966 rs2790897 intergenic variant Has not previously been associated with human adaptation to high altitudes 1:231466456 rs1769795 EGLN1 Bigham et al., 2010; Guo et al., 2020 1:231382930 rs2486739 EGLN1 Has not previously been associated with human adaptation to high altitudes 1:231341043 rs11122273 EGLN1 Has not previously been associated with human adaptation to high altitudes 1:231380704 rs2486741 EGLN1 Pagani et al. 2012; Li et al. 2013; Guo et al., 2020 1:231395730 rs2486732 EGLN1 Bigham et al., 2010 1:231396541 rs2491410 EGLN1 Has not previously been associated with human adaptation to high altitudes 1:231391424 rs2749706 EGLN1 Has not previously been associated with human adaptation to high altitudes 1:231392059 rs2248649 EGLN1 Has not previously been associated with human adaptation to high altitudes 1:231392366 rs2998427 EGLN1 Has not previously been associated with human adaptation to high altitudes 1:231393171 rs5781647 EGLN1 Has not previously been associated with human adaptation to high altitudes 1:231393745 rs2790886 EGLN1 Has not previously been associated with human adaptation to high altitudes 1:231368565 rs2066140 EGLN1 Bigham et al., 2010; Li et al. 2013; Zhanget al. 2014; Pan Zhanget al. 2019; Guo et al., 2020; Shen et al., 2020 1:231462108 rs1765805 EGLN1 Bigham et al., 2010; Guo et al., 2020 1:231395881 rs480902 EGLN1 Pagani et al. 2012; Brutsaertet et al., 2019; Shen et al. 2020; Yasukochi et al. 2020 Declarations Conflict of interest The authors have no competing interests to declare that are relevant to the content of this article. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. Funding This work was supported by the Ministry of Science and Higher Education of the Russian Federation under Grant No. 075-03-2025-407/2; and the work was also supported by the program for supporting bioresource collections (Collection of human biological materials of the Institute of Biochemistry and Genetics of the Ufa Federal Research Center of the Russian Academy of Sciences. Ethics Committee Approval Sample collection was carried out in accordance with the ethical standards of the Bioethics Committee developed by the WMA Declaration of Helsinki ("Ethical principles for medical research involving human subjects"). This study was approved by the Local Ethics Committee of the Institute of Biochemistry and Genetics of the USC RAS (protocol of October 16, 2017). Data Sharing Statement The datasets analyzed during the current study are available from the corresponding author upon reasonable request. Use of artificial intelligence (AI) and AI-based technologies Artificial intelligence (AI) and AI-based technologies were not used in the study. References Akbari A, Vitti JJ, Iranmehr A, Bakhtiari M, Sabeti PC, Mirarab S, Bafna V (2018) Identifying the favored mutation in a positive selective sweep. Nat Methods. 15(4):279-282. https://doi: 10.1038/nmeth.4606 Alekseev VP. Ocherki ekologii cheloveka. Moskva: Nauka; 1993. Alkorta-Aranburu G, Beall CM, Witonsky DB, Gebremedhin A, Pritchard JK, Di Rienzo A (2012) The genetic architecture of adaptations to high altitude in Ethiopia. PLoS Genet. 8(12):e1003110. https://doi: 10.1371/journal.pgen.1003110 Anastasiou K, Morris M, Akam L, Mastana S (2024) The Genetic Profile of Combat Sport Athletes: A Systematic Review of Physiological, Psychological and Injury Risk Determinants. Int J Environ Res Public Health. 21(8):1019. https://doi: 10.3390/ijerph21081019 Bai J, Li L, Li Y, Zhang L (2022) Genetic and immune changes in Tibetan high-altitude populations contribute to biological adaptation to hypoxia. Environmental Health and Preventive Medicine. 27:39. https://doi: 10.1265/ehpm.22-00040 Bigham A, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, Scherer SW, Julian CG, Wilson MJ, López Herráez D, et al. (2010) Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet. 6(9):e1001116. https://doi: 10.1371/journal.pgen.1001116 Bigham AW, Wilson MJ, Julian CG, Kiyamu M, Vargas E, Leon-Velarde F, Rivera-Chira M, Rodriquez C, Browne VA, Parra E, et al. (2013) Andean and Tibetan patterns of adaptation to high altitude. Am J Hum Biol . 25(2):190-7. https://doi: 10.1002/ajhb.22358 Brutsaert TD, Kiyamu M, Elias Revollendo G, et al. (2019) Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude. Proc Natl Acad Sci U S A. 116(48):24006-24011. https://doi: 10.1073/pnas.1906171116 Cerezo M, Sollis E, Ji Y, Lewis E, Abid A, Bircan KO, Hall P, Hayhurst J, John S, Mosaku A, et al. (2025) The NHGRI-EBI GWAS Catalog: standards for reusability, sustainability and diversity. Nucleic Acids Res. 53(D1):D998-D1005. https://doi: 10.1093/nar/gkae1070 Chen MH, Raffield LM, Mousas A, Sakaue S, Huffman JE, Moscati A, Trivedi B, Jiang T, Akbari P, Vuckovic D, et al. (2020) Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations. Cell. 182(5):1198-1213.e14. https://doi: 10.1016/j.cell.2020.06.045 Danecek P, Bonfield JK, Liddle J, Marshall J, Ohan V, Pollard MO, Whitwham A, Keane T, McCarthy SA, Davies RM, et al. (2021) Twelve years of SAMtools and BCFtools. Gigascience. 10(2):giab008. https://doi: 10.1093/gigascience/giab008 Danjou F, Zoledziewska M, Sidore C, Steri M, Busonero F, Maschio A, Mulas A, Perseu L, Barella S, Porcu E, et al. (2015) Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels. Nat Genet. 47(11):1264-71. https://doi: 10.1038/ng.3307 Dzhaubermezov MA, Ekomasova NV, Mustafin RN, Chagarov OS, Fedorova YY, Gabidullina LR, Nurgalieva AK, Prokofyeva DS, Khusnutdinovna EK (2024) Populations of the Caucasus as an object for studying the process of adaptation to conditions of high-altitude hypoxia. Ecological genetics. 22(3):277-292. https://doi: 10.17816/ecogen630869 ENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature. 489(7414):57-74. https://doi: 10.1038/nature11247 Getu A (2022) Ethiopian Native Highlander's Adaptation to Chronic High-Altitude Hypoxia. Biomed Res Int. 2022:5749382. https://doi: 10.1155/2022/5749382 GlaMBIE Team (2025) Community estimate of global glacier mass changes from 2000 to 2023. Nature. 639(8054):382-388. https://doi: 10.1038/s41586-024-08545-z Guo Z, Fan C, Li T, Gesang L, Yin W, Wang N, Weng X, Gong Q, Zhang J, Wang J (2020) Neural network correlates of high-altitude adaptive genetic variants in Tibetans: A pilot, exploratory study. Hum Brain Mapp. 41(9):2406-2430. https://doi: 10.1002/hbm.24954 Gvozdeckij N.A, Golubchikov NYU. Gory. Moskva: Mysl', 1987. Harun-Or-Roshid M, Ali MB, Jesmin, Mollah MNH (2022) Association of hypoxia inducible factor 1-Alpha gene polymorphisms with multiple disease risks: A comprehensive meta-analysis. Plos one. 17(8):e0273042. https://doi: 10.1371/journal.pone.0273042 Heinrich EC, Wu L, Lawrence ES, Cole AM, Anza-Ramirez C, Villafuerte FC, Simonson TS (2019) Genetic variants at the EGLN1 locus associated with high-altitude adaptation in Tibetans are absent or found at low frequency in highland Andeans. Ann Hum Genet. 83(3):171-176. https://doi: 10.1111/ahg.12299 Hodonsky CJ, Baldassari AR, Bien SA, Raffield LM, Highland HM, Sitlani CM, Wojcik GL, Tao R, Graff M, Tang W A, et al. (2020) Ancestry-specific associations identified in genome-wide combined-phenotype study of red blood cell traits emphasize benefits of diversity in genomics. BMC Genomics. 21(1):228. https://doi: 10.1186/s12864-020-6626-9 Koontz Scaffidi B (2020) Spatial paleopathology: A geographic approach to the etiology of cribrotic lesions in the prehistoric Andes. Int J Paleopathol. 