Sequence-space expansion is driven by the emergence of new signaling pathways

Abstract

AbstractThis report presents multi-genomes evidence that sequence-space expansion occurs when pathways with incompatible functions emerge. It is speculated that as pathways evolve within the sequence-space of highly paralogous signaling systems, they insulate against unwanted interactions, and can expand into new sequence-space. To prove that sequence-space expansion is driven by pathway insulation against emergent pathways, we develop a comprehensive, holistic (whole genomes) new pathway discovery pipeline. The holistic pipeline, which uses t-distributed stochastic neighbor embedding algorithms and phylogeny to map the extant sequence-space of thousands of bacterial two-component systems, reveals a new signaling pathway, resultant from domain swapping. By employing functional genomics screens in our model system Pseudomonas putida KT2440, we provide empirical evidence that descendents of the functionally discordant domain swapped pathway and its nearest neighbors in sequence-space are paralogous. We conclude that the emergence of this new pathway necessitated pathway insulation and drove sequence-space expansion.