Frequent Genomic Recombination in the 5′‐Proximal Region Characterizes Human Adenovirus Species C Evolution

To advance our understanding of the molecular recombination dynamics of circulating human adenovirus species C (HAdV-C) strains, whole genome sequence (WGS) analysis of seven strains representing five genotypes (P1H1F1, P1H2F2, P89H5F5, P2H2F2, and Px1/Ps3H1F1) isolated from pediatric severe acute respiratory infection (SARI) cases in China were performed, involving sequence similarity assessment, phylogenetic inference, and recombination mapping. The genomic analysis of seven strains showed substantial nucleotide identity (93.5%-99.2%) and distinct recombination patterns. Further comparative recombinant analysis with eight prototype strains and 214 publicly available strains revealed that strains with high genomic similarity or evolutionary relatedness showed substantial conservation in the posterior genomic regions, while the 5'-proximal ~14 000 bp region, particularly E1 and E2B regulatory and replication-associated genes, displayed significant recombination activity. In addition, identical or similar recombination patterns were found in the genomes of strains with high sequence identity and homology, which had been detected by different surveillance systems, and in multiple provinces in China and other countries. Further analysis revealed an independent evolutionary cluster for two strains (Henan2018-431 and Jilin2019-101), which also harbored fragments of unknown origin within the E3 region, potentially representing novel HAdV-C variants. These findings highlight the critical role of frequent recombination in HAdV-C evolution, particularly in low-diversity genomic regions, and emphasize the importance of WGS-based surveillance for tracking emerging recombinant strains with public health implications.