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Genome Evolution and Host Adaptation in Bartonella
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bacteria of the genus Bartonella infect the red blood cells of a wide range of wild and domestic mammals and are transmitted between hosts by blood-sucking insects. Although most Bartonella infections are asymptomatic, the genus contains several human pathogens. In this work, host adaptation and host switches in Bartonella have been studied from a genomic perspective, with special focus on the acquisition and evolution of genes involved in host interactions.

As part of this study, the complete genome of B. grahamii isolated from a Swedish wood mouse was sequenced. A genus-wide comparison revealed that rodent-associated Bartonella species, which have rarely been associated with human disease, have the largest genomes and the largest number of host-adaptability genes. Analysis of known and putative genes for host interactions identified several families of autotransporters as horizontally transferred to the Bartonella ancestor, with a possible role both during early host adaptation and subsequent host shifts.

In B. grahamii, the association of a gene transfer agent (GTA) and phage-derived run-off replication of a large genomic segment was demonstrated for the first time. Among all acquisitions to the Bartonella ancestor, the only well conserved gene clusters are those that encode the GTA and contain the origin of the run-off replication. This conservation, along with a high density of host-adaptability genes in the amplified region suggest that the GTA provides a strong selective advantage, possibly by increasing recombination frequencies of host-adaptability genes, thereby facilitating evasion of the host immune system and colonization of new hosts.

B. grahamii displays stronger geographic pattern and higher recombination frequencies than the cat-associated B. henselae, probably caused by different lifestyles and/or population sizes of the hosts. The genomic diversity of B. grahamii is markedly lower in Europe and North America than in Asia, possibly an effect of reduced host variability in these areas following the latest ice age.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2009. , p. 68
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 675
Keywords [en]
Bartonella, genome evolution, genome diversity, phage, gene transfer agent, secretion system, microarray
National Category
Bioinformatics and Systems Biology
Research subject
Evolutionary Genetics
Identifiers
URN: urn:nbn:se:uu:diva-108376ISBN: 978-91-554-7616-8 (print)OAI: oai:DiVA.org:uu-108376DiVA, id: diva2:236685
Public defence
2009-11-06, Lindahlsalen, EBC, Norbyvägen 18, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-10-15 Created: 2009-09-17 Last updated: 2009-10-15Bibliographically approved
List of papers
1. Run-off replication of host-adaptability genes is associated with gene transfer agents in the genome of mouse-infecting Bartonella grahamii
Open this publication in new window or tab >>Run-off replication of host-adaptability genes is associated with gene transfer agents in the genome of mouse-infecting Bartonella grahamii
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2009 (English)In: PLoS genetics, ISSN 1553-7404, Vol. 5, no 7, p. e1000546-Article in journal (Refereed) Published
Abstract [en]

The genus Bartonella comprises facultative intracellular bacteria adapted to mammals, including previously recognized and emerging human pathogens. We report the 2,341,328 bp genome sequence of Bartonella grahamii, one of the most prevalent Bartonella species in wild rodents. Comparative genomics revealed that rodent-associated Bartonella species have higher copy numbers of genes for putative host-adaptability factors than the related human-specific pathogens. Many of these gene clusters are located in a highly dynamic region of 461 kb. Using hybridization to a microarray designed for the B. grahamii genome, we observed a massive, putatively phage-derived run-off replication of this region. We also identified a novel gene transfer agent, which packages the bacterial genome, with an over-representation of the amplified DNA, in 14 kb pieces. This is the first observation associating the products of run-off replication with a gene transfer agent. Because of the high concentration of gene clusters for host-adaptation proteins in the amplified region, and since the genes encoding the gene transfer agent and the phage origin are well conserved in Bartonella, we hypothesize that these systems are driven by selection. We propose that the coupling of run-off replication with gene transfer agents promotes diversification and rapid spread of host-adaptability factors, facilitating host shifts in Bartonella.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-108371 (URN)10.1371/journal.pgen.1000546 (DOI)000269219500042 ()19578403 (PubMedID)
Available from: 2009-09-17 Created: 2009-09-17 Last updated: 2010-07-09Bibliographically approved
2. Genome dynamics of Bartonella grahamii in micro-populations of woodland rodents
Open this publication in new window or tab >>Genome dynamics of Bartonella grahamii in micro-populations of woodland rodents
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2010 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, p. 152-Article in journal (Refereed) Published
Abstract [en]

Background: Rodents represent a high-risk reservoir for the emergence of new human pathogens. The recent completion of the 2.3 Mb genome of Bartonella grahamii, one of the most prevalent blood-borne bacteria in wild rodents, revealed a higher abundance of genes for host-cell interaction systems than in the genomes of closely related human pathogens. The sequence variability within the global B. grahamii population was recently investigated by multi locus sequence typing, but no study on the variability of putative host-cell interaction systems has been performed.

