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

Natural selection links immune-gene variation to blood virome burden in indigenous Orang Asli from tropical Southeast Asia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Natural selection links immune-gene variation to blood virome burden in indigenous Orang Asli from tropical Southeast Asia Shuhua Xu, Yao Xiao, Boon-Peng Hoh, Yifei Gao, Yu Chai, Yuanyuan Xu, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8552878/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract 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. Biological sciences/Evolution/Population genetics/Genetic variation Biological sciences/Genetics/Population genetics/Genetic variation Biological sciences/Ecology/Ecological genetics Biological sciences/Evolution/Evolutionary genetics Biological sciences/Ecology/Tropical ecology Full Text Additional Declarations There is NO Competing Interest. Supplementary Files 1SupplementaryFigureLegendallmerged.docx Supplementary figures and legends related to the results of the manuscript 2SupplementaryTable0116R32.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8552878","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":575384166,"identity":"51de6849-e813-412d-b18b-1e78d0ab687d","order_by":0,"name":"Shuhua 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