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  • 51.
    Eklund, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Lindås, Ann-Christin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Molecular Evolution.
    Hamnevik, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Widersten, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Inter-species variation in the pH dependence of tripeptidyl-peptidase IIManuscript (preprint) (Other academic)
    Abstract [en]

    Tripeptidyl-peptidase II (TPP II) is a large enzyme complex (>4 MDa) participating in the general protein turn-over in the cell downstream of the proteasome. In addition, there have been reports of involvement of TPP II in different physiological situations. To facilitate further investigations of the physiological role of TPP II and its enzymatic properties, a characterization at protein level is necessary. Therefore, an expression system for murine TPP II using Escherichia coli has been developed. The pH-optimum for cleavage of two different chromogenic substrates, Ala-Ala-Phe-pNA and Ala-Ala-Ala-pNA, was investigated for mTPP II, and compared with human TPP II and TPP II from Drosophila melanogaster. It was shown that the mouse enzyme had similar pH dependence as the human enzyme, while dTPP II had a slightly lower optimum. Surprisingly, the investigation also demonstrated that TPP II from all sources showed a different pH-profile for hydrolysis of AAA-pNA compared to AAF-pNA. To investigate this observation further, steady-state kinetic parameters were determined at various pH. Since both the KM and Vmax are lower for cleavage of AAA-pNA, a potential explanation could be that the substrate AAA-pNA is non-productively bound to the active site of the enzyme.

  • 52.
    Ellegaard, Kirsten M.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Tamarit, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Javelind, Emelie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Olofsson, Tobias C.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Vasquez, Alejandra
    Extensive intra-phylotype diversity in lactobacilli and bifidobacteria from the honeybee gut2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 284Article in journal (Refereed)
    Abstract [en]

    Background: In the honeybee Apis mellifera, the bacterial gut community is consistently colonized by eight distinct phylotypes of bacteria. Managed bee colonies are of considerable economic interest and it is therefore important to elucidate the diversity and role of this microbiota in the honeybee. In this study, we have sequenced the genomes of eleven strains of lactobacilli and bifidobacteria isolated from the honey crop of the honeybee Apis mellifera. Results: Single gene phylogenies confirmed that the isolated strains represent the diversity of lactobacilli and bifidobacteria in the gut, as previously identified by 16S rRNA gene sequencing. Core genome phylogenies of the lactobacilli and bifidobacteria further indicated extensive divergence between strains classified as the same phylotype. Phylotype-specific protein families included unique surface proteins. Within phylotypes, we found a remarkably high level of gene content diversity. Carbohydrate metabolism and transport functions contributed up to 45% of the accessory genes, with some genomes having a higher content of genes encoding phosphotransferase systems for the uptake of carbohydrates than any previously sequenced genome. These genes were often located in highly variable genomic segments that also contained genes for enzymes involved in the degradation and modification of sugar residues. Strain-specific gene clusters for the biosynthesis of exopolysaccharides were identified in two phylotypes. The dynamics of these segments contrasted with low recombination frequencies and conserved gene order structures for the core genes. Hits for CRISPR spacers were almost exclusively found within phylotypes, suggesting that the phylotypes are associated with distinct phage populations. Conclusions: The honeybee gut microbiota has been described as consisting of a modest number of phylotypes; however, the genomes sequenced in the current study demonstrated a very high level of gene content diversity within all three described phylotypes of lactobacilli and bifidobacteria, particularly in terms of metabolic functions and surface structures, where many features were strain-specific. Together, these results indicate niche differentiation within phylotypes, suggesting that the honeybee gut microbiota is more complex than previously thought.

  • 53.
    Ellegaard, Kirsten Maren
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Genome Evolution and Niche Differentiation of Bacterial Endosymbionts2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Most animals contain chronic microbial infections that inflict no harm on their hosts. Recently, the gut microflora of humans and other animals have been characterized. However, little is known about the forces that shape the diversity of these bacterial communities. In this work, comparative genomics was used to investigate the evolutionary dynamics of host-adapted bacterial communities, using Wolbachia infecting arthropods and Lactobacteria infecting bees as the main model systems.

    Wolbachia are maternally inherited bacteria that cause reproductive disorders in arthropods, such as feminization, male killing and parthenogenesis. These bacteria are difficult to study because they cannot be cultivated outside their hosts. We have developed a novel protocol employing multiple displacement amplification to isolate and sequence their genomes. Taxonomically, Wolbachia is classified into different supergroups. We have sequenced the genomes of Wolbachia strain wHa and wNo that belong to supergroup A and B, respectively, and are present as a double-infection in the fruit-fly Drosophila simulans. Together with previously published genomes, a supergroup comparison of strains belonging to supergroups A and B indicated rampant homologous recombination between strains that belong to the same supergroup but were isolated from different hosts. In contrast, we observed little recombination between strains of different supergroups that infect the same host.

    Likewise, phylogenetically distinct members of Lactic acid bacteria co-exist in the gut of the honeybee, Apis mellifera, without transfer of genes between phylotypes. Nor did we find any evidence of co-diversification between symbionts and hosts, as inferred from a study of 13 genomes of Lactobacillus kunkeei isolated from diverse bee species and different geographic origins. Although Lactobacillus kunkeii is the most frequently isolated strain from the honey stomach, we hypothesize that the primary niche is the beebread where the bacteria are likely to contribute to the fermentation process.

    In the human gut, the microbial community has been shown to interact with the immune system, and likewise the microbial communities associated with insects are thought to affect the health of their host. Therefore, a better understanding of the role and evolution of endosymbiotic communities is important for developing strategies to control the health of their hosts.