29:102-116. https://doi: 10.1016/j.ijpp.2019.07.002 Leon-Velarde F, Richalet JP (2006) Respiratory control in residents at high altitude: physiology and pathophysiology. High Alt Med Biol. 7(2):125-137. https://doi: 10.1089/ham.2006.7.125. PMID: 16764526 Lessel D, Vaz B, Halder S, Lockhart PJ, Marinovic-Terzic I, Lopez-Mosqueda J, Philipp M, Sim JC, Smith KR, Oehler J, et al. (2014) Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat Genet. 46(11):1239-44. https://doi: 10.1038/ng.3103 Li H (2013) Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv [q-bio.GN]. arXiv:1303.3997v2. https://doi: 10.48550/arXiv.1303.3997 Li Q, Liu SY, Lin KQ, Sun H, Yu L, Huang XQ, Chu JY, Yang ZQ (2013) Association between six single nucleotide polymorphisms of EGLN1 gene and adaptation to high-altitude hypoxia. Yi Chuan. 35(8):992-8. https://doi: 10.3724/sp.j.1005.2013.00992 Liu G, Zhao W, Zhang H, Wang T, Han Z, Ji X (2020) rs1769793 variant reduces EGLN1 expression in skeletal muscle and hippocampus and contributes to high aerobic capacity in hypoxia. Proc Natl Acad Sci U S A. 117(47):29283-29285. https://doi: 10.1073/pnas.2010073117 Mallet RT, Burtscher J, Pialoux V, Pasha Q, Ahmad Y, Millet GP, Burtscher M (2023) Molecular Mechanisms of High-Altitude Acclimatization. Int J Mol Sci. 24(2):1698. https:// doi: 10.3390/ijms24021698 Mathew CG (1985) The isolation of high molecular weight eukaryotic DNA. Methods Mol Biol. 2:31-4. https://doi: 10.1385/0-89603-064-4:31 Moksnes MR, Graham SE, Wu KH, Hansen AF, Gagliano Taliun SA, Zhou W, Thorstensen K, Fritsche LG, Gill D, et al. (2022) Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT. Commun Biol. 5(1):591. https://doi: 10.1038/s42003-022-03529-z Pagani L, Ayub Q, MacArthur DG, Xue Y, Baillie JK, Chen Y, Kozarewa I, Turner DJ, Tofanelli S, Bulayeva K et al. (2012) High altitude adaptation in Daghestani populations from the Caucasus. Hum Genet. 131(3):423-33. https://doi: 10.1007/s00439-011-1084-8 Paralikar SJ, Paralikar JH (2010) High-altitude medicine. Indian J Occup Environ Med. 14(1):6-12. https://doi: 10.4103/0019-5278.64608. PMID: 20808661 Peng Y, Cui C, He Y, Ouzhuluobu, Zhang H, Yang D, Zhang Q, Bianbazhuoma, Yang L, He Y. et al. (2017) Down-Regulation of EPAS1 Transcription and Genetic Adaptation of Tibetans to High-Altitude Hypoxia. Mol Biol Evol. 34(4):818-830. https://doi: 10.1093/molbev/msw280 Poplin R, Chang PC, Alexander D, Schwartz S, Colthurst T, Ku A, Newburger D, Dijamco J, Nguyen N, Afshar PT, et al. (2018) A universal SNP and small-indel variant caller using deep neural networks. Nat Biotechnol. 36(10):983-987. https://doi: 10.1038/nbt.4235 Richalet JP, Hermand E, Lhuissier FJ (2024) Cardiovascular physiology and pathophysiology at high altitude. Nat Rev Cardiol. 21(2):75-88. https://doi: 10.1038/s41569-023-00924-9. PMID: 37783743. Scheinfeldt LB, Soi S, Thompson S, Ranciaro A, Woldemeskel D, Beggs W, Lambert C, Jarvis JP, Abate D, Belay G, et al. (2012) Genetic adaptation to high altitude in the Ethiopian highlands. Genome Biol. 3(1):R1. https://doi: 10.1186/gb-2012-13-1-r1 Shen Y, Zhang J, Yang J, Liu C, Bian S, Zhang C, Yu J, Gao X, Huang L (2020) Association of EPAS1 and PPARA Gene Polymorphisms with High-Altitude Headache in Chinese Han Population. Biomed Res Int. 2020:1593068. https://doi: 10.1155/2020/1593068 Smith TG, Robbins PA, Ratcliffe PJ (2008) The human side of hypoxia-inducible factor. Br J Haematol. 141(3):325-34. https://doi: 10.1111/j.1365-2141.2008.07029.x Stuart-Macadam P (1992) Porotic hyperostosis: a new perspective. Am J Phys Anthropol. 87(1):39-47. https://doi: 10.1002/ajpa.1330870105 Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, Gable AL, Fang T, Doncheva NT, Pyysalo S, et al. (2023) The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 51(D1):D638-D646. https://doi: 10.1093/nar/gkac1000 Tang S, Zhou W, Chen L, Yan H, Chen L, Luo F (2024) High altitude polycythemia and its maladaptive mechanisms: an updated review. Front Med (Lausanne). 11:1448654. https://doi: 10.3389/fmed.2024.1448654 Tremblay JC, Ainslie PN (2021) Global and country-level estimates of human population at high altitude. Proc Natl Acad Sci U S A. 118(18):e2102463118. https://doi: 10.1073/pnas.2102463118 Wu B, Guo W (2015) The Exocyst at a Glance. J Cell Sci. 128(16):2957-64. https://doi: 10.1242/jcs.156398 Yasukochi Y, Nishimura T, Ugarte J, Ohnishi M, Nishihara M, Alvarez G, Fukuda H, Mendoza V, Aoyagi K (2020) Effect of EGLN1 Genetic Polymorphisms on Hemoglobin Concentration in Andean Highlanders. Biomed Res Int. 2020:3436581. https://doi: 10.1155/2020/3436581 Yunusbayev B, Metspalu M, Järve M, Kutuev I, Rootsi S, Metspalu E, Behar DM, Varendi K, Sahakyan H, Khusainova R, et al. (2012) The Caucasus as an asymmetric semipermeable barrier to ancient human migrations. Mol Biol Evol. 29(1):359-65. https://doi: 10.1093/molbev/msr221 Zheng W, He Y, Guo Y, Yue T, Zhang H, Li J, Zhou B, Zeng X, Li L, Wang B, et al. (2023) Large-scale genome sequencing redefines the genetic footprints of high-altitude adaptation in Tibetans. Genome Biol. 24(1):73. https://doi: 10.1186/s13059-023-02912-1 Additional Declarations No competing interests reported. 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1","display":"","copyAsset":false,"role":"figure","size":765116,"visible":true,"origin":"","legend":"\u003cp\u003eAltitude zonation and the boundary of mountain sickness development using the Himalayas and the Caucasus as an example (a). Changes in oxygen levels depending on altitude, as well as symptoms of mountain sickness at different altitudes (using the Caucasus as an example) (b)\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7766645/v1/d0fe3ef625a0e63c7082e84e.png"},{"id":94111840,"identity":"6ad1257d-c5ca-4433-8f56-086d873acfd1","added_by":"auto","created_at":"2025-10-22 13:33:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":981753,"visible":true,"origin":"","legend":"\u003cp\u003eRegions of residence of the studied populations and places of collection of biomaterials. The map was created in QGIS Desktop 3.30.3\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7766645/v1/a2b4b2074d08b9f10a44920a.png"},{"id":94111578,"identity":"1490ba31-b5b9-4022-b450-7e5704916eaa","added_by":"auto","created_at":"2025-10-22 13:25:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":429845,"visible":true,"origin":"","legend":"\u003cp\u003eiSAFE results from a ~700 Kbp window surrounding the selected region in Balkar and Karachay samples\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7766645/v1/7ef83254e30ef5e3f8b688b0.png"},{"id":94111580,"identity":"28b320f3-80fb-4bd0-973b-4f89ac811fb4","added_by":"auto","created_at":"2025-10-22 13:25:27","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":288046,"visible":true,"origin":"","legend":"\u003cp\u003eProtein-protein interaction analysis around the ENSP00000499467 (product of the ENSG00000287856 gene) protein according to STRING 12.0. Each node represents proteins produced by one protein-coding gene locus\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7766645/v1/bb306f456cfc7f7cd4194990.png"},{"id":94111582,"identity":"9fedd613-6913-460d-8f6c-5727b2d2d5f4","added_by":"auto","created_at":"2025-10-22 13:25:27","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":347331,"visible":true,"origin":"","legend":"\u003cp\u003eResults of iSAFE calculation in the populations of Ingush and Chechens\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7766645/v1/eca030f64a2af05438fb57f0.png"},{"id":94111584,"identity":"3b42f477-c8b7-449a-934a-be82a1f5e2ec","added_by":"auto","created_at":"2025-10-22 13:25:27","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":290981,"visible":true,"origin":"","legend":"\u003cp\u003eResults of iSAFE and LD calculation in the Armenian population\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7766645/v1/08d95b84aa76cacc191175bb.png"},{"id":100617416,"identity":"0a44dfc2-abc2-4da3-a6f3-6725f6291058","added_by":"auto","created_at":"2026-01-19 17:52:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3685389,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7766645/v1/3c399fcc-a264-40cd-a103-cbd33daeec7f.pdf"},{"id":94111839,"identity":"ec98be16-3294-4698-991a-4c0138fb75cb","added_by":"auto","created_at":"2025-10-22 13:33:27","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":42457,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformation.