The Updateable Human Virome Database and toolkit: A novel framework for human virome analysis

Current computational methods for analyzing viruses in human metagenomes rely on static databases composed largely of fragmented virus genomes mostly derived from gastrointestinal samples. This limits the identification of viruses exclusively found outside the gastrointestinal tract and impairs analyses requiring high-quality genomes. To address these issues, we created the Updateable Human Virome Database (UHVDB), an expandable database of high-quality, clustered, and annotated virus genomes integrated from pre-existing human virome databases and diverse human sample metagenome assemblies. We developed an associated toolkit that enables users to 1) update by UHVDB mining, clustering, and annotating virus sequences, 2) taxonomically profile viruses in metagenomes and metatranscriptomes, 3) estimate phage replication activity using phage-to-host ratios, and 4) identify putatively uninducible prophages from bulk metagenomes. To illustrate the utility of UHVDB and its associated toolkit, we analyzed 1,983 oral/airway samples from people with Cystic Fibrosis, finding that over 25% of viruses present were likely uninducible prophages and that many others had low replication activity, suggesting far less viral activity than estimated from previous studies. UHVDB is a novel framework for virome analysis that expands the capacity to define virus contributions to health and disease.