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Evolution of subspecies of Francisella tularensis
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
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2005 (English)In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 187, no 11, 3903-3908 p.Article in journal (Refereed) Published
Abstract [en]

Analysis of unidirectional genomic deletion events and single nucleotide variations suggested that the four subspecies of Francisella tularensis have evolved by vertical descent. The analysis indicated an evolutionary scenario where the highly virulent F. tularensis subsp. tularensis (type A) appeared before the less virulent F. tularensis subsp. holarctica (type B). Compared to their virulent progenitors, attenuated strains of F. tularensis exhibited specific unidirectional gene losses.

Place, publisher, year, edition, pages
2005. Vol. 187, no 11, 3903-3908 p.
Keyword [en]
Evolution; Molecular, Francisella tularensis/classification/*genetics/pathogenicity, Gene Deletion, Genome; Bacterial, Molecular Sequence Data, Oligonucleotide Array Sequence Analysis, Phylogeny, Virulence
URN: urn:nbn:se:umu:diva-2382DOI: 10.1128/JB.187.11.3903-3908.2005PubMedID: 15901721OAI: diva2:140348
Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2016-03-01Bibliographically approved
In thesis
1. The genetic composition and diversity of Francisella tularensis
Open this publication in new window or tab >>The genetic composition and diversity of Francisella tularensis
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Francisella tularensis is the causative agent of the debilitating, sometimes fatal zoonotic disease tularemia. To date, little information has been available on the genetic makeup of this pathogen, its evolution, and the genetic differences which characterize subspecific lineages. These are the main areas addressed in this thesis.

The work indicated a high degree of genetic conservation of F. tularensis, both on the sequence level as determined by sequencing and on the compositional level, determined by array-based comparative genomic hybridizations (aCGH). One striking finding was that subsp. mediasiatica was most similar to subsp. tularensis, despite their natural confinement to Central Asia and North America, respectively. All genetic Regions of Difference RD found by aCGH distinguishing lineages were had resulted from repeat-mediated excision of DNA. This was used to identify additional RDs. Such data along with a multiple locus sequence analysis suggested an evolutionary scenario for F. tularensis.

Based on genomic information, a novel typing scheme for F. tularensis was furthermore devised and evaluated. This method provided increased robustness compared to previously used methods for F. tularensis typing, while retaining a capacity for high resolution.

Finally, the genomic sequence of the highly virulent F. tularensis strain SCHU S4 was determined and analysed. Evidenced by numerous pseudogenes and disrupted metabolic pathways, the bacterium appears to be undergoing a genome reduction process whereby a large proportion of the genetic capacity gradually is lost. It is likely that F. tularensis has irreversibly has evolved into an obligate host-dependent bacterium, incapable of a free-living existence. Unexpectedly, the bacterium was found to be devoid of common virulence mechanisms such as classic toxins, or type III and IV secretion systems. Instead, the virulence of this bacterium is probably largely the result of specific and unusual mechanisms.

Place, publisher, year, edition, pages
Umeå: Klinisk mikrobiologi, 2007. 51 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1094
Microbiology, tularemia, genotyping, evolution, microarray, genome sequencing, virulence, genome reduction, Mikrobiologi, Francisella tularensis
Research subject
Clinical Bacteriology
urn:nbn:se:umu:diva-1139 (URN)971-91-7264-288-1-X (ISBN)
Public defence
2007-05-31, E04, 6E, NUS, Umeå, 09:00
Available from: 2007-05-11 Created: 2007-05-11Bibliographically approved
2. Genetic genealogy and epidemiology of Francisella
Open this publication in new window or tab >>Genetic genealogy and epidemiology of Francisella
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is about analyzing genetic differences among isolates of Francisella tularensis – the tularemia-causing bacterium. To elucidate how these bacterial isolates are related, and their geographical and genetic origins, I have developed typing assays for Francisella and used them to study the epidemiology of tularemia.

Tularemia is an infectious disease of humans and other mammals found throughout the Northern Hemisphere. The severity of the disease depends on the type of F. tularensis causing the infection. In Sweden, as in other countries of Europe and Eurasia, tularemia is caused by F. tularensis subsp. holarctica, while other varieties of the bacterium occur in Middle Asia and North America. It is important to identify a tularemia infection promptly in order to initiate the correct antibiotic treatment. A rapid identification of the causative F. tularensis variety gives additional clinical information. In recent years, several genomes of various Francisella strains have been sequenced, and in this thesis, I have utilized these genomes to identify genetic markers.

In studies reported in the first paper (I) appended to the thesis, we identified and analyzed insertion/deletion mutations (INDELs) inferred to have resulted from a sequence repeat-mediated excision mechanism. We found eight new Regions of Difference (RDs) among Francisella strains. Using RDs together with single nucleotide polymorphisms (SNPs), we were able to predict an evolutionary scenario for F. tularensis in which Francisella novicida was the oldest variety while F. tularensis subsp. holarctica was the youngest. We also found that all virulence-attenuated isolates analyzed had deletions at two specific genetic regions - denoted RD18 and RD19 – suggesting that repeat-mediated excision is a mechanism of attenuation in F. tularensis.

In subsequent studies (presented in paper II), we developed a combined analysis of INDELs lacking flanking repeats and variable number of tandem repeats (VNTRs). Both markers could be assayed using the same analytical equipment. The inclusion of INDELs provided increased phylogenetic robustness compared with the use of VNTRs alone, while still maintaining a high level of genetic resolution.

In analyses described in the next paper (III), we selected INDELs from paper (II) and discovered novel SNPs by DNA comparisons of multiple Francisella strains. Thirty-four phylogenetically informative genetic markers were included in a hierarchical real-time PCR array for rapid and robust characterization of Francisella. We successfully used the assay to genotype 14 F. tularensis isolates from tularemia patients and DNA in six clinical ulcer specimens.

Finally, in paper (IV) we demonstrated a strategy to enhance epidemiological investigations of tularemia by combining GIS-mapping of disease-transmission place collected from patient interviews, with high-resolution genotyping of F. tularensis subsp. holarctica isolates recovered from tularemia patients. We found the geographic distributions of specific F. tularensis subsp. holarctica sub-populations to be highly localized during outbreaks (infections by some genotypes being restricted to areas as small as 2 km2), indicative of a landscape epidemiology of tularemia with distinct point sources of infection.

In conclusion, the results acquired during the studies underlying this thesis contribute to our understanding of the genetic genealogy of tularemia at both global and local outbreak scales.

Place, publisher, year, edition, pages
Umeå: Department of Clinical Microbiology, Umeå University, 2009. 47 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1270
Francisella tularensis, tularemia, genotyping, epidemiology, GIS
National Category
Infectious Medicine
Research subject
Infectious Diseases
urn:nbn:se:umu:diva-22452 (URN)978-91-7264-803-6 (ISBN)
Infektionssjukdomar, 901 85, Umeå
Public defence
2009-06-05, 933, building 3A, NUS, 13:00 (English)
Available from: 2009-05-19 Created: 2009-05-11 Last updated: 2016-03-01Bibliographically approved

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