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  • 1.
    Ameur, Adam
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Dahlberg, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Olason, Pall
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Vezzi, Francesco
    Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Karlsson, Robert
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Martin, Marcel
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Viklund, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Kähäri, Andreas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Lundin, Par
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Che, Huiwen
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Thutkawkorapin, Jessada
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Eisfeldt, Jesper
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Lampa, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Dahlberg, Mats
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Hagberg, Jonas
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Jareborg, Niclas
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Liljedahl, Ulrika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Jonasson, Inger
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Feuk, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Lundeberg, Joakim
    Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.;Royal Inst Technol, Div Gene Technol, Sch Biotechnol, Sci Life Lab, Stockholm, Sweden..
    Syvänen, Ann-Christine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Lundin, Sverker
    Royal Inst Technol, Div Gene Technol, Sch Biotechnol, Sci Life Lab, Stockholm, Sweden..
    Nilsson, Daniel
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Nystedt, Björn
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Magnusson, Patrik K. E.
    Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Gyllensten, Ulf B.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population2017In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 25, no 11, p. 1253-1260Article in journal (Refereed)
    Abstract [en]

    Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single-nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set.

  • 2.
    Guy, Lionel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Nystedt, Björn
    Sun, Yu
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Berglund, Eva C.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Graf, Alexander
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Zhoupeng, Xie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Näslund, Kristina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Andersson, Siv G.E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Low-coverage pyrosequencing reveals recombination and run-off replication in Bartonella henselae strainsManuscript (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.

  • 3.
    Guy, Lionel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Toft, Christina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zaremba-Niedzwiedzka, Katarzyna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berglund, Eva C.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Granberg, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Näslund, Kristina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Ann-Sofie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A Gene Transfer Agent and a Dynamic Repertoire of Secretion Systems Hold the Keys to the Explosive Radiation of the Emerging Pathogen Bartonella2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 3, p. e1003393-Article in journal (Refereed)
    Abstract [en]

    Gene transfer agents (GTAs) randomly transfer short fragments of a bacterial genome. A novel putative GTA was recently discovered in the mouse-infecting bacterium Bartonella grahamii. Although GTAs are widespread in phylogenetically diverse bacteria, their role in evolution is largely unknown. Here, we present a comparative analysis of 16 Bartonella genomes ranging from 1.4 to 2.6 Mb in size, including six novel genomes from Bartonella isolated from a cow, two moose, two dogs, and a kangaroo. A phylogenetic tree inferred from 428 orthologous core genes indicates that the deadly human pathogen B. bacilliformis is related to the ruminant-adapted clade, rather than being the earliest diverging species in the genus as previously thought. A gene flux analysis identified 12 genes for a GTA and a phage-derived origin of replication as the most conserved innovations. These are located in a region of a few hundred kb that also contains 8 insertions of gene clusters for type III, IV, and V secretion systems, and genes for putatively secreted molecules such as cholera-like toxins. The phylogenies indicate a recent transfer of seven genes in the virB gene cluster for a type IV secretion system from a catadapted B. henselae to a dog-adapted B. vinsonii strain. We show that the B. henselae GTA is functional and can transfer genes in vitro. We suggest that the maintenance of the GTA is driven by selection to increase the likelihood of horizontal gene transfer and argue that this process is beneficial at the population level, by facilitating adaptive evolution of the host-adaptation systems and thereby expansion of the host range size. The process counters gene loss and forces all cells to contribute to the production of the GTA and the secreted molecules. The results advance our understanding of the role that GTAs play for the evolution of bacterial genomes.

  • 4. Kutsenko, Alexey
    et al.
    Svensson, Thomas
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Lundeberg, Joakim
    Bjork, Petra
    Sonnhammer, Erik
    Giacomello, Stefania
    Visa, Neus
    Wieslander, Lars
    The Chironomus tentans genome sequence and the organization of the Balbiani ring genes2014In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, p. 819-Article in journal (Refereed)
    Abstract [en]

    Background: The polytene nuclei of the dipteran Chironomus tentans (Ch. tentans) with their Balbiani ring (BR) genes constitute an exceptional model system for studies of the expression of endogenous eukaryotic genes. Here, we report the first draft genome of Ch. tentans and characterize its gene expression machineries and genomic architecture of the BR genes. Results: The genome of Ch. tentans is approximately 200 Mb in size, and has a low GC content (31%) and a low repeat fraction (15%) compared to other Dipteran species. Phylogenetic inference revealed that Ch. tentans is a sister clade to mosquitoes, with a split 150-250 million years ago. To characterize the Ch. tentans gene expression machineries, we identified potential orthologus sequences to more than 600 Drosophila melanogaster (D. melanogaster) proteins involved in the expression of protein-coding genes. We report novel data on the organization of the BR gene loci, including a novel putative BR gene, and we present a model for the organization of chromatin bundles in the BR2 puff based on genic and intergenic in situ hybridizations. Conclusions: We show that the molecular machineries operating in gene expression are largely conserved between Ch. tentans and D. melanogaster, and we provide enhanced insight into the organization and expression of the BR genes. Our data strengthen the generality of the BR genes as a unique model system and provide essential background for in-depth studies of the biogenesis of messenger ribonucleoprotein complexes.

