The evolutionary landscape of host immunity genes involved in respiratory and other immune-related diseases, and the identification of TLR2 variation associated with severe COVID-19

BACKGROUND: Given its high mortality and broad societal impact, the COVID-19 pandemic is arguably one of the most consequential public health crises of the twenty-first century. Although previous studies have identified several genes associated with COVID-19 susceptibility, relatively little is known about the genes contributing to severe COVID-19, including their evolutionary histories. In the current study, we analyzed IL-4, TLR2, CCL2, and SLC11A1-immunity genes that have previously been implicated in severe COVID-19 and other immune-related diseases-in globally diverse populations from the 1000 Genomes Project. We also tested for associations between genetic variation at these genes and clinical COVID-19 phenotypes in nearly 4000 laboratory-confirmed COVID-19-positive individuals across two datasets from the GEN-COVID Multicenter Study in Italy. RESULTS: Based on our analyses, we identified striking signatures of positive selection within and around all four genes, including extensive haplotype structure, elevated population differentiation, and significant selection coefficients consistent with both ancient and more recent adaptive events. Notably, many of these signals were population-specific, highlighting the role of local selection in shaping immune gene diversity. Several selected alleles were also present in Neanderthal and/or Denisovan genomes, reflecting both shared ancestral polymorphism and archaic introgression within these genes. Functional predictions based on in silico analyses further revealed that a subset of selected alleles maps to transcription factor binding sites and is predicted to influence binding affinity. In addition, our genotype-phenotype analyses uncovered coding variants in TLR2 that were correlated with COVID-19 severity and a related comorbidity, with estimated effect sizes ranging from moderate to large. Interestingly, these significantly associated alleles occur at rare or low frequency in western European and East Asian populations but are absent in populations of African and South Asian descent, indicative of a relatively recent origin. CONCLUSIONS: Overall, our study provides new insights into the evolution of biologically relevant immunity genes in modern human populations and identifies genetic variation that may contribute to differences in risk for severe COVID-19.