<i>Selected Input and Output Files for</i> <b>Data-driven detection of candidate enhancer-activating and repressing SNPs in immune regulation in the Tyrolean population</b>

Research has shown that non‑coding single nucleotide polymorphisms (SNPs) can modulate gene expression by enhancing or disrupting transcription‑factor binding sites. Leveraging whole‑genome sequencing and matched RNA‑sequencing from 23 individuals native to the Tyrolean Alps, we applied our data‑driven protocol to systematically scan each individual for mutations that create <i>de novo</i> gamma‑interferon‑activated sequence (GAS) motifs and therefore into potential activating enhancer elements (creator SNPs) or abolish existing sites (destroyer SNPs). Of approximately 17 million nearly complete GAS motifs (i.e., five out of six matching nucleotides; ncGAS) and approximately 2.4 million genuine GAS motifs, the cohort carried 15,014 creator and 19,779 destroyer SNPs. Of those, 676 creators and 732 destroyers lay within ±10 kb of immune‑related genes. Integrating transcript abundance revealed 33 creator‑associated and 56 destroyer‑associated genes with significant expression changes of nearby genes. H3K27ac ChIP‑seq in peripheral‑blood mononuclear cells aligned well with three creator SNPs, potentially affecting <i>CASP1</i> (rs1045872680), <i>DOCK10</i> (rs149378511), and <i>PICALM</i> (rs41381550), and three destroyer SNPs, potentially affecting <i>CCR1</i> (rs34919616), HDAC4 (rs1476145875), and <i>ORAI1</i> (rs116376569) with potential cytokine‑responsive enhancers. Our study demonstrates that SNPs can create or destroy enhancer elements and thereby alter the expression of immune pathway genes in humans. The scalable framework lays the groundwork for larger multi‑ethnic screens to chart regulatory variants, refine disease biomarkers, and guide precision immunomodulation. With this analysis, we underscore a simple yet powerful premise: one base change can shift the balance of human immunity—mapping those changes charts the path to tailored interventions.