  • 5. Lin, Yao-Cheng
    et al.
    Wang, Jing
    Delhomme, Nicolas
    Schiffthaler, Bastian
    Sundström, Görel
    Zuccolo, Andrea
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hvidsten, Torgeir R.
    de la Torre, Amanda
    Cossu, Rosa M.
    Höppner, Marc P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lantz, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Scofield, Douglas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Zamani, Neda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Anna C. V.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mannapperuma, Chanaka
    Robinson, Kathryn M.
    Mähler, Niklas
    Leitch, Ilia J.
    Pellicer, Jaume
    Park, Eung-Jun
    Van Montagu, Marc
    Van de Peer, Yves
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jansson, Stefan
    Ingvarsson, Pär K.
    Street, Nathaniel R.
    Functional and evolutionary genomic inferences in Populus through genome and population sequencing of American and European aspen2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 46, p. E10970-E10978Article in journal (Refereed)
  • 6.
    Martínez Barrio, Álvaro
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lamichhaney, Sangeet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fan, Guangyi
    State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China; BGI-Shenzhen, Shenzen, China; 5 College of Physics, Qingdao University, Qingdao, China .
    Rafati, Nima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pettersson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, He
    BGI-Shenzhen, Shenzen, China; College of Physics, Qingdao University, Qingdao, China.
    Dainat, Jacques
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ekman, Diana
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University.
    Höppner, Marc P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Martin, Marcel
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University.
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Liu, Xin
    BGI-Shenzhen, Shenzen, China.
    Chen, Wenbin
    BGI-Shenzhen, Shenzhen, China.
    Liang, Xinming
    BGI-Shenzhen, Shenzhen, China.
    Shi, Chengcheng
    BGI-Shenzhen, Shenzhen, China.
    Fu, Yuanyuan
    BGI-Shenzhen, Shenzhen, China.
    Ma, Kailong
    BGI-Shenzhen, Shenzhen, China.
    Zhan, Xiao
    BGI-Shenzhen, Shenzhen, China.
    Feng, Chungang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gustafson, Ulla
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Blass, Martina
    Department of Aquatic Resources, Institute of Coastal Research, Swedish University of Agricultural Sciences, Öregrund, Sweden.
    Casini, Michele
    Swedish University of Agricultural Sciences, Department of Aquatic Resources, Institute of Marine Research.
    Folkvord, Arild
    Department of Biology, University of Bergen, Bergen, Norway; Hjort Center of Marine Ecosystem Dynamics, Bergen, Norway; Institute of Marine Research, Bergen, Norway .
    Laikre, Linda
    Department of Zoology, Stockholm University.
    Ryman, Nils
    Department of Zoology, Stockholm University, Stockholm, Sweden.
    Lee, Simon Ming-Yuen Lee
    State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao.
    Xu, Xun
    BGI-Shenzhen, Shenzhen, China.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden; Department of Veterinary Integrative Biosciences, Texas A&M University, Texas, United States.
    The genetic basis for ecological adaptation of the Atlantic herring revealed by genome sequencing2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e12081Article in journal (Refereed)
    Abstract [en]

    Ecological adaptation is of major relevance to speciation and sustainable population management, but the underlying genetic factors are typically hard to study in natural populations due to genetic differentiation caused by natural selection being confounded with genetic drift in subdivided populations. Here, we use whole genome population sequencing of Atlantic and Baltic herring to reveal the underlying genetic architecture at an unprecedented detailed resolution for both adaptation to a new niche environment and timing of reproduction. We identify almost 500 independent loci associated with a recent niche expansion from marine (Atlantic Ocean) to brackish waters (Baltic Sea), and more than 100 independent loci showing genetic differentiation between spring- and autumn-spawning populations irrespective of geographic origin. Our results show that both coding and non-coding changes contribute to adaptation. Haplotype blocks, often spanning multiple genes and maintained by selection, are associated with genetic differentiation.

  • 7.
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Evolutionary Processes and Genome Dynamics in Host-Adapted Bacteria2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Many bacteria live in close association with other organisms such as plants and animals, with important implications for both health and disease. This thesis investigates bacteria that are well adapted to live inside an animal host, and describes the molecular evolutionary processes underlying host-adaptation, based on bacterial genome comparisons.

