Horizontal gene transfer drives the evolution of dependencies in bacteria.

Many naturally occurring bacteria lead a lifestyle of metabolic dependency for crucial resources. We do not understand what factors drive bacteria toward this lifestyle and how. Here, we systematically show the crucial role of horizontal gene transfer (HGT) in dependency evolution in bacteria. Across 835 bacterial species, we map gene gain-loss dynamics on a deep evolutionary tree and assess the impact of HGT and gene loss on metabolic networks. Our analyses suggest that HGT-enabled gene gains can affect which genes are later lost. HGT typically adds new catabolic routes to bacterial metabolic networks, leading to new metabolic interactions between bacteria. We also find that gaining new routes can promote the loss of ancestral routes ("coupled gains and losses", CGLs). Phylogenetic patterns indicate that both dependencies-mediated by CGLs and those purely by gene loss-are equally likely. Our results highlight HGT as an important driver of metabolic dependency evolution in bacteria.