    List of papers
    1. Comparative Genomics of Wolbachia and the Bacterial Species Concept
    Open this publication in new window or tab >>Comparative Genomics of Wolbachia and the Bacterial Species Concept
    Show others...
    2013 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 4, p. e1003381-Article in journal (Refereed) Published
    Abstract [en]

    The importance of host-specialization to speciation processes in obligate host-associated bacteria is well known, as is also the ability of recombination to generate cohesion in bacterial populations. However, whether divergent strains of highly recombining intracellular bacteria, such as Wolbachia, can maintain their genetic distinctness when infecting the same host is not known. We first developed a protocol for the genome sequencing of uncultivable endosymbionts. Using this method, we have sequenced the complete genomes of the Wolbachia strains wHa and wNo, which occur as natural double infections in Drosophila simulans populations on the Seychelles and in New Caledonia. Taxonomically, wHa belong to supergroup A and wNo to supergroup B. A comparative genomics study including additional strains supported the supergroup classification scheme and revealed 24 and 33 group-specific genes, putatively involved in host-adaptation processes. Recombination frequencies were high for strains of the same supergroup despite different host-preference patterns, leading to genomic cohesion. The inferred recombination fragments for strains of different supergroups were of short sizes, and the genomes of the co-infecting Wolbachia strains wHa and wNo were not more similar to each other and did not share more genes than other A- and B-group strains that infect different hosts. We conclude that Wolbachia strains of supergroup A and B represent genetically distinct clades, and that strains of different supergroups can co-exist in the same arthropod host without converging into the same species. This suggests that the supergroups are irreversibly separated and that barriers other than host-specialization are able to maintain distinct clades in recombining endosymbiont populations. Acquiring a good knowledge of the barriers to genetic exchange in Wolbachia will advance our understanding of how endosymbiont communities are constructed from vertically and horizontally transmitted genes.

    National Category
    Genetics
    Identifiers
    urn:nbn:se:uu:diva-200821 (URN)10.1371/journal.pgen.1003381 (DOI)000318073300004 ()
    Available from: 2013-06-04 Created: 2013-06-04 Last updated: 2017-12-06Bibliographically approved
    2. Testing the Reproducibility of Multiple Displacement Amplification on Genomes of Clonal Endosymbiont Populations
    Open this publication in new window or tab >>Testing the Reproducibility of Multiple Displacement Amplification on Genomes of Clonal Endosymbiont Populations
    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e82319-Article in journal (Refereed) Published
    Abstract [en]

    The multiple displacement amplification method has revolutionized genomic studies of uncultured bacteria, where the extraction of pure DNA in sufficient quantity for next-generation sequencing is challenging. However, the method is problematic in that it amplifies the target DNA unevenly, induces the formation of chimeric reads and also amplifies contaminating DNA. Here, we have tested the reproducibility of the multiple displacement amplification method using serial dilutions of extracted genomic DNA and intact cells from the cultured endosymbiont Bartonella australis. The amplified DNA was sequenced with the Illumina sequencing technology, and the results were compared to sequence data obtained from unamplified DNA in this study as well as from a previously published genome project. We show that artifacts such as the extent of the amplification bias, the percentage of chimeric reads and the relative fraction of contaminating DNA increase dramatically for the smallest amounts of template DNA. The pattern of read coverage was reproducibly obtained for samples with higher amounts of template DNA, suggesting that the bias is non-random and genome-specific. A re-analysis of previously published sequence data obtained after amplification from clonal endosymbiont populations confirmed these predictions. We conclude that many of the artifacts associated with the use of the multiple displacement amplification method can be alleviated or much reduced by using multiple cells as the template for the amplification. These findings should be particularly useful for researchers studying the genomes of endosymbionts and other uncultured bacteria, for which a small clonal population of cells can be isolated.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-214040 (URN)10.1371/journal.pone.0082319 (DOI)000327652100111 ()
    Available from: 2014-01-07 Created: 2014-01-07 Last updated: 2017-12-06Bibliographically approved
    3. Extensive intra-phylotype diversity in lactobacilli and bifidobacteria from the honeybee gut
    Open this publication in new window or tab >>Extensive intra-phylotype diversity in lactobacilli and bifidobacteria from the honeybee gut
    Show others...
    2015 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 284Article in journal (Refereed) Published
    Abstract [en]

    Background: In the honeybee Apis mellifera, the bacterial gut community is consistently colonized by eight distinct phylotypes of bacteria. Managed bee colonies are of considerable economic interest and it is therefore important to elucidate the diversity and role of this microbiota in the honeybee. In this study, we have sequenced the genomes of eleven strains of lactobacilli and bifidobacteria isolated from the honey crop of the honeybee Apis mellifera. Results: Single gene phylogenies confirmed that the isolated strains represent the diversity of lactobacilli and bifidobacteria in the gut, as previously identified by 16S rRNA gene sequencing. Core genome phylogenies of the lactobacilli and bifidobacteria further indicated extensive divergence between strains classified as the same phylotype. Phylotype-specific protein families included unique surface proteins. Within phylotypes, we found a remarkably high level of gene content diversity. Carbohydrate metabolism and transport functions contributed up to 45% of the accessory genes, with some genomes having a higher content of genes encoding phosphotransferase systems for the uptake of carbohydrates than any previously sequenced genome. These genes were often located in highly variable genomic segments that also contained genes for enzymes involved in the degradation and modification of sugar residues. Strain-specific gene clusters for the biosynthesis of exopolysaccharides were identified in two phylotypes. The dynamics of these segments contrasted with low recombination frequencies and conserved gene order structures for the core genes. Hits for CRISPR spacers were almost exclusively found within phylotypes, suggesting that the phylotypes are associated with distinct phage populations. Conclusions: The honeybee gut microbiota has been described as consisting of a modest number of phylotypes; however, the genomes sequenced in the current study demonstrated a very high level of gene content diversity within all three described phylotypes of lactobacilli and bifidobacteria, particularly in terms of metabolic functions and surface structures, where many features were strain-specific. Together, these results indicate niche differentiation within phylotypes, suggesting that the honeybee gut microbiota is more complex than previously thought.