    Insect-transmitted bacteria of the genus Bartonella infect the red blood cells of mammals, and we investigate host adaptation and genome evolution in this genus. In Bartonella, many host-interaction systems are encoded in a highly variable chromosomal segment previously shown to be amplified and packaged into bacteriophage particles. Among all genes imported into the Bartonella ancestor, we identify the short gene cluster encoding these phage particles as the most evolutionary conserved, indicating a strong selective advantage and a role in niche adaptation. We also provide an overview of the remarkable evolutionary dynamics of type IV and type V secretion systems, including a detailed analysis of the type IV secretion system trw. Our results highlight the importance of recombination and gene conversion in the evolution of host-adaptation systems, and reveal how these mutational mechanisms result in strikingly different outcomes depending on the selective constraints.

    In the insect endosymbionts Buchnera and Blochmannia, we show that genes frameshifted at poly(A) tracts can remain functional due to transcriptional slippage. Selection against poly(A) tracts is very inefficient in these genomes compared to other bacteria, and we discuss why this can lead to increased rates of gene loss. Using the human pathogen Helicobacter pylori as a model, we provide a deeper understanding of why highly expressed genes evolve slowly.

    This thesis emphasizes the power of using complete genome sequences to study evolutionary processes. In particular, we argue that knowledge about the complex evolution of duplicated gene segments is crucial to understand host adaptation in bacteria.

    List of papers
    1. Genome reduction in the alpha-Proteobacteria
    Open this publication in new window or tab >>Genome reduction in the alpha-Proteobacteria
    2005 (English)In: Current Opinion in Microbiology, ISSN 1369-5274, E-ISSN 1879-0364, Vol. 8, no 5, p. 579-585Article in journal (Refereed) Published
    Abstract [en]

    More than 20 α-proteobacterial genomes are currently available. These range in size from 1–9 Mb and represent excellent model systems for evolutionary studies of the organizational features of bacterial genomes. Computational inferences have shown that genome reductions have occurred independently in lineages such as Rickettsia and Bartonella that are associated with intracellular lifestyles. Analyses of these reduced genomes have provided insights into the evolution of vector-borne transmission pathways. Further research into the population biology of bacteria, arthropods and vertebrate hosts will help to refine the biology of host–pathogen interactions and will facilitate the design of vaccines and vector-control programs.

    Keywords
    Adaptation; Biological/genetics, Alphaproteobacteria/*genetics, Animals, Eukaryotic Cells/microbiology, Evolution; Molecular, Genome; Bacterial, Humans, Phylogeny, Recombination; Genetic, Research Support; Non-U.S. Gov't, Sequence Deletion
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-77159 (URN)10.1016/j.mib.2005.08.002 (DOI)16099701 (PubMedID)
    Available from: 2006-03-13 Created: 2006-03-13 Last updated: 2017-12-14Bibliographically approved
    2. Protein evolutionary rates correlate with expression independently of synonymous substitutions in Helicobacter pylori
    Open this publication in new window or tab >>Protein evolutionary rates correlate with expression independently of synonymous substitutions in Helicobacter pylori
    Show others...
    2006 (English)In: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 62, no 5, p. 600-614Article in journal (Refereed) Published
    Abstract [en]

    In free-living microorganisms, such as Escherichia coli and Saccharomyces cerevisiae, both synonymous and nonsynonymous substitution frequencies correlate with expression levels. Here, we have tested the hypothesis that the correlation between amino acid substitution rates and expression is a by-product of selection for codon bias and translational efficiency in highly expressed genes. To this end, we have examined the correlation between protein evolutionary rates and expression in the human gastric pathogen Helicobacter pylori, where the absence of selection on synonymous sites enables the two types of substitutions to be uncoupled. The results revealed a statistically significant negative correlation between expression levels and nonsynonymous substitutions in both H. pylori and E. coli. We also found that neighboring genes located on the same, but not on opposite strands, evolve at significantly more similar rates than random gene pairs, as expected by co-expression of genes located in the same operon. However, the two species differ in that synonymous substitutions show a strand-specific pattern in E. coli, whereas the weak similarity in synonymous substitutions for neighbors in H. pylori is independent of gene orientation. These results suggest a direct influence of expression levels on nonsynonymous substitution frequencies independent of codon bias and selective constraints on synonymous sites.

    Keywords
    Amino Acid Substitution/*genetics, Bacterial Proteins/chemistry/*genetics, Chromosomes; Bacterial/genetics, Codon/genetics, Evolution; Molecular, Gene Expression Regulation; Bacterial, Genes; Bacterial/genetics, Helicobacter pylori/chemistry/*genetics, RNA; Messenger/genetics/metabolism, Variation (Genetics)
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-23093 (URN)10.1007/ss00239-005-0104-5 (DOI)16586017 (PubMedID)
    Available from: 2007-01-24 Created: 2007-01-24 Last updated: 2017-12-07Bibliographically approved
    3. Diversifying Selection and Concerted Evolution of a Type IV Secretion System in Bartonella
    Open this publication in new window or tab >>Diversifying Selection and Concerted Evolution of a Type IV Secretion System in Bartonella
    2008 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 25, no 2, p. 287-300Article in journal (Refereed) Published
    Abstract [en]

