Oncogenic HPV types identified in Paleolithic and Chalcolithic human genome sequencing data from Ust'-Ishim and Ötzi.

Human papillomaviruses (HPVs) are ancient viruses with diverse lineages infecting epithelial tissues in primates and humans. Although contemporary distribution and clinical importance are well understood, there is limited knowledge about their occurrence in prehistoric human populations. We investigated the presence of HPV in ancient anatomically modern humans (AMHs) by analyzing genome sequencing data from two exceptionally preserved individuals: Ust’-Ishim (~ 45,000 years BP) and Ötzi the Iceman (~ 5,300 years BP). Using a combination of reference-guided mapping and ancient DNA authentication criteria, we searched for HPV sequences in these ancient genomes. We detected high-confidence papillomavirus fragments in both individuals. Further phylogenetic and comparative analyses revealed that the reconstructed sequences belong to HPV16, the most oncogenic HPV lineage. Our study presents the earliest molecular evidence of HPV16 in anatomically modern humans (AMHs), pushing back its evolutionary history and providing direct temporal constraints on hypotheses proposing a recent introgression of HPV16A into Homo sapiens via archaic hominin admixture. Our results indicate that HPV16 lineage A was present in anatomically modern humans during the Upper Paleolithic, supporting a deep and long-standing host–virus association.