Co-evolution of gene transfer agents and their alphaproteobacterial hosts

Gene transfer agents (GTAs) are enigmatic elements that resemble small viruses and are known to be produced during nutritional stress by some bacteria and archaea. The production of GTAs is regulated by quorum sensing, under which a small fraction of the population acts as GTA producers, while the rest becomes GTA recipients. In contrast to canonical viruses, GTAs cannot propagate themselves because they package pieces of the producing cell's genome. In alphaproteobacteria, GTAs are mostly vertically inherited and reside in their hosts' genomes for hundreds of millions of years. While GTAs' ability to transfer genetic material within a population and their long-term preservation suggest an increased fitness of GTA-producing microbes, the associated benefits and type of selection that maintains GTAs are poorly understood. By comparing rates of evolutionary change in GTA genes to the rates in gene families abundantly present across 293 alphaproteobacterial genomes, we detected 59 gene families that likely co-evolve with GTA genes. These gene families are predominantly involved in stress response, DNA repair, and biofilm formation. We hypothesize that biofilm formation enables the physical proximity of GTA-producing cells, limiting GTA-derived benefits only to a group of closely related cells. We further conjecture that the population structure of biofilm-forming sub-populations ensures that the trait of GTA production is maintained despite the inevitable rise of "cheating" genotypes. Because release of GTA particles kills the producing cell, maintenance of GTAs is an exciting example of social evolution in a microbial population.IMPORTANCEGene transfer agents (GTAs) are viruses domesticated by some archaea and bacteria as vehicles for carrying pieces of the host genome. Produced under certain environmental conditions, GTA particles can deliver DNA to neighboring, closely related cells. The function of GTAs remains uncertain. While making GTAs is suicidal for a cell, GTA-encoding genes are widespread in genomes of alphaproteobacteria. Such GTA persistence implies functional benefits but raises questions about how selection maintains this lethal trait. By showing that GTA genes co-evolve with genes involved in stress response, DNA repair, and biofilm formation, we provide support for the hypothesis that GTAs facilitate DNA exchange during the stress conditions and present a model for how GTAs persist in biofilm-forming bacterial populations despite being lethal.