    We have studied the evolution of a type TV secretion system (T4SS), in Bartonella, which is thought to have changed function from conjugation to erythrocyte adherence following a recent horizontal gene transfer event. The system, called Trw, is unique among T4SSs in that genes encoding both exo- and intracellular components are located within the same duplicated fragment. This provides an opportunity to study the influence of selection on proteins involved in host-pathogen interactions. We sequenced the trw locus from several strains of Bartonella henselae and investigated its evolutionary history by comparisons to other Bartonella species. Several instances of recombination and gene conversion events where detected in the 2- to 5-fold duplicated gene fragments encompassing trwJIH, explaining the homogenization of the anchoring protein TrwI and the divergence of the minor pilus protein TrwJ. A phylogenetic analysis of the 7- to 8-fold duplicated gene coding for the major pilus protein TrwL displayed 2 distinct clades, likely representing a subfunctionalization event. The analyses of the B. henselae strains also identified a recent horizontal transfer event of almost the complete trwL region. We suggest that the switch in function of the T4SS was mediated by the duplication of the genes encoding pilus components and their diversification by combinatorial sequence shuffling within and among genomes. We suggest that the pilus proteins have evolved by diversifying selection to match a divergent set of erythrocyte surface structures, consistent with the trench warfare coevolutionary model.

    Keywords
    type IV secretion system, Bartonella, duplication, recombination, gene conversion, host-pathogen interaction
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-14988 (URN)10.1093/molbev/msm252 (DOI)000253634800007 ()18065487 (PubMedID)
    Available from: 2008-02-01 Created: 2008-02-01 Last updated: 2017-12-11Bibliographically approved
    4. Endosymbiont gene functions impaired and rescued by polymerase infidelity at poly(A) tracts
    Open this publication in new window or tab >>Endosymbiont gene functions impaired and rescued by polymerase infidelity at poly(A) tracts
    Show others...
    2008 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 39, p. 14934-14939Article in journal (Refereed) Published
    Abstract [en]

    Among host-dependent bacteria that have evolved by extreme reductive genome evolution, long-term bacterial endosymbionts of insects have the smallest (160-790 kb) and most A + T-rich (>70%) bacterial genomes known to date. These genomes are riddled with poly(A) tracts, and 5-50% of genes contain tracts of 10 As or more. Here, we demonstrate transcriptional slippage at poly(A) tracts within genes of Buchnera aphidicola associated with aphids and Blochmannia pennsylvanicus associated with ants. Several tracts contain single frameshift deletions; these apparent pseudogenes showed patterns of constraint consistent with purifying selection on the encoded proteins. Transcriptional slippage yielded a heterogeneous population of transcripts with variable numbers of As in the tract. Across several frameshifted genes, including B. aphidicola cell wall biosynthesis genes and a B. pennsylvanicus histidine biosynthesis gene, 12-50% of transcripts contained corrected reading frames that could potentially yield full-length proteins. In situ immunostaining confirmed the production of the cell wall biosynthetic enzyme UDP-N-acetylmuramyl pentapeptide synthase encoded by the frameshifted murF gene. Simulation studies indicated an overrepresentation of poly(A) tracts in endosymbiont genomes relative to other A + T-rich bacterial genomes. Polymerase infidelity at poly(A) tracts rescues the functionality of genes with frameshift mutations and, conversely, reduces the efficiency of expression for in-frame genes carrying poly(A) regions. These features of homopolymeric tracts could be exploited to manipulate gene expression in small synthetic genomes.

    Keywords
    homopolymeric tracts, pseudogenes, Blochmannia pennsylvanicus, transcriptional slippage, Buchnera aphidicola
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-107728 (URN)10.1073/pnas.0806554105 (DOI)000261914300022 ()18815381 (PubMedID)
    Available from: 2009-08-24 Created: 2009-08-24 Last updated: 2017-12-13Bibliographically approved
    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
    Show others...
    (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
    6. 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
    Show others...
    (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
  • 8.
    Nystedt, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Frank, Carolin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Thollesson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Andersson, Siv
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Diversifying Selection and Concerted Evolution of a Type IV Secretion System in Bartonella2008In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 25, no 2, p. 287-300Article in journal (Refereed)
    Abstract [en]

    We have studied the evolution of a type TV secretion system (T4SS), in Bartonella, which is thought to have changed function from conjugation to erythrocyte adherence following a recent horizontal gene transfer event. The system, called Trw, is unique among T4SSs in that genes encoding both exo- and intracellular components are located within the same duplicated fragment. This provides an opportunity to study the influence of selection on proteins involved in host-pathogen interactions. We sequenced the trw locus from several strains of Bartonella henselae and investigated its evolutionary history by comparisons to other Bartonella species. Several instances of recombination and gene conversion events where detected in the 2- to 5-fold duplicated gene fragments encompassing trwJIH, explaining the homogenization of the anchoring protein TrwI and the divergence of the minor pilus protein TrwJ. A phylogenetic analysis of the 7- to 8-fold duplicated gene coding for the major pilus protein TrwL displayed 2 distinct clades, likely representing a subfunctionalization event. The analyses of the B. henselae strains also identified a recent horizontal transfer event of almost the complete trwL region. We suggest that the switch in function of the T4SS was mediated by the duplication of the genes encoding pilus components and their diversification by combinatorial sequence shuffling within and among genomes. We suggest that the pilus proteins have evolved by diversifying selection to match a divergent set of erythrocyte surface structures, consistent with the trench warfare coevolutionary model.

