Viral lifecycle dynamics and spatial structure explain why accessory genes are associated with temperate phages

Abstract Genes encoding for virulence factors are frequently found on prophages, yet the evolutionary forces driving this association remain unclear. The evolutionary association of mobile genetic elements (MGEs) with host-beneficial genes is known to be hindered by the stability of chromosomal loci and competition with MGEs lacking accessory genes. Using a mathematical model that incorporates these constraints, we identify two key mechanisms that help overcome them, resulting in the evolutionary linkage of accessory genes, like virulence genes, to prophages. First, we show that migration across bacterial populations favours the association of genes with prophages when the gene is beneficial in certain environments (e.g. virulence genes in the gut) that also trigger higher rates of prophage induction. Second, we show that within-population spatial dynamics also promotes the association of weakly selected genes and phages. Here, virion dispersal allows phage-encoded genes to spread into patches of bacteria lacking the gene, giving them a selective advantage over immobile chromosomal genes. We argue that these mechanisms are less applicable for plasmids and other MGEs, highlighting a potentially unique role for phages in shaping bacterial adaptation. By demonstrating how phage lifecycle dynamics and spatial heterogeneity drive MGE-gene associations, our work provides new insights into the evolution of phage-encoded virulence. Competing Interest Statement The authors have declared no competing interest. Footnotes More appropriate parameters were chosen to revise Figures 3 and 4. We also introduced new paragraphs in the Discussion to clarify some of our arguments.