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Sigalova et al. BMC Genomics (2019) 20:710 https://doi.org/10.1186/s12864-019-6059-5 RESEARCH ARTICLE Open Access Chlamydia pan-genomic analysis reveals balance between host adaptation and selective pressure to genome reduction Olga M. Sigalova1,2†,AndreiV.Chaplin3†, Olga O. Bochkareva1,4* , Pavel V. Shelyakin1,5,6,VsevolodA. Filaretov1, Evgeny E. Akkuratov7,8,ValentinaBurskaia5 and Mikhail S. Gelfand1,5,9 Abstract Background: Chlamydia are ancient intracellular pathogens with reduced, though strikingly conserved genome. Despite their parasitic lifestyle and isolated intracellular environment, these bacteria managed to avoid accumulation of deleterious mutations leading to subsequent genome degradation characteristic for many parasitic bacteria. Results: We report pan-genomic analysis of sixteen species from genus Chlamydia including identification and functional annotation of orthologous genes, and characterization of gene gains, losses, and rearrangements. We demonstrate the overall genome stability of these bacteria as indicated by a large fraction of common genes with conserved genomic locations. On the other hand, extreme evolvability is confined to several paralogous gene families such as polymorphic membrane proteins and phospholipase D, and likely is caused by the pressure from the host immune system. Conclusions: This combination of a large, conserved core genome and a small, evolvable periphery likely reflect the balance between the selective pressure towards genome reduction and the need to adapt to escape from the host immunity. Keywords: Chlamydia, Intracellular pathogens, Pan-genome, Genome evolution, Comparative genomics, PmpG Background recurrence rate is high, and persistent chlamydial infec- Bacteria of genus Chlamydia are intracellular pathogens tions are associated with higher risk of atherosclerosis, of high medical significance. Chlamydia trachomatis are reactive arthritis, and oncogenic effects [2, 7, 9, 10]. important agents of sexually transmitted disease as well Chlamydia have a complex biphasic lifecycle [11], which as the main cause of preventable blindness in develop- involves changes in DNA compaction [12], metabolism ing countries, and Chlamydia pneumoniae is one of the [13], and temporal expression of early, middle, and late major causes of pneumonia worldwide. Other chlamy- genes [14]. Extracellular forms of Chlamydia (elemen- dial species infect a wide range of animals, and some of tary bodies) attach to host cells and initiate endocytosis, them (in particular, Chlamydia psittaci and Chlamydia yielding formation of a membrane-bound compartment abortus) can cause life-threatening diseases if transmit- termed the inclusion. Once inside the inclusion, elemen- ted to humans [1–6]. No vaccines exist against human tary bodies differentiate into a larger intracellular form chlamydial strains, and the number of cases does not (reticulate bodies), engaging in complex host-pathogen decrease with better examination schemas [7, 8]. The interactions. In particular, these bacteria reorganize vesic- ular transport, prevent apoptosis, slow down the host cell *Correspondence: [email protected] cycle, and suppress inflammatory immune response by †Olga M. Sigalova and Andrei V. Chaplin contributed equally to this work. 1Kharkevich Institute for Information Transmission Problems, RAS, Moscow, damping nuclear factor B transcription; for a review see Russia [1]. The chlamydial inclusion membrane has been referred 4 current address: Institute of Science and Technology Austria, Klosterneuburg, to as a pathogen-specified parasitic organelle [15]. Austria Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sigalova et al. BMC Genomics (2019) 20:710 Page 2 of 17 As summarized in [16], a typical bacterial genome is Table 1 Summary of analyzed genomes. Waddlia chondrophila is shaped by the dynamic interaction of six major evo- the only bacterium outside genus Chlamydia, it was used as an outgroup to construct the rooted phylogenetic tree of the genus lutionary forces directed towards either genome reduc- tion or complexification. Genome streamlining (1) and Species Number of Number of Median Median genomes complete genome number of degradation (2) both lead to genome contraction, though genomes size, mB CDS the underlying evolutionary mechanisms are different. Chlamydia 110 95 1.04 904 Genome streamlining results from strong positive selec- trachomatis tion pressure to