Archaic Introgression Shapes Genetic Variation at Loci Associated With DNA Virus Load in Modern Humans
Archaic introgression has shaped the modern human immune system, particularly components involved in RNA virus responses. In contrast, its contribution to DNA virus defense remains poorly understood. Here, we investigate the contribution of Neandertal- and Denisovan-introgressed haplotypes to viral load of five common DNA viruses in UK Biobank samples, using genome-wide association summary statistics. We identified 18 genome-wide significant associations, predominantly involving Epstein–Barr virus (EBV) and loci within the Major Histocompatibility Complex, including a Denisovan-like haplotype tightly linked to HLA-A*11:01. Notably, the archaic alleles of these haplotypes showed a directional bias toward increased viral loads. Focusing on two chromosome 17 haplotypes associated with higher EBV load, we identified phenotypic associations with blood cell traits and disease markers, as well as functional effects on immune-relevant genes, including GSDMB, ARRB2, and ALOX15. Allele frequency analysis of one of the chromosome 17 haplotypes revealed signatures of shifting modes of selection, possibly reflecting changes in pathogen landscapes over time. Our results suggest that archaic DNA systematically contributes to DNA virus immunity in modern humans, with effects distinct from previously described RNA virus associations. These findings provide novel evolutionary and functional insights into host–virus interactions and the role of archaic admixture in antiviral defense.