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7766645/v1/860afc57f8f70ee64a2c1fb8.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Search for genetic variations that allow populations to thrive in high-altitude environment of Caucasus highlands","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHigh altitude areas are extreme habitats primarily due to hypobaric hypoxia conditions. High altitude sickness has a severe impact on the human body and is a direct consequence of the exponential decrease in barometric pressure with increasing altitude (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The body's response to stressful conditions is extremely diverse. These include changes in the respiratory, cardiovascular, hematological systems, and cellular adaptation (Leon-Velarde et. al. 2006; Richalet et al. 2024). Despite the negative impact of these conditions on the human body, approximately 400\u0026nbsp;million people worldwide currently live at altitudes above 1,500 m above sea level, and approximately 82\u0026nbsp;million people live permanently at altitudes above 2,500 m (Tremblay et al. 2021). It should be noted that the scientific community does not have a clear understanding of altitudes at which high-altitude conditions begin to affect humans. Thus, the rarefaction of the air begins to affect people at an altitude of about 1000 m above sea level, while the conventional high-altitude boundary adopted in the study of mountain populations is considered to be 1500\u0026ndash;2000 m (Alekseev, 1993; Paralikar et al. 2010). It is also important that the altitude at which mountain sickness begins to manifest itself in different mountainous countries can differ significantly, and if in the Himalayas the conventional boundary is at an altitude of 5000 m, then in the Caucasus signs of mountain sickness begin to manifest themselves already at 3000 m (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) (Gvozdeckij et al. 1987).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIt is now known that humans have adapted to the conditions of chronic oxygen deficiency at high altitudes in several locations independently, and recent genome-wide studies have revealed the genetic basis for this adaptation (Peng et al. 2017; Brutsaert et al. 2019; Heinrich et al. 2019). A detailed description of all known genes associated with successful colonization of high-altitude regions has been previously presented in review publications and we will not repeat them here (Mallet et al. 2023; Dzhaubermezov et al. 2024). However, the most significant genes in this context are \u003cem\u003eEGLN1\u003c/em\u003e, \u003cem\u003eEXOC8\u003c/em\u003e, and \u003cem\u003eSPRTN\u003c/em\u003e, all located in the 1q42.2 locus. Studies of the genetic mechanisms of adaptation to adverse conditions were previously conducted on the populations of such high-mountain regions as the Andes, Tibet, and the Ethiopian Highlands (Brutsaert et al. 2019; Heinrich et al. 2019; Bigham et al. 2010; Pagani et al. 2012; Scheinfeldt et al. 2012; Alkorta-Aranburu et al. 2012; Bigham et al. 2013; Lessel et al. 2014; Wu et al. 2015; Getu, 2022). It should be noted that the Caucasus populations were previously characterized as the most promising for the search for genetic associations with hypobaric hypoxia (Dzhaubermezov et al. 2024). However, the genetic contribution to the formation of adaptation to high-altitude living conditions in the Caucasus has been studied very fragmentarily to date. Thus, in the only work devoted to this issue, 15 candidate genes for adaptation to high-altitude conditions were analysed in three populations of the northeastern Caucasus (Avars N\u0026thinsp;=\u0026thinsp;16, Kubachins N\u0026thinsp;=\u0026thinsp;12 and Laks N\u0026thinsp;=\u0026thinsp;21) (Pagani et al. 2012). As a result of the study, the presence of positive selection signals in the \u003cem\u003eHIF1A\u003c/em\u003e gene, whose function of improving oxygen metabolism had already been confirmed earlier, was confirmed for the Laks, and a cluster of 13 SNPs located in the conservative intronic region of the \u003cem\u003eEGLN1\u003c/em\u003e gene was found in the Kubachins (Pagani et al. 2012; Harun-Or-Roshid et al. 2022; Bai et al. 2022; Anastasiou et al. 2024). Thus, taking into account the data of previous studies, the 1q42.2 locus is a priority in studying the genetic mechanisms of adaptation of Caucasian populations to conditions of hypobaric hypoxia.\u003c/p\u003e\u003cp\u003eDue to the complete lack of archaeogenetic studies of ancient populations of mountainous regions for already known genetic variants associated with adaptation to life at high altitudes, it is necessary to point out some indirect signs showing a complex process of development of adaptive traits to unfavorable conditions. The discovery of archaeological samples with the so-called cribra orbitalia (a pathological condition affecting the bones of the cranial vault) may indicate a long and complex process of adaptation of the ancient population to the highlands of the Caucasus. Thus, among the population of the Central Caucasus of the 5th-6th centuries AD living at altitudes of 1700\u0026ndash;2500 m above sea level, cribra orbitalia occurs with a frequency of 7.4% (Biyaslan Kh. Atabiev, unpublished data). This may indicate that the population was poorly adapted to the environment and / or was in a state of nutritional stress (Stuart-Macadam, 1992; Scaffidi, 2020). It should be noted that currently there is interest not only in the population-genetic aspects of adaptation of the autochthonous mountain population to the conditions of hypobaric hypoxia, but also in the search for genes that have adaptive significance in various lowland populations. This direction will improve the understanding of the distribution of functional alleles in multiethnic groups and will allow the development of new approaches for a medical control during the adaptation of lowland residents to highland conditions. This part of personalized medicine is extremely relevant at present due to the constant growth of tourist flow to mountainous regions. Just in Russia in 2024, about 4.8\u0026nbsp;million people visited the most popular mountain resorts of the North Caucasus: the Sochi Mountain Cluster, Arkhyz, Dombay, and Elbrus region. It is important to note that these resorts are developing rapidly and new cable cars are being built that rise ever higher above sea level (Online Resource/File 1), which, coupled with the rapid melting of glaciers in the Caucasus and the increasing tourist flow, will inevitably lead to a stricter medical control (GlaMBIE Team, 2025).