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Exploring the Diversity Within the Genus Francisella http://www.diva-portal.org This is the published version of a paper published in Frontiers in Microbiology. Citation for the original published paper (version of record): Kumar, R., Bröms, J E., Sjöstedt, A. (2020) Exploring the Diversity Within the Genus Francisella – An Integrated Pan-Genome and Genome-Mining Approach Frontiers in Microbiology, 11: 1928 https://doi.org/10.3389/fmicb.2020.01928 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. Permanent link to this version: http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-175078 fmicb-11-01928 August 7, 2020 Time: 19:4 # 1 ORIGINAL RESEARCH published: 11 August 2020 doi: 10.3389/fmicb.2020.01928 Exploring the Diversity Within the Genus Francisella – An Integrated Pan-Genome and Genome-Mining Approach Rajender Kumar, Jeanette E. Bröms and Anders Sjöstedt* Department of Clinical Microbiology and Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden Pan-genome analysis is a powerful method to explore genomic heterogeneity and diversity of bacterial species. Here we present a pan-genome analysis of the genus Francisella, comprising a dataset of 63 genomes and encompassing clinical as well as environmental isolates from distinct geographic locations. To determine the evolutionary relationship within the genus, we performed phylogenetic whole-genome studies utilizing the average nucleotide identity, average amino acid identity, core genes and non-recombinant loci markers. Based on the analyses, the phylogenetic trees obtained identified two distinct clades, A and B and a diverse cluster designated C. Edited by: The sizes of the pan-, core-, cloud-, and shell-genomes of Francisella were estimated Iain Sutcliffe, Northumbria University, and compared to those of two other facultative intracellular pathogens, Legionella and United Kingdom Piscirickettsia. Francisella had the smallest core-genome, 692 genes, compared to Reviewed by: 886 and 1,732 genes for Legionella and Piscirickettsia respectively, while the pan- Jean Challacombe, genome of Legionella was more than twice the size of that of the other two genera. UC San Diego Health, United States Jochen Blom, Also, the composition of the Francisella Type VI secretion system (T6SS) was analyzed. University of Giessen, Germany Distinct differences in the gene content of the T6SS were identified. In silico approaches *Correspondence: performed to identify putative substrates of these systems revealed potential effectors Anders Sjöstedt [email protected] targeting the cell wall, inner membrane, cellular nucleic acids as well as proteins, thus constituting attractive targets for site-directed mutagenesis. The comparative Specialty section: analysis performed here provides a comprehensive basis for the assessment of the This article was submitted to Evolutionary and Genomic phylogenomic relationship of members of the genus Francisella and for the identification Microbiology, of putative T6SS virulence traits. a section of the journal Frontiers in Microbiology Keywords: whole-genome analysis, T6SS, Francisella, ANI, core-genome and pan-genome Received: 05 May 2020 Accepted: 22 July 2020 Published: 11 August 2020 INTRODUCTION Citation: Kumar R, Bröms JE and The genus Francisella belongs to the g-subclass of Proteobacteria, but shows no close relationship Sjöstedt A (2020) Exploring to other human pathogens (Sjöstedt, 2005). The genus is diverse with many species adapted to the Diversity Within the Genus specific ecological niches and some of the pathogenic species to a very broad range of mammals, as Francisella – An Integrated well as fish (Sjöstedt, 2007; Birkbeck et al., 2011; Colquhoun and Duodu, 2011; Sjödin et al., 2012; Pan-Genome and Genome-Mining Approach. Front. Microbiol. 11:1928. Abbreviations: AAI, Average Amino acid Identity; ANI, Average Nucleotide Identity; DUF, domain of unknown function; doi: 10.3389/fmicb.2020.01928 F, Francisella; FPI, Francisella Pathogenicity Island; MIX, Marker for type six effectors; T6SS, Type VI secretion system. Frontiers in Microbiology| www.frontiersin.org 1 August 2020| Volume 11| Article 1928 fmicb-11-01928 August 7, 2020 Time: 19:4 # 2 Kumar et al. Pan-Genome Analysis of Genus Francisella Pilo, 2018; Yon et al., 2019). A feature of the genus is an unusual Siddaramappa et al., 2011, 2012; Kreizinger et al., 2013; Qu fatty acid composition and a high lipid content of the cell wall et al., 2013; Respicio-Kingry et al., 2013; Rydzewski et al., 2014; (Sjöstedt, 2005). The important human pathogen, F. tularensis, Challacombe et al., 2017; Wang Y. et al., 2018; Vallesi et al., 2019). has for 50 years been divided into several subspecies (Keim In view of the rapidly evolving diversity within many bacterial et