Pangenome-Wide Association Study in the Chlamydiaceae Family Reveals Key Evolutionary Aspects of Their Relationship with Their Hosts

The <i>Chlamydiaceae</i> are a family of obligate intracellular bacteria known for their unique biphasic developmental cycle. <i>Chlamydial</i> are associated with various host organisms, including humans, and have been proposed as emerging pathogens. Genomic studies have significantly enhanced our understanding of <i>chlamydial</i> biology, host adaptation, and evolutionary processes. In this study, we conducted a complete pangenome association analysis (pan-GWAS) using 101 genomes from the <i>Chlamydiaceae</i> family to identify differentially represented genes in <i>Chlamydia</i> and <i>Chlamydophila</i>, revealing their distinct evolutionary strategies for interacting with eukaryotic hosts. Our analysis identified 289 genes with differential abundance between the two clades: 129 showed a strong association with <i>Chlamydia</i> and 160 with <i>Chlamydophila</i>. Most genes in <i>Chlamydia</i> were related to the type III secretion system, while <i>Chlamydophila</i> genes corresponded to various functional categories, including translation, replication, transport, and metabolism. These findings suggest that <i>Chlamydia</i> has developed a high dependence on mammalian cells for replication, facilitated by a complex T3SS for intracellular manipulation. In contrast, the metabolic and functional diversity in <i>Chlamydophila</i> allows it to colonize a broad range of hosts, such as birds, reptiles, amphibians, and mammals, making it a less specialized clade.