High-impact Genetic Variants in EGLN1, EPAS1, and Other Genes Identified in Mountaineers by Exome Sequencing

Background: Investigating the genetic basis of adaptation to environmental stresses, such as hypoxia, can enhance our understanding of human biology and resilience. High-altitude adaptation provides a valuable model for studying the genetic mechanisms of the hypoxic response. Indeed, most known loci associated with hypoxic adaptation have been identified in indigenous mountain populations; however, research on elite climbers remains limited. In our previous study, we conducted exome sequencing of experienced mountaineers and identified two pathogenic variants in the RTEL1 and COL6A1 genes, both of which are linked to respiratory failure. These findings encouraged this study, which conducted exome sequencing to explore genetic variation in a larger cohort. Methods: We performed exome sequencing for a cohort of 114 mountaineers with varying levels of experience. Variant calling was performed in the sequencing data using a pipeline based on the Genome Analysis Toolkit (GATK) v.4.1.9. Annotated variants were used to identify rare and common variants with possible effects on high-altitude adaptation. Results: The analysis did not identify any common adaptive variants in these individuals; however, nine variants were identified as potentially relevant to high-altitude adaptation and climbing performance. These included novel variants in the EPAS1 and EGLN1 genes, which may have a positive effect under hypoxic conditions, as well as variants in TCAP, F5, GP1BA, and other genes involved in muscle activity and blood coagulation. Conclusions: This study identified rare variants in the EPAS1 and EGLN1 genes, which had previously been associated with high-altitude adaptation. Additionally, we describe several potentially pathogenic variants in genes not previously linked to hypoxia, highlighting the value of studying elite mountaineers as a unique cohort for broader interpretation of genetic variation.