    Keywords
    Lactic acid bacteria, Lactobacillus spp, Firmicutes, Bifidobacteria, Comparative genomics, Phosphotransferase systems, Niche specialization
    National Category
    Genetics
    Identifiers
    urn:nbn:se:uu:diva-256855 (URN)10.1186/s12864-015-1476-6 (DOI)000355302300001 ()25880915 (PubMedID)
    External cooperation:
    Note

    De två förstaförfattarna delar förstaförfattarskapet.

    Available from: 2015-06-26 Created: 2015-06-26 Last updated: 2017-12-04Bibliographically approved
    4. Comparative Genomics of Lactobacillus kunkeii indicates Selection for Rapid Growth in the Beebread
    Open this publication in new window or tab >>Comparative Genomics of Lactobacillus kunkeii indicates Selection for Rapid Growth in the Beebread
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Evolutionary Biology
    Research subject
    Biology with specialization in Molecular Evolution
    Identifiers
    urn:nbn:se:uu:diva-217720 (URN)
    Available from: 2014-02-04 Created: 2014-02-04 Last updated: 2014-04-29
  • 54.
    Ellegaard, Kirsten Maren
    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.
    Klasson, Lisa
    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.
    Testing the Reproducibility of Multiple Displacement Amplification on Genomes of Clonal Endosymbiont Populations2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e82319-Article in journal (Refereed)
    Abstract [en]

    The multiple displacement amplification method has revolutionized genomic studies of uncultured bacteria, where the extraction of pure DNA in sufficient quantity for next-generation sequencing is challenging. However, the method is problematic in that it amplifies the target DNA unevenly, induces the formation of chimeric reads and also amplifies contaminating DNA. Here, we have tested the reproducibility of the multiple displacement amplification method using serial dilutions of extracted genomic DNA and intact cells from the cultured endosymbiont Bartonella australis. The amplified DNA was sequenced with the Illumina sequencing technology, and the results were compared to sequence data obtained from unamplified DNA in this study as well as from a previously published genome project. We show that artifacts such as the extent of the amplification bias, the percentage of chimeric reads and the relative fraction of contaminating DNA increase dramatically for the smallest amounts of template DNA. The pattern of read coverage was reproducibly obtained for samples with higher amounts of template DNA, suggesting that the bias is non-random and genome-specific. A re-analysis of previously published sequence data obtained after amplification from clonal endosymbiont populations confirmed these predictions. We conclude that many of the artifacts associated with the use of the multiple displacement amplification method can be alleviated or much reduced by using multiple cells as the template for the amplification. These findings should be particularly useful for researchers studying the genomes of endosymbionts and other uncultured bacteria, for which a small clonal population of cells can be isolated.

  • 55.
    Ellegaard, Kirsten Maren
    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.
    Klasson, Lisa
    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.
    Bourtzis, Kostas
    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.
    Comparative Genomics of Wolbachia and the Bacterial Species Concept2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 4, p. e1003381-Article in journal (Refereed)
    Abstract [en]

    The importance of host-specialization to speciation processes in obligate host-associated bacteria is well known, as is also the ability of recombination to generate cohesion in bacterial populations. However, whether divergent strains of highly recombining intracellular bacteria, such as Wolbachia, can maintain their genetic distinctness when infecting the same host is not known. We first developed a protocol for the genome sequencing of uncultivable endosymbionts. Using this method, we have sequenced the complete genomes of the Wolbachia strains wHa and wNo, which occur as natural double infections in Drosophila simulans populations on the Seychelles and in New Caledonia. Taxonomically, wHa belong to supergroup A and wNo to supergroup B. A comparative genomics study including additional strains supported the supergroup classification scheme and revealed 24 and 33 group-specific genes, putatively involved in host-adaptation processes. Recombination frequencies were high for strains of the same supergroup despite different host-preference patterns, leading to genomic cohesion. The inferred recombination fragments for strains of different supergroups were of short sizes, and the genomes of the co-infecting Wolbachia strains wHa and wNo were not more similar to each other and did not share more genes than other A- and B-group strains that infect different hosts. We conclude that Wolbachia strains of supergroup A and B represent genetically distinct clades, and that strains of different supergroups can co-exist in the same arthropod host without converging into the same species. This suggests that the supergroups are irreversibly separated and that barriers other than host-specialization are able to maintain distinct clades in recombining endosymbiont populations. Acquiring a good knowledge of the barriers to genetic exchange in Wolbachia will advance our understanding of how endosymbiont communities are constructed from vertically and horizontally transmitted genes.

  • 56.
    Eme, Laura
    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.
    Ettema, Thijs J. G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The eukaryotic ancestor shapes up2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 562, no 7727, p. 352-354Article in journal (Other academic)
    Abstract [en]

    Asgard archaea are the closest known relatives of nucleus-bearing organisms called eukaryotes. A study indicates that these archaea have a dynamic network of actin protein - a trait thought of as eukaryote-specific.

