A hierarchical orthology framework reveals viral carbohydrate-active genes across the global virosphere

Carbohydrate-active enzymes (CAZymes) are key players in virus-host interactions, yet their diversity and origins in viruses are poorly understood due to limited annotations. To fill this gap, the authors constructed VirGenes, a database of viral orthologous groups built from the KEGG viral gene dataset. VirGenes integrates sequence similarity, remote homology, and structural similarity to support evolutionary and functional analyses of viral proteins.

Screening VirGenes identified 558 CAZyme-associated gene clusters spanning 102 CAZyme families, with notably enriched repertoires in dsDNA viral lineages. Two bacteriophage families, Kleczkowskaviridae and Pootjesviridae, encoded more than 10 CAZymes per genome, followed by Mimiviridae, a family of eukaryotic giant viruses. Phylogenetic analyses revealed divergent evolutionary histories of viral CAZyme genes, including frequent horizontal transfer of endolysin genes from bacteria, likely reflecting an evolutionary arms race between viruses and their hosts.

Structurally, many viral genes contained CAZyme-like folds despite over 85% lacking detectable sequence similarity to known CAZymes. Notably, numerous hypothetical sequences from giant viruses exhibited glycoside hydrolase-like five-bladed propeller folds. The findings suggest that viral carbohydrate-active systems exemplify how distributed innovations constrained by ancient folds collectively build functional complexity across the virosphere. VirGenes is publicly available at https://www.genome.jp/vogdb/.