International Journal of Molecular Evolution and Biodiversity 2024, Vol.14, No.1, 10-17 http://ecoevopublisher.com/index.php/ijmeb 14 3 Genetic mechanisms revealed by GWAS 3.1 Key genes and pathways GWAS has made significant progress in revealing the genetic basis of adaptability to high-altitude environments. Through large-scale population genetic analysis, researchers have identified multiple key genes and biological pathways associated with high-altitude adaptability. Here are some important findings: EPAS1 gene: EPAS1 gene encodes hypoxia inducible factor 2α (HIF-2α). It is one of the earliest genes discovered to be associated with high-altitude adaptability. In high-altitude residents, specific EPAS1 gene mutations are associated with low hemoglobin levels and high blood oxygen saturation, indicating their crucial role in adapting to hypoxic environments. Research has shown that certain single nucleotide polymorphisms (SNPs) in the EPAS1 gene exhibit significant frequency differences between Tibetan and Han samples (Simonson et al., 2010), representing the fastest observed allele frequency changes in any human gene to date. The association between this SNP and red blood cell abundance supports the role of EPAS1in high-altitude adaptation. EGLN1 gene: The EGLN1 gene encodes proline hydroxylase, which is involved in the degradation process of HIF. Research has shown that certain mutations in EGLN1 may enhance the ability to stabilize HIF under low oxygen conditions and promote high-altitude adaptability (Peng et al., 2011). EGLN1 and EPAS1 genes exhibit strong selective scanning signals in the Tibetan population, indicating that these genes may be crucial for long-term biological adaptation in high-altitude areas. PAPPA2 gene: The PAPPA2 gene is associated with regulating insulin-like growth factor activity. Research has found that mutations in the PAPPA2 gene are associated with higher physical adaptability, such as improved energy utilization efficiency and growth rate, in populations in certain high-altitude areas. Through the discovery of these genes, GWAS has revealed the complex genetic mechanisms by which humans adapt to high-altitude environments, which mainly involve aspects such as blood oxygen transport, energy metabolism, and cell growth. 3.2 The evolutionary significance of genetic variation These genetic variations related to high-altitude adaptability not only demonstrate the physiological adaptation mechanisms of humans in specific environments, but also reflect the ability of humans to cope with environmental stress through genetic variations during the evolutionary process. For example: Buroker et al. (2012) found that three SNPs found in the EPAS1 and EGLN1 genes were evaluated in Han Chinese patients with acute mountain disease (AMS) and Tibetan patients with chronic mountain disease (CMS). The study found a significant correlation between EPAS1 and EGLN1 SNPs and AMS and CMS, indicating that these nucleotide changes have physiological effects on the development of high-altitude diseases. Jeong et al. (2014) found that Tibetans are a mixture of ancestral populations related to Mount Everest and Han Chinese. The EGLN1 and EPAS1 genes show significant enrichment in the Tibetan genome of high-altitude ancestors, indicating that immigrants from low altitudes obtained adaptive alleles from highland residents. Peng et al. (2011) conducted a genome-wide sequence variation analysis on the Tibetan population and found that the EPAS1 and EGLN1 genes exhibited strong selection signals. These gene mutations have a higher frequency among Tibetans, but a lower frequency among Han and Japanese populations, indicating that these genes play an important role in obtaining biological adaptation to high-altitude hypoxia for long-term survival in high-altitude environments. These studies indicate that mutations in the EPAS1 and EGLN1 genes undergo positive selection in Tibetan populations in high-altitude environments, providing survival advantages and gradually accumulating in gene pools. This provides important biological insights for understanding human genetic adaptation in high-altitude environments.
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