  • 57.
    Eme, Laura
    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.
    Spang, Anja
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lombard, Jonathan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stairs, Courtney W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ettema, Thijs J. G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Archaea and the origin of eukaryotes2017In: Nature Reviews Microbiology, ISSN 1740-1526, E-ISSN 1740-1534, Vol. 15, no 12, p. 711-723Article, review/survey (Refereed)
    Abstract [en]

    Woese and Fox's 1977 paper on the discovery of the Archaea triggered a revolution in the field of evolutionary biology by showing that life was divided into not only prokaryotes and eukaryotes. Rather, they revealed that prokaryotes comprise two distinct types of organisms, the Bacteria and the Archaea. In subsequent years, molecular phylogenetic analyses indicated that eukaryotes and the Archaea represent sister groups in the tree of life. During the genomic era, it became evident that eukaryotic cells possess a mixture of archaeal and bacterial features in addition to eukaryotic-specific features. Although it has been generally accepted for some time that mitochondria descend from endosymbiotic alphaproteobacteria, the precise evolutionary relationship between eukaryotes and archaea has continued to be a subject of debate. In this Review, we outline a brief history of the changing shape of the tree of life and examine how the recent discovery of a myriad of diverse archaeal lineages has changed our understanding of the evolutionary relationships between the three domains of life and the origin of eukaryotes. Furthermore, we revisit central questions regarding the process of eukaryogenesis and discuss what can currently be inferred about the evolutionary transition from the first to the last eukaryotic common ancestor.

  • 58.
    Ettema, Thijs
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Andersson, Siv
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Comment on "A 3-hydroxypropionate/4-hydroxybutyrate autotrophic carbon dioxide assimilation pathway in Archaea"2008In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 321, no 5887, p. 342-Article in journal (Refereed)
    Abstract [en]

    Berg et al. (Reports, 14 December 2007, p. 1782) reported the discovery of an autotrophic carbon dioxide-fixation pathway in Archaea and implicated a substantial role of this pathway in global carbon cycling based on sequence analysis of Global Ocean Sampling data. We question the validity of the latter claim.

  • 59.
    Ettema, Thijs J. G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mitochondria in the second act2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 531, no 7592, p. 39-40Article in journal (Other academic)
    Abstract [en]

    A large phylogenomics study reveals that the symbiotic event that led to the emergence of organelles known as mitochondria may have occurred later in the evolution of complex cells than was thought.

  • 60.
    Ettema, Thijs J. G.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Lindas, Ann-Christin
    Hjort, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Poplawski, Andrzej B.
    Kaessmann, Henrik
    Grogan, Dennis W.
    Kelman, Zvi
    Andersson, Anders F.
    Pelve, Erik A.
    Lundgren, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Rolf Bernander (1956-2014): pioneer of the archaeal cell cycle Obituary2014In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 92, no 5, p. 903-909Article in journal (Refereed)
    Abstract [en]

    On 19 January 2014 Rolf (Roffe') Bernander passed away unexpectedly. Rolf was a dedicated scientist; his research aimed at unravelling the cell biology of the archaeal domain of life, especially cell cycle-related questions, but he also made important contributions in other areas of microbiology. Rolf had a professor position in the Molecular Evolution programme at Uppsala University, Sweden for about 8 years, and in January 2013 he became chair professor at the Department of Molecular Biosciences, The Wenner-Gren Institute at Stockholm University in Sweden. Rolf was an exceptional colleague and will be deeply missed by his family and friends, and the colleagues and co-workers that he leaves behind in the scientific community. He will be remembered for his endless enthusiasm for science, his analytical mind, and his quirky sense of humour.

  • 61.
    Ettema, Thijs J. G.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Molecular Evolution.
    Lindås, Ann-Christin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Molecular Evolution.
    Bernander, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Molecular Evolution.
    An actin-based cytoskeleton in archaea2011In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 80, no 4, p. 1052-1061Article in journal (Refereed)
    Abstract [en]

    In eukaryotic and bacterial cells, spatial organization is dependent upon cytoskeletal filaments. Actin is a main eukaryotic cytoskeletal element, involved in key processes such as cell shape determination, mechanical force generation and cytokinesis. We describe an archaeal cytoskeleton which forms helical structures within Pyrobaculum calidifontis cells, as shown by in situ immunostaining. The core components include an archaeal actin homologue, Crenactin, closely related to the eukaryotic counterpart. The crenactin gene belongs to a conserved gene cluster denoted Arcade (actin-related cytoskeleton in Archaea involved in shape determination). The phylogenetic distribution of arcade genes is restricted to the crenarchaeal Thermoproteales lineage, and to Korarchaeota, and correlates with rod-shaped and filamentous cell morphologies. Whereas Arcadin-1, -3 and -4 form helical structures, suggesting cytoskeleton-associated functions, Arcadin-2 was found to be localized between segregated nucleoids in a cell subpopulation, in agreement with possible involvement in cytokinesis. The results support a crenarchaeal origin of the eukaryotic actin cytoskeleton and, as such, have implications for theories concerning the origin of the eukaryotic cell.