\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThe study involved 308 presumably healthy individuals from 5 populations of the North and South Caucasus. Sample collection was carried out in accordance with the ethical standards of the Bioethics Committee developed by the WMA Declaration of Helsinki (\"Ethical principles for medical research involving human subjects\"). Blood sampling was performed after signing an informed consent to participate in the scientific study of those who have reached the age of 18 and filled out questionnaires indicating ancestors up to the third generation (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eDNA extraction was performed from peripheral venous blood using the phenol-chloroform method (Mathew, 1985). Genomic libraries were prepared using the MGIEasy FS PCR-Free Library Prep Set. Whole-genome sequencing in 2\u0026times;150 bp reads was performed on a DNBSEQ-T7 device with a target coverage of 30\u0026times;. Reads were mapped to the human reference genome GRCh38 analysis set using BWA (Li, 2013). Variants were called using DeepVariant (Poplin et al. 2018). Sequencing quality indicators were calculated using the Samtools coverage tool (Danecek et al. 2021).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eIn our case, classical association (GWAS) analysis was undesirable due to the significant level of genetic similarity between the populations of the Caucasus (Yunusbayev et al. 2012). Also, due to the fact that most of the populations, both those studied in this work and those not included in it, inhabited both high-mountain and foothill (often lowland) zones for many generations, it is extremely difficult to select a control group. Therefore, we investigated genetic variants within a\u0026thinsp;~\u0026thinsp;700 Kbp region surrounding the rs2739515 variant of the \u003cem\u003eEGLN1\u003c/em\u003e gene using the integrated selection of alleles favored by evolution (iSAFE) method (Akbari et al. 2018). Visualization of the obtained data, as well as the calculation of linkage disequilibrium (LD) were performed using R.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eCaucasian populations living in high-altitude conditions for centuries represent a unique model for studying natural selection and human genetic adaptation to extreme environmental conditions. Using the integrated selection of alleles favored by evolution (iSAFE) method, a region was identified for the Balkar population that includes 6 genetic variants of the \u003cem\u003eSPRTN\u003c/em\u003e and \u003cem\u003eEGLN1\u003c/em\u003e genes, as well as one variant in the regulatory region (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The \u003cem\u003eSPRTN\u003c/em\u003e gene is the DNA-Dependent Metalloprotease \u003cem\u003eSPRTN\u003c/em\u003e, which mediates the proteolytic cleavage of covalent DNA-protein crosslinks during DNA synthesis, thereby playing a key role in maintaining genomic integrity. It should be noted that the rs2437150 variant of this gene has previously been noted to be significant in adaptation to high-altitude conditions in Quechua and Tibetan populations (Brutsaert et al. 2019; Bigham et al. 2010; Guo et al. 2020; Liu et al. 2020; Moksnes et al. 2022; Zheng et al. 2023; Tang et al. 2024). However, rs2250749 and rs2250734 have not been previously described in this context, which suggests the existence of both universal and unique adaptation strategies to high-altitude conditions in populations of various high-mountain regions of the world.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe \u003cem\u003eEGLN1\u003c/em\u003e (Egl-9 Family Hypoxia Inducible Factor 1) gene is a cellular oxygen sensor that catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins under normoxic conditions. In addition to the three markers with the highest score that we identified, another variant (rs2486741) of this gene was previously noted as significant in adaptation to high-altitude conditions in mountain populations of Dagestan and in Tibetans (Pagani et al. 2012; Guo et al. 2020; Li et al. 2013).\u003c/p\u003e\u003cp\u003eIn the Karachay population, 5 positions in a given region with the highest iSAFE score were identified. Unlike the Balkars, among the markers with the highest score there were no variants previously associated with life in high-altitude conditions. In addition to \u003cem\u003eEGLN1\u003c/em\u003e, variants in the following genes were selected.\u003c/p\u003e\u003cp\u003e\u003cem\u003eDISC1\u003c/em\u003e (Disrupted In Schizophrenia 1 Protein) is involved in the regulation of multiple aspects of embryonic and adult neurogenesis. It is involved in the proliferation of neuronal precursors in the ventral/subventricular zone during the embryonic brain development and in the adult dentate gyrus of the hippocampus.\u003c/p\u003e\u003cp\u003eGene ID ENSG00000287856 denotes a novel gene that is still undergoing analysis and fine mapping. At the time of this study, HGNC haven\u0026rsquo;t yet assigned a preferred symbol for it. The GWAS catalog lists genetic variants of this gene as associated with the number of red blood cells in the blood, changes in hemoglobin levels, hematocrit, and mean corpuscular hemoglobin concentration (Cerezo et al. 2025; Danjou et al. 2015; Hodonsky et al. 2020; Chen et al. 2020). The product of this gene (hypoxia-inducible factor-proline dioxygenase) allows the cell to physiologically respond to low oxygen concentrations, which is critically important during prolonged exposure to high altitude conditions (Smith et al. 2008). The product of this gene\u0026mdash;ENSP00000499467\u0026mdash;shows close functional connections according to STRING 12.0 with the proteins EPAS1, HIF1A, HIF3A, NPAS3, NPAS1, which emphasizes the leading role of this locus in the process of evolutionary adaptation of the Caucasus population to constant conditions of hypoxia (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) (Szklarczyk et al. 2023).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn addition to new genetic variants not previously described in this context, SNPs previously associated with life under hypobaric hypoxia in Dagestan populations and Tibetans (rs2437150 and rs2486741) were confirmed with a significant (but not the maximum) level in the Karachay population, as well as in Balkar samples. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e (also extended data in the Supplementary Note/Files 2, 3) shows the genetic variants with the highest iSAFE value in Balkars and Karachays. Variant rs2247124 is of probably regulatory nature due to intersection with a prominent cluster of ChIP-seq peaks of various transcriptional factors, according to the ENCODE V4 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) (ENCODE Project Consortium, 2012).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eGenetic variants with the highest iSAFE value in Balkar and Karachay populations.