The important role of homologous recombination has been extensively demonstrated to be fundamental for genetic variation in bacterial genomes. In contrast to extracellular or facultative intracellular bacteria, obligate intracellular bacteria are considered to be less prone to recombination, especially for their core genomes. In Rickettsia, only antigen-related genes were identified to have experienced homologous recombination. In this study, we employed evolutionary genomic approaches to investigate the impact of recombination on the core genome of Rickettsia. Phylogenetic network and phylogenetic compatibility matrix analyses are clearly consistent with the hypothesis that recombination has occurred frequently during Rickettsia evolution. 28% of Rickettsia core genes (194 out of 690) are found to present the evidence of recombination under four independent statistical methods. Further functional classification shows that these recombination events occur across all functional categories, with a significant overrepresentation in the cell wall/membrane/envelope biogenesis, which may provide a molecular basis for the parasite adaptation to host immunity. This evolutionary genomic analysis provides insight into the substantial role of recombination in the evolution of the intracellular pathogenic bacteria Rickettsia.

Rickettsia spp. is obligate intracellular bacteria that are classified as gram-negative bacteria and belong to alpha subgroup of proteobacteria. They often live in arthropods, such as ticks, mites, louse, and fleas and can stably coexist within the host population. Some Rickettsia species can infect humans through bites or feces of the vectors, and then cause mild to serious diseases. It has been reported that various kinds of diseases caused by Rickettsia can be found worldwide. Based on phenotypic and phylogenetic evidence, Rickettsia have been classified into three different groups, including the spotted fever group (e.g., R. africae, R. conorii, and R. massiliae), the typhus group (e.g., R. prowazekii and R. typhi), and the unclassified group (e.g., R. bellii). Characterizing the evolutionary mechanism of Rickettsia is a key step towards understanding its adaptation to different hosts and the design of more effective drugs.

Homologous recombination, involved in transferring of a specific DNA fragment from one strain into the homologous region of another strain, is considered to be fundamental for generating genetic variation and to be one of the most important evolutionary mechanisms in bacterial evolution. Meanwhile, it was believed that recombination is largely restricted to extracellular or facultative intracellular bacteria, such as Escherichia coli, Mycobacterium, Helicobacter pylori, and Streptococcus. By contrast, obligate intracellular bacteria are often considered to be less prone to recombination, and recombination cases are rarely reported. Especially, their core genomes are thought to be free of recombination. Recently, however, a completely different scenario was addressed in Wolbachia genome. Based on four housekeeping genes (gltA, dnaA, ftsZ, and groEL) as well as other previously reported cases of Wolbachia recombination, Baldo et al. suggested that Wolbachia could be subject to widespread recombination. More recently, by investigating of multiple loci dispersed throughout the Chlamydia trachomatis chromosome, Gomes et al. showed that recombination is widely spread in Chlamydia trachomatis. However, Rickettsia, as a group of important obligate intracellular bacteria, is often considered to have evolved with little impact of recombination. Till now, only the antigens have been reported to present the evidence of recombination.

In this study, a number of evolutionary genomic methods have been employed to reveal the evidence of recombination in the evolution of Rickettsia. As a result, significant evidence for recombination is found among Rickettsia core genomes through phylogenetic network reconstruction and phylogenetic compatibility matrix analyses. We also found that 28% of the core genes may have been under recombination, which is unexpected for intracellular bacteria. Functional classification showed that recombination events occurred across all functional categories but with a significant bias in the genes involved in cell wall/membrane/envelope biogenesis. This evolutionary genomic analysis provided insight into the important role of recombination in Rickettsia.

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