  • 9.
    Nystedt, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Guy, Lionel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Berglund, Eva
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Bjursell, Magnus
    School of Biotechnology, Royal Institute of Technology.
    Granberg, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Toft, Christina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Zaremba, Katarzyna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Näslund, Kristina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Eriksson, Ann-Sofie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Evolution of Host Adaptation Systems in  the Mammalian Blood Specialist BartonellaManuscript (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.

  • 10.
    Reischauer, Sven
    et al.
    Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA.;Max Planck Inst Heart & Lung Res, Dept Dev Genet, D-61231 Bad Nauheim, Germany..
    Stone, Oliver A.
    Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA.;Max Planck Inst Heart & Lung Res, Dept Dev Genet, D-61231 Bad Nauheim, Germany..
    Villasenor, Alethia
    Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA.;Max Planck Inst Heart & Lung Res, Dept Dev Genet, D-61231 Bad Nauheim, Germany..
    Chi, Neil
    Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA.;Univ Calif San Diego, Inst Genom Med, Div Cardiol, Dept Med, La Jolla, CA 92037 USA..
    Jin, Suk-Won
    Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA.;Gwangju Inst Sci & Technol, Sch Life Sci, Gwangju 61005, South Korea.;Yale Univ, Sch Med, Yale Cardiovasc Res Ctr, New Haven, CT 06511 USA..
    Martin, Marcel
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, S-17121 Solna, Sweden..
    Lee, Miler T.
    Yale Univ, Dept Genet, Sch Med, New Haven, CT 06520 USA.;Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA..
    Fukuda, Nana
    Max Planck Inst Heart & Lung Res, Dept Dev Genet, D-61231 Bad Nauheim, Germany..
    Marass, Michele
    Max Planck Inst Heart & Lung Res, Dept Dev Genet, D-61231 Bad Nauheim, Germany..
    Witty, Alec
    Univ Calif San Diego, Inst Genom Med, Div Cardiol, Dept Med, La Jolla, CA 92037 USA..
    Fiddes, Ian
    Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA.;Univ Calif Santa Cruz, Genom Inst, Santa Cruz, CA 95064 USA.;Howard Hughes Med Inst, Santa Cruz, CA 95064 USA..
    Kuo, Taiyi
    Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA.;Columbia Univ Coll Phys & Surg, Dept Med, 630 W 168th St, New York, NY 10032 USA.;Columbia Univ Coll Phys & Surg, Berrie Diabet Ctr, 630 W 168th St, New York, NY 10032 USA..
    Chung, Won-Suk
    Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA.;Korea Adv Inst Sci & Technol, Dept Biol Sci, Daejeon 34141, South Korea..
    Salek, Sherveen
    Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA.;Johns Hopkins Univ Hosp, Wilmer Eye Inst, Baltimore, MD 21224 USA..
    Lerrigo, Robert
    Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA.;Univ Washington, Div Gen Internal Med, Seattle, WA 98104 USA..
    Alsio, Jessica
    Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA.;Novartis, CH-4056 Basel, Switzerland..
    Luo, Shujun
    Illumina, San Diego, CA 92122 USA.;Personalis, Menlo Pk, CA 94025 USA..
    Tworus, Dominika
    Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden..
    Augustine, Sruthy M.
    Max Planck Inst Heart & Lung Res, Dept Dev Genet, D-61231 Bad Nauheim, Germany..
    Mucenieks, Sophie
    Max Planck Inst Heart & Lung Res, Dept Dev Genet, D-61231 Bad Nauheim, Germany..
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Giraldez, Antonio J.
    Yale Univ, Dept Genet, Sch Med, New Haven, CT 06520 USA..
    Schroth, Gary P.
    Illumina, San Diego, CA 92122 USA..
    Andersson, Olov
    Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden..
    Stainier, Didier Y. R.
    Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA.;Max Planck Inst Heart & Lung Res, Dept Dev Genet, D-61231 Bad Nauheim, Germany..
    Cloche is a bHLH-PAS transcription factor that drives haemato-vascular specification2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 535, no 7611, p. 294-+Article in journal (Refereed)
    Abstract [en]