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ers ID\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGene\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eBalkars\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ers2250749\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eSPRTN\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ers2250734\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eSPRTN\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ers2437150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eSPRTN\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ers2247124\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eintergenic (2.9 Kbp downstream of \u003cem\u003eSPRTN\u003c/em\u003e, 5.7 Kbp downstream of \u003cem\u003eEGLN1\u003c/em\u003e)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ers2486732\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ers2491410\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ers1416914\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eKarachays\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ers183616633\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enew\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eENSG00000287856\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enew\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eTSNAX-DISC1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ers148596923\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eDISC1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ers187890664\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eDISC1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFor the genetic variants with the highest iSAFE value, linkage disequilibrium (LD) analysis revealed r2\u0026thinsp;=\u0026thinsp;1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In other studied populations, as well as in the 1000 Genomes Project data, the LD r2 was below 1, which may indicate the evolutionary significance of this region in each of the populations considered.\u003c/p\u003e\u003cp\u003eUnlike previous populations, there was only one variant with the maximum iSAFE value in the \u003cem\u003eEGLN1\u003c/em\u003e gene (rs2739508) for Ingush samples (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). It is also new and has not been previously cited in any population or clinical context. However, it is necessary to point out the fact that both variants previously described by other authors and variants discovered in this study were identified with slightly lower iSAFE values (Online Resource/File 4).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFor genetic variants with iSAFE values slightly below the maximum (0.173), the linkage disequilibrium (LD) analysis revealed r2\u0026thinsp;=\u0026thinsp;1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). In other populations, both those studied by us and those published earlier, LD r2 was less than 1.\u003c/p\u003e\u003cp\u003eChechens are related to the Ingush people. Only one intergenic variant was found in Chechen samples, not characteristic of any other of the populations considered (rs147029201). Its iSAFE value turned out to be borderline, amounting to only 0.104 (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The functional significance of this variant is also unknown (Online Resource/File 5).\u003c/p\u003e\u003cp\u003eAmong the populations of the South Caucasus, Armenians are of great interest due to their small territorial distance from other ethnic groups of the Caucasus, as well as their geographical and historical rapprochement with the populations of Western Asia. However, the fact of the geographical distance of Armenians did not affect the nature of the selection of alleles favored by evolution. Thus, the variant in the \u003cem\u003eEGLN1\u003c/em\u003e gene (rs480902) was identified with the highest iSAFE score, previously described in this context for the populations of Dagestan, Tibet, and the Andes, and confirmed by us for the Ingush population (Brutsaert et al. 2019; Pagani et al. 2012; Shen et al. 2020; Yasukochi et al. 2020). Most of other genetic variants confirmed in Armenians were either previously described in the scientific literature or identified in this study (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e. Online Resource/File 6).\u003c/p\u003e\u003cp\u003eFor genetic variants with iSAFE values slightly below the maximum (0.172), the linkage disequilibrium (LD) analysis revealed r2\u0026thinsp;=\u0026thinsp;1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Again, in other populations, both those studied by us and those published earlier, the LD r2 was less than 1.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the course of this study, we have found the evidence of positive selection for 2 variants of the \u003cem\u003eSPRTN\u003c/em\u003e gene (rs2437150, rs4486439), which were confirmed for all analyzed populations except for Chechens. Of particular interest is the fact that one of them was previously noted as significant in adaptation to high-altitude conditions in the Quechua and Tibetan populations, which may indicate similar processes of adaptation to identical environmental conditions in the populations of Tibet, the Andes, and the Caucasus. However, most of identified genetic variants have not been previously identified in this context and in this regard, of particular interest is the cluster of 8 SNPs located in the conservative intronic region of the ENSG00000287856 gene. It may also indicate the existence of other ways of adaptation to high altitudes in the peoples of the Caucasus. The study of the processes of adaptation to high-altitude conditions in the populations of the Caucasus should be continued, and this especially concerns the Chechens, who demonstrate results that differ from those of other studied populations.\u003c/p\u003e\u003cp\u003eTo date, \u003cem\u003eEGLN1\u003c/em\u003e (Egl-9 Family Hypoxia Inducible Factor 1) is one of the most studied genes associated with adaptation to life at high altitude. It is the most important component of the hypoxia response pathway. Adaptive variants of this gene are associated, among other things, with lower hemoglobin concentrations. As it turned out, this region also demonstrates one of the strongest signals of selection in the Caucasus populations. Without listing the large number of variants that are common to two or more ethnic groups (all of which are listed in Online Resource/File 7), we provide a list of genetic variants with high iSAFE values ​​that have been confirmed in several of the populations we studied (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Thus, in addition to the widely known variants, another 8 SNPs were identified in this gene for the studied populations. These variants may be of great importance in adaptation to high-altitude conditions in the populations of Caucasus.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMarkers preferred for natural selection in the Caucasus populations.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePosition\u003c/p\u003e\u003cp\u003e(GRCh38.