PHAGENET: PHAge GEnetic NETworking in the microbiome

ongoing

Horizontal gene transfer (HGT) is one of the primary forces driving rapid adaptation and long term evolution of complex microbial communities such as the human microbiome. The same process is involved in the dissemination of virulence and antimicrobial resistance genes and emergence of “superbugs”. The precise mechanisms and role of HGT in the structure and function of the microbiome remain largely unexplored. Bacteriophages are ubiquitous and highly abundant members of the human microbiome, accounting for ~5% of total microbial DNA. Many of them, such as crAssphage, are highly prevalent and have evolved complex relationships with their microbial hosts. At the same time their role in microbiome composition and function is unclear. Recently we observed the accumulation of considerable amounts of bacterial genomic DNA in the phage-encapsulated fraction of human faeces (up to 50% in some instances). Analysis of this chromosomal fraction reveals that it does not appear to be due to contamination, but rather represents phage-mediated mobilisation and transfer (transduction) of DNA from specific bacterial taxa and specific genomic regions. PHAGENET argues that phage-mediated transduction plays a significant role in the genetic plasticity of the human microbiome, and that the phageome provides individual microbes with access to a wider pangenome and enables dissemination of genes both within and across individual human microbiomes. I propose to thoroughly test this hypothesis at molecular, cellular and organismal levels. This will involve an array of approaches, including long-read high-throughput sequencing, faecal chemostat models, random transposon insertion libraries in gut bacteria and animal models. By addressing an important gap in our understanding of the microbiome, PHAGENET will impact across the research areas of microbiology, virology, gastroenterology, evolutionary ecology and epidemiology.