Fig. 2: vPECA systematically reveals active REs, positively selected active REs, and regulatory network.

a vPECA models how positively selected noncoding SNPs affect the RE’s selection status, chromatin accessibility and activity, and further determine the target gene’s (TG) expression by integrating paired expression and chromatin accessibility profiling with population genetics, epigenome, and 3D chromatin interaction data. Refer to Table 1 for model components and notations and “Methods” for details of vPECA). b Active REs revealed by vPECA are significantly enriched in H3K27ac peaks exposed to 1% hypoxia environment for 24 h from an independent public data source (Fisher’s exact test). c Active selected REs associated genes are enriched in the literature reported high altitude adaption gene. P-value is calculated by hypergeometric test. d Active selected REs are ranked by their selection (maximum Fst score of all SNPs in the given RE) and chromatin accessibility change score. e The active selected REs are enriched in biological processes related to hypoxia adaptation. P-values were calculated by hypergeometric test with Benjamini–Hochberg correction. f eQTL data in the GTEx database significantly overlapped with the vPECA identified RE-TG pairs. The null distribution by a random selection of the same number of REs nearby expressed genes for 1000 times. “Fix distance” means only selecting TG-RE pairs with the same distance distribution as eQTL data. P-values were calculated by one-sided t-test. g A RE-TG pair is validated if their RE and promoter are linked by at least one Hi–C loop in hypoxia or normoxia. h HiC loop under hypoxia significantly overlapped with the vPECA identified RE-TG pairs. The null distribution is constructed by the random selection of the same number of REs nearby expressed genes in HUVEC for 1000 times. “Fix distance” means only selecting TG-RE pairs with the same distance distribution as Hi–C loop. Sensitivity is calculated by the number of RE-TG pairs validated by Hi–C loops normalized by the total number. P-values were calculated by one-sided t-test. i vPECA tends to link proximal REs to the promoter, while Hi–C loops detect distal interactions. Source data are provided as a Source data file.