р14)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers ID\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGene\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePrevious references\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231352778\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2437150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eSPRTN\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBigham et al., 2010; Brutsaertet et al., 2019; Guo et al., 2020; Liu et al., 2020; Moksnes et al., 2022; Zheng et al., 2023; Tang et al., 2024\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231341724\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers4486439\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eSPRTN\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231350017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2250749\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eSPRTN\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231350212\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2250734\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eSPRTN\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231471136\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2790860\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eENSG00000287856\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231474293\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers1769798\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eENSG00000287856\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231453252\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers1765814\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eENSG00000287856\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231515529\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers1765795\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eENSG00000287856\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231487727\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers1765797\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eENSG00000287856\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231497405\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers1765787\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eENSG00000287856\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231498611\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers1765786\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eENSG00000287856\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231499512\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers1765785\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eENSG00000287856\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231327455\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers7546511\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eintergenic variant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231355966\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2790897\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eintergenic variant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231466456\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers1769795\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBigham et al., 2010; Guo et al., 2020\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231382930\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2486739\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231341043\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers11122273\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231380704\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2486741\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePagani et al. 2012; Li et al. 2013; Guo et al., 2020\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231395730\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2486732\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBigham et al., 2010\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231396541\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2491410\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231391424\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2749706\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231392059\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2248649\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231392366\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2998427\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231393171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers5781647\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231393745\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2790886\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHas not previously been associated with human adaptation to high altitudes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231368565\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers2066140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBigham et al., 2010; Li et al. 2013; Zhanget al. 2014; Pan Zhanget al. 2019; Guo et al., 2020; Shen et al., 2020\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231462108\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers1765805\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBigham et al., 2010; Guo et al., 2020\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1:231395881\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ers480902\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eEGLN1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePagani et al. 2012; Brutsaertet et al., 2019; Shen et al. 2020; Yasukochi et al. 2020\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eConflict of interest\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Ministry of Science and Higher Education of the Russian Federation under Grant No. 075-03-2025-407/2; and the work was also supported by the program for supporting bioresource collections (Collection of human biological materials of the Institute of Biochemistry and Genetics of the Ufa Federal Research Center of the Russian Academy of Sciences.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthics Committee Approval\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSample collection was carried out in accordance with the ethical standards of the Bioethics Committee developed by the WMA Declaration of Helsinki (\u0026quot;Ethical principles for medical research involving human subjects\u0026quot;). This study was approved by the Local Ethics Committee of the Institute of Biochemistry and Genetics of the USC RAS (protocol of October 16, 2017).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData Sharing Statement\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUse of artificial intelligence (AI) and AI-based technologies\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eArtificial intelligence (AI) and AI-based technologies were not used in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAkbari A, Vitti JJ, Iranmehr A, Bakhtiari M, Sabeti PC, Mirarab S, Bafna V (2018) Identifying the favored mutation in a positive selective sweep. Nat Methods. 15(4):279-282. https://doi: 10.1038/nmeth.4606\u003c/li\u003e\n\u003cli\u003eAlekseev VP. Ocherki ekologii cheloveka. Moskva: Nauka; 1993.\u003c/li\u003e\n\u003cli\u003eAlkorta-Aranburu G, Beall CM, Witonsky DB, Gebremedhin A, Pritchard JK, Di Rienzo A (2012) The genetic architecture of adaptations to high altitude in Ethiopia. PLoS Genet. 8(12):e1003110. https://doi: 10.1371/journal.pgen.1003110\u003c/li\u003e\n\u003cli\u003eAnastasiou K, Morris M, Akam L, Mastana S (2024) The Genetic Profile of Combat Sport Athletes: A Systematic Review of Physiological, Psychological and Injury Risk Determinants. Int J Environ Res Public Health. 21(8):1019. https://doi: 10.3390/ijerph21081019\u003c/li\u003e\n\u003cli\u003eBai J, Li L, Li Y, Zhang L (2022) Genetic and immune changes in Tibetan high-altitude populations contribute to biological adaptation to hypoxia. Environmental Health and Preventive Medicine. 