  • 62.
    Ettema, Thijs
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Rolf, Bernander
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Cell division and the ESCRT complex: A surprise from the archaea2009In: Communicative & Integrative Biology, ISSN 1942-0889, E-ISSN 1942-0889, Vol. 2, no 2, p. 86-88Article in journal (Refereed)
    Abstract [en]

    The Archaea constitute the third domain of life, a separate evolutionary lineage together with the Bacteria and the Eukarya.1 Species belonging to the Archaea contain a surprising mix of bacterial (metabolism, life style, genomic organization) and eukaryotic (replication, transcription, translation) features.2 The archaeal kingdom comprises two main phyla, the Crenarchaeota and the Euryarchaeota. Regarding the cell division process in archaeal species (reviewed in ref. 3), members of the Euryarchaeota rely on an FtsZ-based cell division mechanism4 whereas, previously, no division genes had been detected in the crenarchaea. However, we recently reported the discovery of the elusive cell division machinery in crenarchaea from the genus Sulfolobus.5 The minimal machinery consists of three genes, which we designated cdvA, B and C (for cell division), organized into an operon that is widely conserved among crenarchaea. The gene products polymerize between segregating nucleoids at the early mitotic stage, forming a complex that remains associated with the leading edge of constriction throughout cytokinesis. Interestingly, CdvB and CdvC were shown to be related to the eukaryotic ESCRT-III protein sorting machinery (reviewed in ref. 6), indicating shared common ancestry and mechanistic similarities to endosomal vesicle formation and viral (HIV) budding in eukaryotes. We also demonstrated that the cdv operon is subject to checkpoint-like regulation, and that the genes display a complementary phylogenetic distribution within the Archaea domain relative to FtsZ-dependent division systems.5 Here, the findings are further explored and discussed, and topics for further investigation are suggested.

  • 63.
    Fange, David
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Berg, Otto G
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Sjöberg, Paul
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stochastic reaction-diffusion kinetics in the microscopic limit2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 46, p. 19820-19825Article in journal (Refereed)
    Abstract [en]

    Quantitative analysis of biochemical networks often requires consideration of both spatial and stochastic aspects of chemical processes. Despite significant progress in the field, it is still computationally prohibitive to simulate systems involving many reactants or complex geometries using a microscopic framework that includes the finest length and time scales of diffusion-limited molecular interactions. For this reason, spatially or temporally discretized simulations schemes are commonly used when modeling intracellular reaction networks. The challenge in defining such coarse-grained models is to calculate the correct probabilities of reaction given the microscopic parameters and the uncertainty in the molecular positions introduced by the spatial or temporal discretization. In this paper we have solved this problem for the spatially discretized Reaction-Diffusion Master Equation; this enables a seamless and physically consistent transition from the microscopic to the macroscopic frameworks of reaction-diffusion kinetics. We exemplify the use of the methods by showing that a phosphorylation-dephosphorylation motif, commonly observed in eukaryotic signaling pathways, is predicted to display fluctuations that depend on the geometry of the system.

     

     

