Signatures of high-altitude adaptation in Caucasus populations: evidence from the EGLN1-SPRTN locus.

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 populations of the Caucasus 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 chr1:231046413–231,737,003 (GRCh38.p14) was selected due to its established role in high-altitude adaptation across various global populations. In the Balkar population, out of 120 informative variants analysed, 54 (45%) exceeded the iSAFE significance threshold of 0.1. Seven of these variants reached the maximum observed iSAFE score of 0.219, representing the strongest and most widespread signal of positive selection in this cohort. A similar pattern was observed in the Karachay population. Of the 123 informative variants analysed, 74 (60%) surpassed the threshold, with five variants sharing the highest score of 0.206. In contrast, the Ingush and Armenian cohorts each exhibited a single top-scoring candidate variant within the EGLN1 gene. In the Ingush population, 50 out of 79 informative variants exceeded the threshold, with the top variant scoring 0.182. Among Armenians, 36 of 80 variants passed the threshold, and the maximum iSAFE score was 0.193. Conversely, evidence for positive selection at this locus was minimal in the Chechen population. Although 152 informative variants were included in the analysis, only a single variant yielded an iSAFE score (0.105) that marginally exceeded the 0.1 threshold.