27:39. https://doi: 10.1265/ehpm.22-00040\u003c/li\u003e\n\u003cli\u003eBigham A, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, Scherer SW, Julian CG, Wilson MJ, L\u0026oacute;pez Herr\u0026aacute;ez D, et al. (2010) Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet. 6(9):e1001116. https://doi: 10.1371/journal.pgen.1001116\u003c/li\u003e\n\u003cli\u003eBigham AW, Wilson MJ, Julian CG, Kiyamu M, Vargas E, Leon-Velarde F, Rivera-Chira M, Rodriquez C, Browne VA, Parra E, et al. (2013) Andean and Tibetan patterns of adaptation to high altitude. \u003cem\u003eAm J Hum Biol\u003c/em\u003e. 25(2):190-7. https://doi: 10.1002/ajhb.22358\u003c/li\u003e\n\u003cli\u003eBrutsaert TD, Kiyamu M, Elias Revollendo G, et al. (2019) Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude. Proc Natl Acad Sci U S A. 116(48):24006-24011. https://doi: 10.1073/pnas.1906171116\u003c/li\u003e\n\u003cli\u003eCerezo M, Sollis E, Ji Y, Lewis E, Abid A, Bircan KO, Hall P, Hayhurst J, John S, Mosaku A, et al. (2025) The NHGRI-EBI GWAS Catalog: standards for reusability, sustainability and diversity. Nucleic Acids Res. 53(D1):D998-D1005. https://doi: 10.1093/nar/gkae1070\u003c/li\u003e\n\u003cli\u003eChen MH, Raffield LM, Mousas A, Sakaue S, Huffman JE, Moscati A, Trivedi B, Jiang T, Akbari P, Vuckovic D, et al. (2020) Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations. Cell. 182(5):1198-1213.e14. https://doi: 10.1016/j.cell.2020.06.045\u003c/li\u003e\n\u003cli\u003eDanecek P, Bonfield JK, Liddle J, Marshall J, Ohan V, Pollard MO, Whitwham A, Keane T, McCarthy SA, Davies RM, et al. (2021) Twelve years of SAMtools and BCFtools. Gigascience. 10(2):giab008. https://doi: 10.1093/gigascience/giab008\u003c/li\u003e\n\u003cli\u003eDanjou F, Zoledziewska M, Sidore C, Steri M, Busonero F, Maschio A, Mulas A, Perseu L, Barella S, Porcu E, et al. (2015) Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels. Nat Genet. 47(11):1264-71. https://doi: 10.1038/ng.3307\u003c/li\u003e\n\u003cli\u003eDzhaubermezov MA, Ekomasova NV, Mustafin RN, Chagarov OS, Fedorova YY, Gabidullina LR, Nurgalieva AK, Prokofyeva DS, Khusnutdinovna EK (2024) Populations of the Caucasus as an object for studying the process of adaptation to conditions of high-altitude hypoxia. Ecological genetics. 22(3):277-292. https://doi: 10.17816/ecogen630869\u003c/li\u003e\n\u003cli\u003eENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature. 489(7414):57-74. https://doi: 10.1038/nature11247\u003c/li\u003e\n\u003cli\u003eGetu A (2022) Ethiopian Native Highlander\u0026apos;s Adaptation to Chronic High-Altitude Hypoxia. Biomed Res Int. 2022:5749382. https://doi: 10.1155/2022/5749382\u003c/li\u003e\n\u003cli\u003eGlaMBIE Team (2025) Community estimate of global glacier mass changes from 2000 to 2023. Nature. 639(8054):382-388. https://doi: 10.1038/s41586-024-08545-z\u003c/li\u003e\n\u003cli\u003eGuo Z, Fan C, Li T, Gesang L, Yin W, Wang N, Weng X, Gong Q, Zhang J, Wang J (2020) Neural network correlates of high-altitude adaptive genetic variants in Tibetans: A pilot, exploratory study. Hum Brain Mapp. 41(9):2406-2430. https://doi: 10.1002/hbm.24954\u003c/li\u003e\n\u003cli\u003eGvozdeckij N.A, Golubchikov NYU. Gory. Moskva: Mysl\u0026apos;, 1987.\u003c/li\u003e\n\u003cli\u003eHarun-Or-Roshid M, Ali MB, Jesmin, Mollah MNH (2022) Association of hypoxia inducible factor 1-Alpha gene polymorphisms with multiple disease risks: A comprehensive meta-analysis. Plos one. 17(8):e0273042. https://doi: 10.1371/journal.pone.0273042\u003c/li\u003e\n\u003cli\u003eHeinrich EC, Wu L, Lawrence ES, Cole AM, Anza-Ramirez C, Villafuerte FC, Simonson TS (2019) Genetic variants at the EGLN1 locus associated with high-altitude adaptation in Tibetans are absent or found at low frequency in highland Andeans. Ann Hum Genet. 83(3):171-176. https://doi: 10.1111/ahg.12299\u003c/li\u003e\n\u003cli\u003eHodonsky CJ, Baldassari AR, Bien SA, Raffield LM, Highland HM, Sitlani CM, Wojcik GL, Tao R, Graff M, Tang W A, et al. (2020) Ancestry-specific associations identified in genome-wide combined-phenotype study of red blood cell traits emphasize benefits of diversity in genomics. BMC Genomics. 21(1):228. https://doi: 10.1186/s12864-020-6626-9\u003c/li\u003e\n\u003cli\u003eKoontz Scaffidi B (2020) Spatial paleopathology: A geographic approach to the etiology of cribrotic lesions in the prehistoric Andes. Int J Paleopathol. 29:102-116. https://doi: 10.1016/j.ijpp.2019.07.002\u003c/li\u003e\n\u003cli\u003eLeon-Velarde F, Richalet JP (2006) Respiratory control in residents at high altitude: physiology and pathophysiology. High Alt Med Biol. 7(2):125-137. https://doi: 10.1089/ham.2006.7.125. PMID: 16764526\u003c/li\u003e\n\u003cli\u003eLessel D, Vaz B, Halder S, Lockhart PJ, Marinovic-Terzic I, Lopez-Mosqueda J, Philipp M, Sim JC, Smith KR, Oehler J, et al. (2014) Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat Genet. 46(11):1239-44. https://doi: 10.1038/ng.3103\u003c/li\u003e\n\u003cli\u003eLi H (2013) Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv [q-bio.GN]. arXiv:1303.3997v2. https://doi: 10.48550/arXiv.1303.3997\u003c/li\u003e\n\u003cli\u003eLi Q, Liu SY, Lin KQ, Sun H, Yu L, Huang XQ, Chu JY, Yang ZQ (2013) Association between six single nucleotide polymorphisms of EGLN1 gene and adaptation to high-altitude hypoxia. Yi Chuan. 35(8):992-8. https://doi: 10.3724/sp.j.1005.2013.00992\u003c/li\u003e\n\u003cli\u003eLiu G, Zhao W, Zhang H, Wang T, Han Z, Ji X (2020) rs1769793 variant reduces EGLN1 expression in skeletal muscle and hippocampus and contributes to high aerobic capacity in hypoxia. Proc Natl Acad Sci U S A. 117(47):29283-29285. https://doi: 10.1073/pnas.2010073117\u003c/li\u003e\n\u003cli\u003eMallet RT, Burtscher J, Pialoux V, Pasha Q, Ahmad Y, Millet GP, Burtscher M (2023) Molecular Mechanisms of High-Altitude Acclimatization. Int J Mol Sci. 24(2):1698. https:// doi: 10.3390/ijms24021698\u003c/li\u003e\n\u003cli\u003eMathew CG (1985) The isolation of high molecular weight eukaryotic DNA. Methods Mol Biol. 2:31-4. https://doi: 10.1385/0-89603-064-4:31\u003c/li\u003e\n\u003cli\u003eMoksnes MR, Graham SE, Wu KH, Hansen AF, Gagliano Taliun SA, Zhou W, Thorstensen K, Fritsche LG, Gill D, et al. (2022) Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT. Commun Biol. 5(1):591. https://doi: 10.1038/s42003-022-03529-z\u003c/li\u003e\n\u003cli\u003ePagani L, Ayub Q, MacArthur DG, Xue Y, Baillie JK, Chen Y, Kozarewa I, Turner DJ, Tofanelli S, Bulayeva K et al. (2012) High altitude adaptation in Daghestani populations from the Caucasus. Hum Genet. 131(3):423-33. https://doi: 10.1007/s00439-011-1084-8\u003c/li\u003e\n\u003cli\u003eParalikar SJ, Paralikar JH (2010) High-altitude medicine. Indian J Occup Environ Med. 14(1):6-12. https://doi: 10.4103/0019-5278.64608. PMID: 20808661\u003c/li\u003e\n\u003cli\u003ePeng Y, Cui C, He Y, Ouzhuluobu, Zhang H, Yang D, Zhang Q, Bianbazhuoma, Yang L, He Y. et al. (2017) Down-Regulation of EPAS1 Transcription and Genetic Adaptation of Tibetans to High-Altitude Hypoxia. Mol Biol Evol. 34(4):818-830. https://doi: 10.1093/molbev/msw280\u003c/li\u003e\n\u003cli\u003ePoplin R, Chang PC, Alexander D, Schwartz S, Colthurst T, Ku A, Newburger D, Dijamco J, Nguyen N, Afshar PT, et al. (2018) A universal SNP and small-indel variant caller using deep neural networks. Nat Biotechnol. 36(10):983-987. https://doi: 10.1038/nbt.4235\u003c/li\u003e\n\u003cli\u003eRichalet JP, Hermand E, Lhuissier FJ (2024) Cardiovascular physiology and pathophysiology at high altitude. Nat Rev Cardiol. 