Neanderthal Introgressed COVID-19 Risk Locus 3p21.31 Under Positive Selection in East Asia via LZTFL1-Driven Ciliary Changes

Abstract

The Neanderthal introgressed 3p21.31 locus has been repeatedly associated as a major host genetic determinant of severe COVID-19, particularly in European and South Asian populations. However, the evolutionary history and likely effector gene remain unclear. We investigated signatures of historical selection at this locus and the mechanism by which it might influence COVID-19 severity. Using 1000 Genomes Project data from diverse global populations, we applied various selection scans methods and integrated it with functional analysis. Multiple, independent lines of evidence indicate strong positive selection at 3p21.31 in East Asians. The region exceeds the 99.99th-percentile PBS threshold in EAS, shows extended ROH and the slowest LD decay among populations, and exhibits reduced nucleotide diversity and significantly negative Tajimas D, consistent with a selective sweep. XP-EHH identified a pronounced signal centred on LZTFL1. Marginal-tree reconstruction indicates the derived allele arose in modern humans and swept to high frequency in East Asia at a time consistent with an ancient corona or related virus-like epidemic [~]20,000-25,000 (20-25 Kya) years ago. LD and pathway analyses implicate a high-LD haplotype tagging LZTFL1 shows significant enrichment for cilium-assembly and BBSome-mediated cargo-targeting pathways likely causing subtle shifts in cilium number or beat frequency, in lung and airway epithelia, thereby profoundly affecting the mucus and pathogens clearance. Based on the Overall observation, we propose that after the Neanderthal introgression, East Asia went through pathogen pressure for [~]20-25 Kya old ancient coronavirus- or related virus epidemic leading to positive selection at 3p21.31locus. These findings underscore the complex interplay between ancient admixture and adaptive events linked to modern COVID-19 severity.