    Vascular and haematopoietic cells organize into specialized tissues during early embryogenesis to supply essential nutrients to all organs and thus play critical roles in development and disease. At the top of the haemato-vascular specification cascade lies cloche, a gene that when mutated in zebrafish leads to the striking phenotype of loss of most endothelial and haematopoietic cells(1-4) and a significant increase in cardiomyocyte numbers(5). Although this mutant has been analysed extensively to investigate mesoderm diversification and differentiation(1-7) and continues to be broadly used as a unique avascular model, the isolation of the cloche gene has been challenging due to its telomeric location. Here we used a deletion allele of cloche to identify several new cloche candidate genes within this genomic region, and systematically genome-edited each candidate. Through this comprehensive interrogation, we succeeded in isolating the cloche gene and discovered that it encodes a PAS-domain-containing bHLH transcription factor, and that it is expressed in a highly specific spatiotemporal pattern starting during late gastrulation. Gain-of-function experiments show that it can potently induce endothelial gene expression. Epistasis experiments reveal that it functions upstream of etv2 and tal1, the earliest expressed endothelial and haematopoietic transcription factor genes identified to date. A mammalian cloche orthologue can also rescue blood vessel formation in zebrafish cloche mutants, indicating a highly conserved role in vertebrate vasculogenesis and haematopoiesis. The identification of this master regulator of endothelial and haematopoietic fate enhances our understanding of early mesoderm diversification and may lead to improved protocols for the generation of endothelial and haematopoietic cells in vivo and in vitro.

  • 11.
    Sällström, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Andersson, Siv
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Genome reduction in the alpha-Proteobacteria2005In: Current Opinion in Microbiology, ISSN 1369-5274, E-ISSN 1879-0364, Vol. 8, no 5, p. 579-585Article in journal (Refereed)
    Abstract [en]

    More than 20 α-proteobacterial genomes are currently available. These range in size from 1–9 Mb and represent excellent model systems for evolutionary studies of the organizational features of bacterial genomes. Computational inferences have shown that genome reductions have occurred independently in lineages such as Rickettsia and Bartonella that are associated with intracellular lifestyles. Analyses of these reduced genomes have provided insights into the evolution of vector-borne transmission pathways. Further research into the population biology of bacteria, arthropods and vertebrate hosts will help to refine the biology of host–pathogen interactions and will facilitate the design of vaccines and vector-control programs.

  • 12.
    Sällström, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Andersson, Siv G.E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Genome reduction in the alpha-Proteobacteria2005In: Current Opinion in Microbiology, ISSN 1369-5274, E-ISSN 1879-0364, Vol. 8, no 5, p. 579-585Article in journal (Refereed)
    Abstract [en]

    More than 20 alpha-proteobacterial genomes are currently available. These range in size from 1–9 Mb and represent excellent model systems for evolutionary studies of the organizational features of bacterial genomes. Computational inferences have shown that genome reductions have occurred independently in lineages such as Rickettsia and Bartonella that are associated with intracellular lifestyles. Analyses of these reduced genomes have provided insights into the evolution of vector-borne transmission pathways. Further research into the population biology of bacteria, arthropods and vertebrate hosts will help to refine the biology of host–pathogen interactions and will facilitate the design of vaccines and vector-control programs.

  • 13.
    Sällström, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Arnaout, Ramy A.
    Davids, Wagied
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Bjelkmar, Pär
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Andersson, Siv
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Protein evolutionary rates correlate with expression independently of synonymous substitutions in Helicobacter pylori2006In: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 62, no 5, p. 600-614Article in journal (Refereed)
    Abstract [en]

    In free-living microorganisms, such as Escherichia coli and Saccharomyces cerevisiae, both synonymous and nonsynonymous substitution frequencies correlate with expression levels. Here, we have tested the hypothesis that the correlation between amino acid substitution rates and expression is a by-product of selection for codon bias and translational efficiency in highly expressed genes. To this end, we have examined the correlation between protein evolutionary rates and expression in the human gastric pathogen Helicobacter pylori, where the absence of selection on synonymous sites enables the two types of substitutions to be uncoupled. The results revealed a statistically significant negative correlation between expression levels and nonsynonymous substitutions in both H. pylori and E. coli. We also found that neighboring genes located on the same, but not on opposite strands, evolve at significantly more similar rates than random gene pairs, as expected by co-expression of genes located in the same operon. However, the two species differ in that synonymous substitutions show a strand-specific pattern in E. coli, whereas the weak similarity in synonymous substitutions for neighbors in H. pylori is independent of gene orientation. These results suggest a direct influence of expression levels on nonsynonymous substitution frequencies independent of codon bias and selective constraints on synonymous sites.

