Doran, B. A.; Chen, R. Y.; Giba, H.; Behera, V.; Barat, B.; Sundararajan, A.; Lin, H.; Sidebottom, A.; Pamer, E. G.; Raman, A.

The human gut microbiome contains many bacterial strains of the same species (\"strain-level variants\"). Describing strains in a biologically meaningful way rather than purely taxonomically is an important goal but challenging due to the genetic complexity of strain-level variation. Here, we measured patterns of co-evolution across >7,000 strains spanning the bacterial tree-of-life. Using these patterns as a prior for studying hundreds of gut commensal strains that we isolated, sequenced, and metabolically profiled revealed widespread structure beneath the phylogenetic level of species. Defining strains by their co-evolutionary signatures enabled predicting their metabolic phenotypes and engineering consortia from strain genome content alone. Our findings demonstrate a biologically relevant organization to strain-level variation and motivate a new schema for describing bacterial strains based on their evolutionary history.