The evolutionary landscape of host immunity genes involved in respiratory and other immune-related diseases, and their association with severe COVID-19 outcomes

Given its high mortality and broad societal impacts, the COVID-19 pandemic is a particularly notable global outbreak of a respiratory illness in the 21 ^st 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 —four immunity genes that have 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 in these genes and clinical COVID-19 phenotypes in more than 4,000 laboratory-confirmed COVID-19–positive individuals from Italy. Based on our analyses, we identified 72 single nucleotide polymorphisms (SNPs) across these genes as targets of positive selection, including several derived alleles shared with archaic Neanderthal and/or Denisovan genomes—a finding not previously reported in the literature. Furthermore, we found that common SNPs—implicated in respiratory diseases such as tuberculosis and chronic obstructive pulmonary disorder—were also under selection. Functional predictions based on in silico analyses revealed that a subset of selected alleles map to transcription factor binding sites and are predicted to affect binding affinity. In addition, our genetic association analyses uncovered significant correlations between derived alleles in the coding region of TLR2 and COVID-19 severity. Interestingly, these candidate alleles occurred at relatively low frequency in western European and East Asian populations but were absent in populations of African and South Asian descent. Overall, our study provides new insights into the evolution of biologically relevant immunity genes in the modern human lineage and highlights genetic variants that may underlie differential risk for severe COVID-19.