  • 14.
    Sällström, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Arnaout, Ramy A.
    Davids, Wagied
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Bjelkmar, Pär
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Protein Evolutionary Rates Correlate with Expression Independently of Synonymous Substitutions in Helicobacter pylori2006In: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 62, no 5, p. 600-614Article in journal (Refereed)
    Abstract [en]

    In free-living microorganisms, such as Escherichia coli and Saccharomyces cerevisiae, both synonymous and nonsynonymous substitution frequencies correlate with expression levels. Here, we have tested the hypothesis that the correlation between amino acid substitution rates and expression is a by-product of selection for codon bias and translational efficiency in highly expressed genes. To this end, we have examined the correlation between protein evolutionary rates and expression in the human gastric pathogen Helicobacter pylori, where the absence of selection on synonymous sites enables the two types of substitutions to be uncoupled. The results revealed a statistically significant negative correlation between expression levels and nonsynonymous substitutions in both H. pylori and E. coli. We also found that neighboring genes located on the same, but not on opposite strands, evolve at significantly more similar rates than random gene pairs, as expected by co-expression of genes located in the same operon. However, the two species differ in that synonymous substitutions show a strand-specific pattern in E. coli, whereas the weak similarity in synonymous substitutions for neighbors in H. pylori is independent of gene orientation. These results suggest a direct influence of expression levels on nonsynonymous substitution frequencies independent of codon bias and selective constraints on synonymous sites.

  • 15.
    Sällström, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Visser, Sandra A G
    Forsberg, Tomas
    Peletier, Lambertus A
    Ericson, Ann-Christine
    Gabrielsson, Johan
    A Pharmacodynamic Turnover Model Capturing Asymmetric Circadian Baselines of Body Temperature, Heart Rate and Blood Pressure in Rats: Challenges in Terms of Tolerance and Animal-handling Effects2005In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 32, no 5-6, p. 835-859Article in journal (Refereed)
    Abstract [en]

    This study presents development and behaviour of a feedback turnover model that mimics asymmetric circadian oscillations of body temperature, blood pressure and heart rate in rats.The study also includes an application to drug-induced hypothermia, tolerance and handling effects. Data were collected inn normotensive Sprague-Dawley rats, housed at 25 degrees C with a 12:12 hr light dark cycle (light on at 06:00 am) and with free access of food and water. The model consisted of two intertwined parallel compartments which captured a free-running rhythm with a period close to but not exactly 24 hrs. The free-running rhythm was synchronised to exactly 24 hrs by the environmental timekeeper (12:12 hr light on/off cycle) in experimental settings. The baseline model was fitted to a standardised 24-hr period derived from mean data of six animals over a period of nine consecutive days. The first-order rate constants related to the turnover of the baseline temperature, alpha and beta, were 0.026 min(-1) (+/-5%) and 0.0037 min(-1) (+/-3%). The alpha and beta parameters are approximately 2/transition time between day and night and 2/night time, respectively. The day:night timekeeper g(t), reference point T(ref) and amplitude were 0.053(+/-2%),37.3(+/-0.02%) and 3.3% (+/-2%), respectively. Simulations with the baseline model revealed stable oscillations (free-running rhythm) in the absence of the timekeeper. This temperature-time profile was then symmetric and had a smaller amplitude, with a slightly shorter period and less pronounced temperature shift as compared to the profile in the presence of an external Timekeeper. Fitting the model to 96 hr mean profiles of blood pressure and heart rate from 10 control animals demonstrated the usefulness of the model.Simulations of the integrated temperature model succeeded in mimicking other modes of administration such as oral dosing.

  • 16. Visser, Sandra A. G.
    et al.
    Sällström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Forsberg, Tomas
    Peletier, Lambertus A.
    Gabrielsson, Johan
    Modeling drug- and system-related changes in body temperature: application to clomethiazole-induced hypothermia, long-lasting tolerance development, and circadian rhythm in rats2006In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 317, no 1, p. 209-219Article in journal (Refereed)
    Abstract [en]

    The aim of the present investigation was to develop a pharmacokinetic-pharmacodynamic model for the characterization of clomethiazole (CMZ)-induced hypothermia and the rapid development of long-lasting tolerance in rats while taking into account circadian rhythm in baseline and the influence of handling. CMZ-induced hypothermia and tolerance was measured using body temperature telemetry in male Sprague-Dawley rats, which were given s.c. bolus injections of 0, 15, 150, 300, and 600 micromol kg(-1) and 24-h s.c. continuous infusions of 0, 20, and 40 micromol kg(-1) h(-1) using osmotic pumps. The duration of tolerance was studied by repeated injections of 300 micromol kg(-1) at 3- to 32-day intervals. Plasma exposure to CMZ was obtained in satellite groups of catheterized rats. Fitted population concentration-time profiles served as input for the pharmacodynamic analysis. The asymmetric circadian rhythm in baseline body temperature was successfully described by a novel negative feedback model incorporating external light-dark conditions. An empirical function characterized the transient increase in temperature upon handling of the animal. A feedback model for temperature regulation and tolerance development allowed estimation of CMZ potency at 30 +/- 1 microM. The delay in onset of tolerance was estimated via a series of four transit compartments at 7.6 +/- 2 h. The long-lasting tolerance was assumed to be caused by inactivation of a mediator with an estimated turnover time of 46 +/- 3 days. This multicomponent turnover model was able to quantify the CMZ-induced hypothermia, circadian rhythm in baseline, and rapid onset of a long-lasting tolerance to CMZ in rats.