  • 64.
    Franceschini, Nora
    et al.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27516 USA.
    Giambartolomei, Claudia
    Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA.
    de Vries, Paul S.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA.
    Finan, Chris
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.
    Huntley, Rachael P.
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    Lovering, Ruth C.
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    Tajuddin, Salman M.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA.
    Winkler, Thomas W.
    Univ Regensburg, Dept Genet Epidemiol, D-93053 Regensburg, Germany.
    Graff, Misa
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27516 USA.
    Kavousi, Maryam
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands.
    Dale, Caroline
    UCL, Inst Hlth Informat, London WC1E 6BT, England.
    Smith, Albert V.
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland;Univ Iceland, IS-101 Reykjavik, Iceland.
    Hofer, Edith
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, A-8036 Graz, Austria;Med Univ Graz, Inst Med Informat Stat & Documentat, A-8036 Graz, Austria.
    van Leeuwen, Elisabeth M.
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands.
    Nolte, Ilja M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-3015 Groningen, Netherlands.
    Lu, Lingyi
    Wake Forest Univ, Bowman Gray Sch Med, Dept Biostatist Sci, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA.
    Scholz, Markus
    Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04107 Leipzig, Germany;Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany.
    Sargurupremraj, Muralidharan
    Univ Bordeaux, INSERM, CHU Bordeaux, Bordeaux Populat Hlth Res Ctr,UMR 1219, F-33000 Bordeaux, France.
    Pitkanen, Niina
    Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland.
    Franzen, Oscar
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA;Clin Gene Networks AB, S-10462 Stockholm, Sweden.
    Joshi, Peter K.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland.
    Noordam, Raymond
    Leiden Univ, Med Ctr, Sect Gerontol & Geriatr, Dept Internal Med, NL-2300 RC Leiden, Netherlands.
    Marioni, Riccardo E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland;Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH4 2XU, Midlothian, Scotland.
    Hwang, Shih-Jen
    NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Framingham, MA 01702 USA;NHLBI, Intramural Res Program, Framingham Heart Study, Framingham, MA 01702 USA.
    Musani, Solomon K.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA.
    Schminke, Ulf
    Univ Med Greifswald, Dept Neurol, D-17475 Greifswald, Germany.
    Palmas, Walter
    Columbia Univ, Dept Med, New York, NY 10032 USA.
    Isaacs, Aaron
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Maastricht Univ, CARIM Sch Cardiovasc Dis, Maastricht Ctr Syst Biol MaCSBio, Dept Biochem, NL-6229 Maastricht, Netherlands.
    Correa, Adolfo
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA.
    Zonderman, Alan B.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA.
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany.
    Cox, Amanda J.
    Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC 25157 USA;Griffith Univ, Menzies Hlth Inst Queensland, Southport, Qld 4222, Australia.
    Uitterlinden, Andre G.
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Univ Med Ctr Rotterdam, Erasmus Med Ctr, Dept Internal Med, NL-3015 Rotterdam, Netherlands.
    Wong, Andrew
    UCL, MRC Unit Lifelong Hlth & Ageing, London WC1E 6BT, England.
    Smit, Andries J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Med, NL-2300 Groningen, Netherlands.
    Newman, Anne B.
    Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA;Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA 15213 USA.
    Britton, Annie
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England.
    Ruusalepp, Arno
    Clin Gene Networks AB, S-10462 Stockholm, Sweden;Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, EE-51010 Tartu, Estonia;Tartu Univ Hosp, Dept Cardiac Surg, EE-51010 Tartu, Estonia.
    Sennblad, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, S-17177 Stockholm, Sweden.
    Hedblad, Bo
    Lund Univ, Dept Clin Sci Malmo, SE-20502 Malmo, Sweden.
    Pasaniuc, Bogdan
    Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA;Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA.
    Penninx, Brenda W.
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci Campus Amste, Department Psychiat, NL-1081 HL Amsterdam, Netherlands.
    Langefeld, Carl D.
    Wake Forest Univ, Bowman Gray Sch Med, Dept Biostatist Sci, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA.
    Wassel, Christina L.
    Premier Inc, Appl Sci, Charlotte, NC 28277 USA.
    Tzourio, Christophe
    Univ Bordeaux, INSERM, CHU Bordeaux, Bordeaux Populat Hlth Res Ctr,UMR 1219, F-33000 Bordeaux, France.
    Fava, Cristiano
    Lund Univ, Dept Clin Sci Malmo, SE-20502 Malmo, Sweden;Univ Verona, Dept Med, I-37134 Verona, Italy.
    Baldassarre, Damiano
    Univ Milan, Dept Med Biotechnol & Translat Med, I-20133 Milan, Italy;IRCCS, Ctr Cardiol Monzino, I-20138 Milan, Italy.
    O'Leary, Daniel H.
    Tufts Univ, Sch Med, St Elizabeths Med Ctr, Boston, MA 02135 USA.
    Teupser, Daniel
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany;LMU, Univ Hosp Munich, Inst Lab Med, D-80539 Munich, Germany.
    Kuh, Diana
    UCL, MRC Unit Lifelong Hlth & Ageing, London WC1E 6BT, England.
    Tremoli, Elena
    IRCCS, Ctr Cardiol Monzino, I-20138 Milan, Italy;Univ Milan, Dipartimento Sci Farmacol Biomol, I-20133 Milan, Italy.
    Mannarino, Elmo
    Univ Perugia, Internal Med Angiol & Arteriosclerosis Dis, Dept Clin & Expt Med, I-06123 Perugia, Italy.
    Grossi, Enzo
    Ctr Diagnost Italiano, I-20147 Milan, Italy.
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.
    Schadt, Eric E.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA;Clin Gene Networks AB, S-10462 Stockholm, Sweden.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94309 USA;Stanford Univ, Stanford Cardiovasc Inst, G1120, Stanford, CA USA.
    Veglia, Fabrizio
    IRCCS, Ctr Cardiol Monzino, I-20138 Milan, Italy.
    Rivadeneira, Fernando
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Univ Med Ctr Rotterdam, Erasmus Med Ctr, Dept Internal Med, NL-3015 Rotterdam, Netherlands.
    Beutner, Frank
    Heart Ctr Leipzig, D-04103 Leipzig, Germany.
    Chauhan, Ganesh
    Univ Bordeaux, INSERM, CHU Bordeaux, Bordeaux Populat Hlth Res Ctr,UMR 1219, F-33000 Bordeaux, France;Indian Inst Sci, Ctr Brain Res, Bangalore 560012, Karnataka, India.
    Heiss, Gerardo
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27516 USA.
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-3015 Groningen, Netherlands.
    Campbell, Harry
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland.
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany.
    Markus, Hugh S.
    Univ Cambridge, Dept Clin Neurosci, Stroke Res Grp, Cambridge CB2 0QQ, England.
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland.
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands.
    de Graaf, Jacqueline
    Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands.
    Price, Jacqueline
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland.
    Pott, Janne
    Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04107 Leipzig, Germany;Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany.
    Hopewell, Jemma C.
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford OX3 7LF, England;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford OX3 7LF, England.
    Liang, Jingjing
    Case Western Reserve Univ, Sch Med, Dept Populat & Quantitat Hlth Sci, Cleveland, OH 44106 USA.
    Thiery, Joachim
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany;Univ Leipzig, Inst Lab Med, D-04109 Leipzig, Germany.
    Engmann, Jorgen
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    Gertow, Karl
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, S-17177 Stockholm, Sweden.
    Rice, Kenneth
    Univ Washington, Dept Biostat, Seattle, WA 98105 USA.
    Taylor, Kent D.
    Univ Calif Los Angeles, Los Angeles Biomed Res Inst Harbor, Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.
    Dhana, Klodian
    Rush Univ, Med Ctr, Dept Internal Med, Chicago, IL 60612 USA.
    Kiemeney, Lambertus A. L. M.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 GA Nijmegen, Netherlands.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Raffield, Laura M.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27516 USA.
    Launer, Lenore J.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA.
    Holdt, Lesca M.
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany;LMU, Univ Hosp Munich, Inst Lab Med, D-80539 Munich, Germany.
    Doer, Marcus
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany;Univ Med Greifswald, Dept Internal Med B, D-17475 Greifswald, Germany.
    Dichgans, Martin
    LMU, Univ Hosp, Inst Stroke & Dementia Res ISD, D-80539 Munich, Germany;Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany.
