Natural selection links immune-gene variation to blood virome burden in indigenous Orang Asli from tropical Southeast Asia

Pathogen-rich tropical rainforest provides natural setting to investigate how natural selection shapes human immunity. The Orang Asli, among the oldest indigenous groups in Southeast Asia have experienced long-term exposure to diverse infectious agents and ecological stressors. We profile immune-gene variation in five Orang Asli populations using deep whole-genome sequencing, together with 1,266 individuals from global reference populations. Across 9,856 immune-related genes, we uncover distinctive structural and regulatory features and identify 390 genes showing signatures of positive selection. Pronounced signals were enriched at HLA class II loci (HLA-DPA1 and HLA-DQB1), consistent with population-specific tuning of antigen presentation, and at WWP2, an antiviral regulatory node in TLR3–TRIF signaling. Leveraging blood virome reads captured incidentally from whole-genome sequencing, we identified ten selected immune genes associated with viral read abundance. SPNS1, a factor implicated in viral entry, stands out as a top whole-blood–expressed hit, and an Orang Asli–specific haplotype allele is significantly associated with lower blood-virome abundance Finally, several lead variants show parallel allele-frequency shifts in Orang Asli and other indigenous populations, consistent with shared selection pressures in pathogen-rich settings. Together, our genome–virome framework connects selection signals to an exposure-proximal functional readout, providing evidence that natural selection links immune-gene variation to blood virome burden and advancing understanding of host–microbe coevolution in health and disease.