Abstract
Hypoxia inducible factor pathway genes are linked to adaptation in both human and non-human highland species. EPAS1, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetan highlanders. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380, A>G p.[His194Arg]) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth, a lobe-finned fish. CRISPR-base-edited human cells with this variant exhibit functional shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations and validation in a lowland population. Although this genocopy of relatively lower hematocrit in Andean highlanders parallels well-replicated findings in Tibetans, it likely involves distinct pathway responses based on a protein-coding versus non-coding variants, respectively. Together, these findings illuminate how unique variants at EPAS1 contribute to the same phenotype in Tibetans and a subset of Andean highlanders despite distinct evolutionary trajectories.
Data structure
.
├── EPAS1 Genotype
│ └── epas1_genotype.csv
├── EPAS1 Sequencing
│ └── epas1_region.vcf.gz
├── Metabolomics
│ └── metabolite_master.csv
├── Phylogenetics
│ └── H194_conversvation.xlsx
├── Physiology
│ └── Andean Physiology.csv
├── README.md
├── Selection Scan
│ ├── cms_components1.csv.gz
│ └── cms_components2.csv.gz
├── WesternBlot
│ └── WesternData.xlsx
├── auto_sync.bat
└── auto_sync.sh