Phylogenetic distribution of bacterial α2-macroglobulin homologs (α2M). Pink, species that possess bacterial α2-macroglobulin genes; yellow, species without bacterial α2-macroglobulin genes. Shared genomic context is indicated for genes found to co-occur with bacterial α2-macroglobulin genes. Because bacterial phylogeny has many uncertainties, the tree is simplified into multiple nodes representing three levels of divergence. There is little phylogenetic consistency for bacterial α2-macroglobulin possession. Colonizing proteobacteria are overwhelmingly expected to have a bacterial α2-macroglobulin gene, although exceptions occur, notably Helicobacter pylori, Vibrio cholerae and Neisseria meningitidis. No examples of bacterial α2-macroglobulin genes have been found in colonizing Gram-positives in the Firmicutes or Actinobacteria, which include such major infectious clades as streptococci and mycobacteria. Anabaena is a facultative plant symbiont, while other free-living cyanobacteria (here represented by Synechocystis) lack bacterial α2-macroglobulin. Thermotoga maritima, Magnetospirillum magnetotacticum and Caulobacter crescentus are the only species possessing bacterial α2-macroglobulin for which no apparent connection exists with niches linked to exploitation of higher eukaryotes. Genome context of bacterial α2Ms is based on automated STRING annotation , supplemented by re-analysis of individual genomes. Double slanted bars between genes indicate that they are not tightly linked. Bacterial α2-macroglobulins make up two distinct groups typified by the E. coli genes yfhM and yfaS. The members of the yfhM group (on the left side of the figure) almost always co-occur with pbpC and are often, but not always, found adjacent to and on the same strand as one another in an operon configuration. Members of the yfaS group (grouped on the right side of the figure), when present in β- or γ-proteobacteria, are linked to four other gene families. All their predicted gene products also possess signal peptides, but are otherwise of unknown function. In other taxa, members of the yfaS group of bacterial α2-macroglobulins are either unassociated with any of these gene families (planctomycetes and deinococci), or linked to a member of just one of the families (thermotogae).