Plasmid Evolutionary Innovation and Adaptation to Defense Systems

Plasmids are self-copying genetic elements that can move between bacterial species. They frequently carry antimicrobial resistance (AMR) genes, making understanding the factors that affect their spread through bacterial communities an urgent challenge. Exploiting bacteria’s natural defence systems to block plasmid spread is an exciting possibility. Recent years have seen a huge increase in the known number of ‘anti-phage’ systems that stop bacterial viruses (phage) from gaining a foothold in the cell. Some of these systems also defend against incoming plasmids, but the pace of discovery has outstripped the ability to experimentally test all relationships. We need computational approaches: by developing new methods, PLEIADES will bridge the gap and give us new insights into plasmid evolution.The central hypothesis of PLEIADES is that selective pressure from ‘anti-phage’ defence systems also shapes the genomic architecture of plasmids. To better understand plasmid evolution we need to explore how variation in plasmid content and structure is linked to defence systems. We will tackle three objectives. First, we will build statistical models that relate the diversity of defence systems and plasmids across bacteria, controlling for other factors to deliver a systematic understanding of their relationship. Second, we will investigate the modular evolution of plasmids, which evolve by frequent rearrangements, using new computational frameworks that capture this plasticity together with tools to predict functions for plasmid proteins (the majority of which are currently unknown). Third, we will explore the role of defence systems in plasmid competition, investigating diverse plasmids from metagenomes to build a data-driven theory of their coevolutionary dynamics. By combining cutting-edge computational analysis with evolutionary theory, PLEIADES will advance our understanding of plasmid evolution, paving the way for new experimental efforts to address the threat of AMR.