Computational approaches to predict bacteriophage–host relationships

Metagenomics has changed the face of virus discovery by enabling the accurate identification of viral genome sequences without requiring isolation of the viruses. As a result, metagenomic virus discovery leaves the first and most fundamental question about any novel virus unanswered: What host does the virus infect? The diversity of the global virosphere and the volumes of data obtained in metagenomic sequencing projects demand computational tools for virus–host prediction. We focus on bacteriophages (phages, viruses that infect bacteria), the most abundant and diverse group of viruses found in environmental metagenomes. By analyzing 820 phages with annotated hosts, we review and assess the predictive power of in silico phage–host signals. Sequence homology approaches are the most effective at identifying known phage–host pairs. Compositional and abundance-based methods contain significant signal for phage–host classification, providing opportunities for analyzing the unknowns in viral metagenomes. Together, these computational approaches further our knowledge of the interactions between phages and their hosts. Importantly, we find that all reviewed signals significantly link phages to their hosts, illustrating how current knowledge and insights about the interaction mechanisms and ecology of coevolving phages and bacteria can be exploited to predict phage–host relationships, with potential relevance for medical and industrial applications. New viruses infecting bacteria are increasingly being discovered in many environments through sequence-based explorations. To understand their role in microbial ecosystems, computational tools are indispensable to prioritize and guide experimental efforts. This review assesses and discusses a range of bioinformatic approaches to predict bacteriophage–host relationships when all that is known is their genome sequence. Graphical Abstract Figure. New viruses infecting bacteria are increasingly being discovered in many environments through sequence-based explorations. To understand their role in microbial ecosystems, computational tools are indispensable to prioritize and guide experimental efforts. This review assesses and discusses a range of bioinformatic approaches to predict bacteriophage–host relationships when all that is known is their genome sequence.