Results: To study the population dynamics of B. grahamii, we analyzed the genomic diversity on a whole-genome scale of 27 B. grahamii strains isolated from four different species of wild rodents in three geographic locations separated by less than 30 km. Even using highly variable spacer regions, only 3 sequence types were identified. This low sequence diversity contrasted with a high variability in genome content. Microarray comparative genome hybridizations identified genes for outer surface proteins, including a repeated region containing the fha gene for filamentous hemaggluttinin and a plasmid that encodes a type IV secretion system, as the most variable. The estimated generation times in liquid culture medium for a subset of strains ranged from 5 to 22 hours, but did not correlate with sequence type or presence/absence patterns of the fha gene or the plasmid.

Conclusion: Our study has revealed a geographic microstructure of B. grahamii in wild rodents. Despite near-identity in nucleotide sequence, major differences were observed in gene presence/absence patterns that did not segregate with host species. This suggests that genetically similar strains can infect a range of different hosts.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-108379 (URN)10.1186/1471-2164-11-152 (DOI)000276363100003 ()
Available from: 2009-09-23 Created: 2009-09-17 Last updated: 2017-12-13Bibliographically approved
3. Diversification by recombination in Bartonella grahamii from wild rodents in Asia contrasts with a clonal population structure in Northern Europe and America
Open this publication in new window or tab >>Diversification by recombination in Bartonella grahamii from wild rodents in Asia contrasts with a clonal population structure in Northern Europe and America
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-108384 (URN)
Available from: 2009-09-24 Created: 2009-09-17 Last updated: 2010-01-14
4. Evolution of Host Adaptation Systems in  the Mammalian Blood Specialist Bartonella
Open this publication in new window or tab >>Evolution of Host Adaptation Systems in  the Mammalian Blood Specialist Bartonella
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Bacteria of the genus Bartonella are facultative intracellular bacteria infecting the red blood cells of mammals. Bartonella isolates have now been reported from a wide range of mammalian host species, including humans, domestic animals such as pets and livestock, as well as many wild animals such as deer, moose, kangaroo, and whales. Here, we present the first major genus-wide investigation of host-adaptation systems in Bartonella, using 5 published and 5 draft genome sequences. The sampling includes both clinical and natural isolates, and represent well the major phylogenetic diversity of the genus. Our study reveals four distinct protein families of Type V Secretion Systems (T5SS) shared by all sequenced members of the genus. We also show that a recently identified gene transfer agent (GTA) consisting of a defective phage is, surprisingly, the most conserved gene cluster among all Bartonella-specific or imported genes, strongly emphasizing the functional importance of this system for the life-style and evolution of Bartonella.

Keywords
host adaptation, pathogen, secretion systems, flagella, gene transfer agent, evolution
National Category
Bioinformatics and Systems Biology
Research subject
Evolutionary Genetics
Identifiers
urn:nbn:se:uu:diva-107784 (URN)
Available from: 2009-08-26 Created: 2009-08-26 Last updated: 2010-01-14
5. Low-coverage pyrosequencing reveals recombination and run-off replication in Bartonella henselae strains
Open this publication in new window or tab >>Low-coverage pyrosequencing reveals recombination and run-off replication in Bartonella henselae strains
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Bartonella henselae is a natural intracellular colonizer of cats, and is transferred by blood-sucking insect vectors. It is also an opportunistic human pathogen. Two strains of B. henselae, thought to be representative of the diversity of the species, were selected for low-coverage 454 sequencing. The comparison of these two strains to the published Houston-1 reveals very high nucleotide identity and low substitution and recombination, with the remarkable exception of phages and host-interaction genes such as type IV and V secretion systems. Among the few variable genes of unknown function, BH14680, an alpha-Proteobacteria-specific gene, shows faster evolution in Bartonella compared to other alpha-Proteobacteria. Its 5’ end, which is likely coding for a domain exposed extracellularly, is under positive or very relaxed selection, and might be involved in host-interaction processes. Finally, we show that a simple genome coverage analysis reveal major genomic events such as duplications and unusual replication modes, such as the run-off replication. The latter, combined with a gene transfer agent, is thought to be a novel way to increase substitution and recombination frequencies. An extensive analysis of all bacterial pyrosequencing projects showed that it is probably Bartonella-specific.

Keywords
pathogen, recombination, run-off replication, phage, gene transfer agent, pyrosequencing, evolution
National Category
Bioinformatics and Systems Biology
Research subject
Evolutionary Genetics
Identifiers
urn:nbn:se:uu:diva-107785 (URN)
Available from: 2009-08-27 Created: 2009-08-26 Last updated: 2010-01-14

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