remove non-essential genes. Genome Chlamydia suis 30 11 1.09 924 degradation implies gene loss under weak or neutral selec- Chlamydia 27 7 1.16 982 tion, which is typically manifested by high numbers of abortus pseudogenes and integrated selfish elements. Genome Chlamydia 25 20 1.17 977 streamlining is characteristic of highly abundant and evo- psittaci lutionary successful organisms, whereas genome degra- Chlamydia 12 12 1.23 1046 dation has been reported for some parasitic and symbi- pneumoniae otic microorganisms which have small effective popula- Chlamydia 10 6 1.11 950 tion sizes due to their lifestyle [16, 17]. As counteracting pecorum forces, genome reduction is contained by genome com- Chlamydia 3 2 1.07 905 plexification and innovation via gene duplications (3), muridarum operon shuffling (4), horizontal gene transfer (5), or prop- Chlamydia 2 2 1.06 907 agation of mobile elements (6). And although all these gallinacea forces might act simultaneously, their contribution to Chlamydia 1 1 1.04 895 shaping individual prokaryotic genomes is strikingly dif- avium ferent, reflecting the ecological niche and the lifestyle of a Chlamydia 1 1 1.17 981 microorganism. caviae As a consequence of their obligatory intracellular Candidatus 1 0 1.20 1005 lifestyle, Chlamydia have reduced genomes of about 1 Chlamydia corallus Mb and 850–1100 genes. At most 14 transcription fac- tors (TFs) have been predicted to regulate gene expression Chlamydia felis 1 1 1.17 981 [18]. However, as opposed to many other pathogens with Chlamydia 1 0 1.15 955 ibidis reduced genomes [17], this apparent simplification likely resulted from genome streamlining rather than degra- Chlamydia 1 1 1.16 972 poikilothermis dation. In particular, genomes of all chlamydial species Chlamydia 1 1 1.11 932 have a low number of pseudogenes [2, 19]. The gene sanzinia order is highly conserved everywhere outside the plas- Chlamydia 1 1 1.20 992 ticity zone, a genomic region of about 81 kB around serpentis the replication terminus [20]. Similarly, the gene content Waddlia 1 1 2.12 1839 is conserved, with the majority of genes being shared chondrophila with other representatives of the phylum [21]. Multiple studies shown the genome-wide homologous recombi- nation among Chlamydia species, which may prevent accumulation of deleterious mutations [22–24]. Finally, common causes of respiratory infections in humans, also genomes of Chlamydia spp. are generally free of dis- able to infect animals, e.g. horses, marsupials, and frogs. ruptive mobile elements, with the exception of the IS- Otherspeciesinfectabroadrangeofanimalsinclud- associated tetracycline-resistance genomic island in C. ing mice, guinea pigs, birds, cattle, sheep, swine, horses, suis and the remnants of IS-like elements and prophages cats, koalas, frogs, and snakes, causing various diseases, in some genomes [2, 25–27]. which in some cases can be transmitted to humans (for Furthermore, the reduced genome of Chlamydia allows areviewsee[2]). The source of this phenotypic diversity for significant phenotypic variation with sixteen currently is limited, and most differences in the host specificity and recognized species (Table 1)havingabroadrangeofhost tissue tropism have been attributed to several highly vari- specificities and tissue tropisms [25–27]. In particular, able gene families including cytotoxin [28], polymorphic C. trachomatis are exclusively human pathogens causing outer membrane proteins [29], inclusion membrane pro- trachoma (serovars A-C), lymphogranuloma venereum teins [30], and phospholipase D enzymes [31], as well as (LGV, serovars L1-L3), and epithelial urogenital infec- several metabolic pathways, such as tryptophan [32]and tions (serovars D-K). C. pneumoniae is one of the most biotin [2] biosynthesis. Sigalova et al. BMC Genomics (2019) 20:710 Page 3 of 17 The pan-genome approach [33]isacomparative study of the Polymorphic membrane protein G (PmpG) genomic technique which involves analysis of conserva- gene family representing an interesting combination of tion and evolution of individual gene families from a extensive paralogisation, phase and antigen variation, and clade of microorganisms. To construct the pan-genome, pseudogenisation. all genes from a group of closely related prokaryotic genomes are pooled together and then clustered into Results orthologous groups (OGs) by sequence similarity. OGs Pan-genome of genus Chlamydia: large core, small are then classified into universally conserved