  • 17. Wang, Jing
    et al.
    Ding, Jihua
    Tan, Biyue
    Robinson, Kathryn M.
    Michelson, Ingrid H.
    Johansson, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nystedt, Björn
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Scofield, Douglas G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Nilsson, Ove
    Jansson, Stefan
    Street, Nathaniel R.
    Ingvarsson, Pär K.
    A major locus controls local adaptation and adaptive life history variation in a perennial plant2018In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 19, article id 72Article in journal (Refereed)
  • 18.
    Zhu, Yafeng
    et al.
    Karolinska Inst, Sci Life Lab, Dept Oncol Pathol, S-17121 Solna, Sweden..
    Engstrom, Par G.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, S-17121 Solna, Sweden..
    Tellgren-Roth, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Baudo, Charles D.
    St Louis Univ, Dept Biol, St Louis, MO 63103 USA..
    Kennell, John C.
    St Louis Univ, Dept Biol, St Louis, MO 63103 USA..
    Sun, Sheng
    Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA..
    Billmyre, R. Blake
    Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA..
    Schroder, Markus S.
    Univ Coll Dublin, Conway Inst, Sch Biomed & Biomol Sci, Dublin 4, Ireland..
    Andersson, Anna
    Karolinska Inst, Dept Med Solna, Translat Immunol Unit, S-17177 Stockholm, Sweden.;Univ Hosp, Stockholm, Sweden..
    Holm, Tina
    Karolinska Inst, Dept Med Solna, Translat Immunol Unit, S-17177 Stockholm, Sweden.;Univ Hosp, Stockholm, Sweden..
    Sigurgeirsson, Benjamin
    Royal Inst Technol, Sci Life Lab, Sch Biotechnol, S-17121 Solna, Sweden..
    Wu, Guangxi
    ASTAR, Comp & Syst Biol Genome Inst Singapore, Singapore 138672, Singapore..
    Sankaranarayanan, Sundar Ram
    Jawaharlal Nehru Ctr Adv Sci Res, Mol Mycol Lab, Mol Biol & Genet Unit, Bangalore 560064, Karnataka, India..
    Siddharthan, Rahul
    Inst Math Sci HBNI, Chennai 600113, Tamil Nadu, India..
    Sanyal, Kaustuv
    Jawaharlal Nehru Ctr Adv Sci Res, Mol Mycol Lab, Mol Biol & Genet Unit, Bangalore 560064, Karnataka, India..
    Lundeberg, Joakim
    Royal Inst Technol, Sci Life Lab, Sch Biotechnol, S-17121 Solna, Sweden..
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Boekhout, Teun
    CBS Fungal Biodivers Ctr, Utrecht, Netherlands.;Univ Amsterdam, IBED, NL-1012 WL Amsterdam, Netherlands..
    Dawson, Thomas L., Jr.
    ASTAR, Inst Med Biol, Singapore 138648, Singapore..
    Heitman, Joseph
    Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA..
    Scheynius, Annika
    Karolinska Inst, Sci Life Lab, Dept Clin Sci & Educ, SE-11883 Stockholm, Sweden.;Sachs Children & Youth Hosp, SE-11883 Stockholm, Sweden..
    Lehtio, Janne
    Karolinska Inst, Sci Life Lab, Dept Oncol Pathol, S-17121 Solna, Sweden..
    Proteogenomics produces comprehensive and highly accurate protein-coding gene annotation in a complete genome assembly of Malassezia sympodialis2017In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 5, p. 2629-2643Article in journal (Refereed)
    Abstract [en]

    Complete and accurate genome assembly and annotation is a crucial foundation for comparative and functional genomics. Despite this, few complete eukaryotic genomes are available, and genome annotation remains a major challenge. Here, we present a complete genome assembly of the skin commensal yeast Malassezia sympodialis and demonstrate how proteogenomics can substantially improve gene an-notation. Through long-read DNA sequencing, we obtained a gap-free genome assembly for M. sympodi-alis (ATCC 42132), comprising eight nuclear and one mitochondrial chromosome. We also sequenced and assembled four M. sympodialis clinical isolates, and showed their value for understanding Malassezia reproduction by confirming four alternative allele combinations at the two mating-type loci. Importantly, we demonstrated how proteomics data could be readily integrated with transcriptomics data in standard annotation tools. This increased the number of annotated protein-coding genes by 14% (from 3612 to 4113), compared to using transcriptomics evidence alone. Manual curation further increased the number of protein-coding genes by 9% (to 4493). All of these genes have RNA-seq evidence and 87% were confirmed by proteomics. The M. sympodialis genome assembly and annotation presented here is at a quality yet achieved only for a few eukaryotic organisms, and constitutes an important reference for future host-microbe interaction studies.

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