al., 2007; Kingry et al., 2013), the most important being subsp. genera and families, the need to obtain additional data to holarctica and subsp. tularensis, both harboring isolates that cause provide a robust platform for species delineation is essential. human tularemia (Tärnvik and Berglund, 2003). This disease is This is particularly true of the genus Francisella, since for rather common in many countries of the Northern hemisphere, many decades, there has been much ambiguity regarding the however, isolates of subsp. tularensis are found in North America taxonomical relationships between many species and subspecies, only (Kingry et al., 2013). Isolates of subsp. tularensis, in further emphasized by the discoveries of previously unrecognized particular the lineage A1b, are the most virulent, both in humans bacterial isolates with unclear taxonomic belonging. The rapidly but also in animal models (Kugeler et al., 2009). The designations evolving diversity within the genus Francisella many times of type A and type B are often used to designate subsp. challenges the traditional taxonomical classification, since several tularensis and holarctica, but these have no formal approval. of the aforementioned isolates have only been identified by means In addition, there is a third subspecies, subsp. mediasiatica, of genetic characterization and may be unculturable, or are represented by strains from the Central Asian republics of former phenotypically ill-defined. To this end, recent work is attempting Soviet Union, but in contrast to the other subspecies, it has to define unambiguous criteria that can be generally applied to low virulence and has not been reported as a human pathogen delineate bacterial species in Francisella as well as in other genera (Olsufiev et al., 1959). The three subspecies demonstrate distinct (Sjödin et al., 2012; Challacombe et al., 2017). In this regard, the genomic differences as demonstrated by multiple whole-genome utility of the dramatically increasing amount of genomic data sequences present in current databases. Some 30 years ago, has to be incorporated in the species definition alongside other F. novicida was recognized, a rare human pathogen with many relevant, more traditional taxonomic data. isolates derived from environmental sources (Hollis et al., 1989; For the genus Francisella, a large number of completed and Kingry et al., 2013). This is also true for a second species of draft genome assemblies are available in biological sequence the genus, F. philomiragia, which possesses distinct biochemical databases, such as the National Center for Biotechnology characteristics compared to F. tularensis (Hollis et al., 1989). As Information (NCBI) assembly database and the Joint Genome for F. novicida, the few cases of human F. philomiragia-infections Institute (JGI) Genome Portal. These huge sequence datasets that have been described are healthy individuals with a history offer not only the possibility to understand the functional of contact with natural water, e.g., near-drowning, or which are and evolutionary repertoire of bacterial genera, but also immunocompromised (Robles-Marhuenda et al., 2018). open up possibilities for developing therapies and engineering In contrast to the aforementioned, since long recognized applications. The objective of this study was to elucidate the members of the genus Francisella, a large number of new species core- and pan-genome features of the Francisella genus to have been described during the last decade, often identified shed light on its diversity and characteristics, as well as to by genomic characterization of one or a few isolates. The identify putative T6SS substrates in silico. Our analysis identifies rapidly expanding number of species demonstrate that the genus conceptual and technical approaches that may be used for studies Francisella is very diverse, likely exists globally, and many of pathogenicity, especially related to secretion systems. species are adapted to highly specialized environmental niches (Hollis et al., 1989; Clarridge et al., 1996; Barns et al., 2005; Kuske et al., 2006; Siddaramappa et al., 2011, 2012; Qu et al., MATERIALS AND METHODS 2013; Challacombe et al., 2017). The best-described example is F. noatunensis, an economically important pathogen that globally Genomic Data Sets causes serious disease in farmed and wild fish in both salt and All 62 publicly available (January 2018) whole genome sequences fresh water (Birkbeck et al., 2011; Colquhoun and Duodu, 2011; of Francisella bacteria were downloaded from the NCBI assembly McDermott and Palmeiro, 2013). Two subspecies have been database1 and used for analysis. Allofrancisella guangzhouensis, recognized, subsp. noatunensis and subsp. orientalis. Recently,
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