21(2):75-88. https://doi: 10.1038/s41569-023-00924-9. PMID: 37783743.\u003c/li\u003e\n\u003cli\u003eScheinfeldt LB, Soi S, Thompson S, Ranciaro A, Woldemeskel D, Beggs W, Lambert C, Jarvis JP, Abate D, Belay G, et al. (2012) Genetic adaptation to high altitude in the Ethiopian highlands. Genome Biol. 3(1):R1. https://doi: 10.1186/gb-2012-13-1-r1\u003c/li\u003e\n\u003cli\u003eShen Y, Zhang J, Yang J, Liu C, Bian S, Zhang C, Yu J, Gao X, Huang L (2020) Association of EPAS1 and PPARA Gene Polymorphisms with High-Altitude Headache in Chinese Han Population. Biomed Res Int. 2020:1593068. https://doi: 10.1155/2020/1593068\u003c/li\u003e\n\u003cli\u003eSmith TG, Robbins PA, Ratcliffe PJ (2008) The human side of hypoxia-inducible factor. Br J Haematol. 141(3):325-34. https://doi: 10.1111/j.1365-2141.2008.07029.x\u003c/li\u003e\n\u003cli\u003eStuart-Macadam P (1992) Porotic hyperostosis: a new perspective. Am J Phys Anthropol. 87(1):39-47. https://doi: 10.1002/ajpa.1330870105\u003c/li\u003e\n\u003cli\u003eSzklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, Gable AL, Fang T, Doncheva NT, Pyysalo S, et al. (2023) The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 51(D1):D638-D646. https://doi: 10.1093/nar/gkac1000\u003c/li\u003e\n\u003cli\u003eTang S, Zhou W, Chen L, Yan H, Chen L, Luo F (2024) High altitude polycythemia and its maladaptive mechanisms: an updated review. Front Med (Lausanne). 11:1448654. https://doi: 10.3389/fmed.2024.1448654\u003c/li\u003e\n\u003cli\u003eTremblay JC, Ainslie PN (2021) Global and country-level estimates of human population at high altitude. Proc Natl Acad Sci U S A. 118(18):e2102463118. https://doi: 10.1073/pnas.2102463118\u003c/li\u003e\n\u003cli\u003eWu B, Guo W (2015) The Exocyst at a Glance. J Cell Sci. 128(16):2957-64. https://doi: 10.1242/jcs.156398\u003c/li\u003e\n\u003cli\u003eYasukochi Y, Nishimura T, Ugarte J, Ohnishi M, Nishihara M, Alvarez G, Fukuda H, Mendoza V, Aoyagi K (2020) Effect of EGLN1 Genetic Polymorphisms on Hemoglobin Concentration in Andean Highlanders. Biomed Res Int. 2020:3436581. https://doi: 10.1155/2020/3436581\u003c/li\u003e\n\u003cli\u003eYunusbayev B, Metspalu M, J\u0026auml;rve M, Kutuev I, Rootsi S, Metspalu E, Behar DM, Varendi K, Sahakyan H, Khusainova R, et al. (2012) The Caucasus as an asymmetric semipermeable barrier to ancient human migrations. Mol Biol Evol. 29(1):359-65. https://doi: 10.1093/molbev/msr221\u003c/li\u003e\n\u003cli\u003eZheng W, He Y, Guo Y, Yue T, Zhang H, Li J, Zhou B, Zeng X, Li L, Wang B, et al. (2023) Large-scale genome sequencing redefines the genetic footprints of high-altitude adaptation in Tibetans. Genome Biol. 24(1):73. https://doi: 10.1186/s13059-023-02912-1\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"genetica","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"gene","sideBox":"Learn more about [Genetica](http://link.springer.com/journal/10709)","snPcode":"10709","submissionUrl":"https://submission.nature.com/new-submission/10709/3","title":"Genetica","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Caucasus, evolution, hypoxia, SPRTN, EGLN1","lastPublishedDoi":"10.21203/rs.3.rs-7766645/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7766645/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHigh-altitude hypoxia refers to the state of reduced oxygen availability experienced at high elevations, which poses significant physiological challenges. Genetic adaptations to this condition involve mutations in various genes that regulate oxygen sensing, erythropoiesis, and metabolic processes, enabling populations indigenous to high-altitude regions to maintain adequate tissue oxygenation and metabolic function under chronic hypoxic conditions. The aim of the study was to investigate the 1q42.2 region in Caucasian populations to identify alleles that may contribute to evolutionary adaptation. We studied a\u0026thinsp;~\u0026thinsp;700 kb region within the 1q42.2 locus in Caucasus populations using the integrated selection of alleles favored by evolution (iSAFE) method. The study included 308 individuals from five ethnic groups inhabiting the high-altitude regions of the North Caucasus (Balkars, Ingush, Karachays, and Chechens) and the South Caucasus (Armenians). Whole-genome sequencing of the samples was performed on the DNBSEQ-T7 platform. The genomic region chr1:231046413\u0026ndash;231737003 (GRCh38.p14) was selected due to its established role in high-altitude adaptation across various global populations. Analysis revealed a region encompassing five variants in the \u003cem\u003eSPRTN\u003c/em\u003e and \u003cem\u003eEGLN1\u003c/em\u003e genes with the highest iSAFE scores in Balkar samples. Similarly, five high-scoring genetic variants were identified in the Karachay population within the same locus. In contrast, only one variant in the \u003cem\u003eEGLN1\u003c/em\u003e gene showed a maximum score in both the Ingush and Armenian groups. The study found evidence of positive selection for two \u003cem\u003eSPRTN\u003c/em\u003e gene variants, confirmed across all studied populations except Chechens.\u003c/p\u003e","manuscriptTitle":"Search for genetic variations that allow populations to thrive in high-altitude environment of Caucasus highlands","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-22 13:25:22","doi":"10.21203/rs.3.rs-7766645/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-13T11:23:01+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-10T07:01:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-04T18:32:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-04T14:45:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"222694880546965489694346857430328526567","date":"2025-10-15T12:14:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"105964377762462311508431812982024156123","date":"2025-10-14T14:08:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"219965820900946254324689000488295764989","date":"2025-10-09T22:16:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"321672879355329966586064111154455639485","date":"2025-10-09T12:55:02+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-09T11:52:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-09T11:46:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-07T08:15:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Genetica","date":"2025-10-02T12:52:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"genetica","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"gene","sideBox":"Learn more about [Genetica](http://link.springer.com/journal/10709)","snPcode":"10709","submissionUrl":"https://submission.nature.com/new-submission/10709/3","title":"Genetica","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"503a81ae-ed31-4e2f-83d4-dbbd4ec853c0","owner":[],"postedDate":"October 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T17:21:53+00:00","versionOfRecord":{"articleIdentity":"rs-7766645","link":"https://doi.org/10.1007/s10709-026-00259-6","journal":{"identity":"genetica","isVorOnly":false,"title":"Genetica"},"publishedOn":"2026-01-16 16:29:00","publishedOnDateReadable":"January 16th, 2026"},"versionCreatedAt":"2025-10-22 13:25:22","video":"","vorDoi":"10.1007/s10709-026-00259-6","vorDoiUrl":"https://doi.org/10.1007/s10709-026-00259-6","workflowStages":[]},"version":"v1","identity":"rs-7766645","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7766645","identity":"rs-7766645","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}