    Traylor, Matthew
    Univ Cambridge, Dept Clin Neurosci, Stroke Res Grp, Cambridge CB2 0QQ, England.
    Sitzer, Matthias
    Goethe Univ Frankfurt, Ctr Neurol & Neurosurg, Dept Neurol, D-60323 Frankfurt, Germany.
    Kumari, Meena
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England;Essex Univ, Inst Social & Econ Res, Colchester CO4 3SQ, Essex, England.
    Kivimaki, Mika
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England.
    Nalls, Mike A.
    NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA;Data Tecn Int, Glen Echo, MD 20812 USA.
    Melander, Olle
    Lund Univ, Dept Clin Sci Malmo, SE-20502 Malmo, Sweden.
    Raitakari, Olli
    Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland;Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland.
    Franco, Oscar H.
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Univ Bern, ISPM, CH-3012 Bern, Switzerland.
    Rueda-Ochoa, Oscar L.
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Univ Ind Santander, Sch Med, Electrocardiog Res Grp, Santander 680003, Colombia.
    Roussos, Panos
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA;James J Peters VA Med Ctr, MIRECC, Bronx, NY 10468 USA.
    Whincup, Peter H.
    St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England.
    Amouyel, Philippe
    INSERM, U1167, F-59000 Lille, France;Inst Pasteur, U1167, F-59000 Lille, France;Univ Lille, U1167, RID AGE, F-59000 Lille, France;CHU Lille, U1167, F-59000 Lille, France.
    Giral, Philippe
    Sorbonne Univ, Pitie Salpetriere Hosp, Cardiovasc Prevent Unit, F-75013 Paris, France.
    Anugu, Pramod
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA.
    Wong, Quenna
    Univ Washington, Dept Biostat, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA.
    Malik, Rainer
    LMU, Univ Hosp, Inst Stroke & Dementia Res ISD, D-80539 Munich, Germany.
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Fdn Res Hlth Exercise & Nutr, Kuopio 70100, Finland;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland.
    Burkhardt, Ralph
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany;Univ Leipzig, Inst Lab Med, D-04109 Leipzig, Germany;Univ Hosp Regensburg, Inst Clin Chem & Lab Med, D-93053 Regensburg, Germany.
    Hardy, Rebecca
    UCL, MRC Unit Lifelong Hlth & Ageing, London WC1E 6BT, England.
    Schmidt, Reinhold
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, A-8036 Graz, Austria.
    de Mutsert, Renee
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2333 Leiden, Netherlands.
    Morris, Richard W.
    Univ Bristol, Bristol Med Sch, Dept Populat Hlth Sci, Bristol BS8 1QU, Avon, England.
    Strawbridge, Rona J.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, S-17177 Stockholm, Sweden;Univ Glasgow, Inst Hlth & Wellbeing, Mental Hlth & Wellbeing, Glasgow G12 0XH, Lanark, Scotland.
    Wannamethee, S. Goya
    UCL, Dept Primary Care & Populat Hlth, London WC1E 6BT, England.
    Hagg, Sara
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden.
    Shah, Sonia
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    McLachlan, Stela
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland.
    Trompet, Stella
    Leiden Univ, Med Ctr, Sect Gerontol & Geriatr, Dept Internal Med, NL-2300 RC Leiden, Netherlands;Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands.
    Seshadri, Sudha
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.
    Kurl, Sudhir
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio Campus, FI-70210 Kuopio, Finland.
    Heckbert, Susan R.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA;Kaiser Permanente Washington Hlth Res Inst, Seattle, WA 98101 USA.
    Ring, Susan
    Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol BS8 1QU, Avon, England;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 1TH, Avon, England.
    Harris, Tamara B.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA.
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere 33014, Finland;Univ Tampere, Sch Med, Dept Clin Chem, Tampere 33014, Finland.
    Galesloot, Tessel E.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 GA Nijmegen, Netherlands.
    Shah, Tina
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, Dept Cardiol, S-17177 Stockholm, Sweden.
    Plagnol, Vincent
    UCL, Genet Inst, London WC1E 6BT, England.
    Rosamond, Wayne D.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27516 USA.
    Post, Wendy
    Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA;Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21205 USA.
    Zhu, Xiaofeng
    Case Western Reserve Univ, Sch Med, Dept Populat & Quantitat Hlth Sci, Cleveland, OH 44106 USA.
    Zhang, Xiaoling
    NHLBI, Intramural Res Program, Framingham Heart Study, Framingham, MA 01702 USA;Boston Univ, Sch Med, Sect Biomed Genet, Boston, MA 02215 USA.
    Guo, Xiuqing
    Univ Calif Los Angeles, Los Angeles Biomed Res Inst Harbor, Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA;Univ Calif Los Angeles, Los Angeles Biomed Res Inst Harbor, Dept Pediat, Med Ctr, Torrance, CA 90502 USA.
    Saba, Yasaman
    Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, A-8010 Graz, Austria.
    Dehghan, Abbas
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Imperial Coll London, Dept Epidemiol & Biostat, London SW7 2AZ, England.
    Seldenrijk, Adrie
    Univ Amsterdam, Med Ctr, Dept Psychiat, GGZ inGeest & Amsterdam Publ Hlth Res Inst, NL-1081 HV Amsterdam, Netherlands.
    Morrison, Alanna C.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA.
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, S-17177 Stockholm, Sweden.
    Psaty, Bruce M.
    Kaiser Permanente Washington Hlth Res Inst, Seattle, WA 98101 USA;Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA;Univ Washington, Dept Med, Seattle, WA 98195 USA;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA.
    van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford OX3 7LF, England;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford OX3 7LF, England.
    Lawlor, Deborah A.
    Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol BS8 1QU, Avon, England;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 1TH, Avon, England.
    Mook-Kanamori, Dennis O.
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2333 Leiden, Netherlands;Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, NL-2333 ZA Leiden, Netherlands.
    Bowden, Donald W.
    Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Gen, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA.
    Schmidt, Helena
    Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, A-8010 Graz, Austria.
    Wilson, James F.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland;Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland.
    Wilson, James G.
    Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA.
    Rotter, Jerome I.
    Univ Calif Los Angeles, Los Angeles Biomed Res Inst Harbor, Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA;Univ Calif Los Angeles, Los Angeles Biomed Res Inst Harbor, Dept Pediat, Med Ctr, Torrance, CA 90502 USA.
    Wardlaw, Joanna M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland;Univ Edinburgh, UK Dementia Res Inst, Edinburgh EH16 4SB, Midlothian, Scotland.
    Deanfield, John
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    Halcox, Julian
    Swansea Univ, Med Sch, Swansea SA2 8PP, W Glam, Wales.
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere 33014, Finland;Univ Tampere, Sch Med, Dept Clin Chem, Tampere 33014, Finland.
    Loeffler, Markus
    Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04107 Leipzig, Germany;Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany.
    Evans, Michele K.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA.
    Debette, Stephanie
    Univ Bordeaux, INSERM, CHU Bordeaux, Bordeaux Populat Hlth Res Ctr,UMR 1219, F-33000 Bordeaux, France.
    Humphries, Steve E.
    UCL, Inst Cardiovasc Sci, Crt Cardiovasc Genet, London WC1E 6BT, England.
    Voelker, Uwe
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany;Univ Med Greifswald, Interfac Inst Genet & Funct Gen, D-17475 Greifswald, Germany.
    Gudnason, Vilmundur
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland;Univ Iceland, IS-101 Reykjavik, Iceland.
    Hingorani, Aroon D.
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    Bjorkegren, Johan L. M.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA;Clin Gene Networks AB, S-10462 Stockholm, Sweden;Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, EE-51010 Tartu, Estonia;Karolinska Univ Sjukhuset, Karolinska Inst, Dept Med, Integrated Cardio Metab Ctr, SE-14157 Huddinge, Sweden.
    Casas, Juan P.
    UCL, Inst Hlth Informat, London WC1E 6BT, England.
    O'Donnell, Christopher J.
    NHLBI, Intramural Adm Management Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Boston Vet Adm Healthcare, Cardiol Sect, Boston, MA 02130 USA;Harvard Med Sch, Boston, MA 02115 USA.
    GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 5141Article in journal (Refereed)
    Abstract [en]

    Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

  • 65.
    Franco, Irene
    et al.
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, S-14157 Huddinge, Sweden..
    Johansson, Anna C. V.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Olsson, Karl
    Karolinska Inst, Dept Lab Med, Div Clin Physiol, S-14186 Huddinge, Sweden..
    Vrtacnik, Peter
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, S-14157 Huddinge, Sweden..
    Lundin, Par
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, S-14157 Huddinge, Sweden.;Stockholm Univ, DBB, Sci Life Lab, S-10691 Stockholm, Sweden..
    Helgadottir, Hafdis T.
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, S-14157 Huddinge, Sweden..
    Larsson, Malin
    Linkoping Univ, Dept Phys Chem & Biol, Sci Life Lab, S-58183 Linkoping, Sweden..
    Revechon, Gwladys
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, S-14157 Huddinge, Sweden..
    Bosia, Carla
    IIGM, I-10126 Turin, Italy.;Politecn Torino, Dept Appl Sci & Technol, I-10129 Turin, Italy..
    Pagnani, Andrea
    IIGM, I-10126 Turin, Italy.;Politecn Torino, Dept Appl Sci & Technol, I-10129 Turin, Italy..
    Provero, Paolo
    Mol Biotechnol Ctr, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy.;Ist Sci San Raffaele, Ctr Translat Genom & Bioinformat, I-20132 Milan, Italy..
    Gustafsson, Thomas
    Fischer, Helene
    Eriksson, Maria
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, S-14157 Huddinge, Sweden..
    Somatic mutagenesis in satellite cells associates with human skeletal muscle aging2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 800Article in journal (Refereed)
    Abstract [en]

    Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21-78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function.

  • 66.
    Fu, Cheng-Jie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Sheikh, Sanea
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Miao, Wei
    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.
    Baldauf, Sandra L.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Missing Genes, Multiple ORFs, and C-to-U Type RNA Editing in Acrasis kona (Heterolobosea, Excavata) Mitochondrial DNA2014In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 6, no 9, p. 2240-2257Article in journal (Refereed)
    Abstract [en]

    Discoba (Excavata) is an ancient group of eukaryotes with great morphological and ecological diversity. Unlike the other major divisions of Discoba (Jakobida and Euglenozoa), little is known about the mitochondrial DNAs(mtDNAs) of Heterolobosea. We have assembled a complete mtDNA genome from the aggregating heterolobosean amoeba, Acrasis kona, which consists of a single circular highly AT-rich (83.3%) molecule of 51.5 kb. Unexpectedly, A. kona mtDNA is missing roughly 40% of the protein-coding genes and nearly half of the transfer RNAs found in the only other sequenced heterolobosean mtDNAs, those of Naegleria spp. Instead, over a quarter of A. kona mtDNA consists of novel open reading frames. Eleven of the 16 protein-coding genes missing from A. kona mtDNA were identified in its nuclear DNA and polyA RNA, and phylogenetic analyses indicate that at least 10 of these 11 putative nuclear-encoded mitochondrial (NcMt) proteins arose by direct transfer from the mitochondrion. Acrasis kona mtDNA also employs C-to-U type RNA editing, and 12 homologs of DYW-type pentatricopeptide repeat (PPR) proteins implicated in plant organellar RNA editing are found in A. kona nuclear DNA. A mapping of mitochondrial gene content onto a consensus phylogeny reveals a sporadic pattern of relative stasis and rampant gene loss in Discoba. Rampant loss occurred independently in the unique common lineage leading to Heterolobosea + Tsukubamonadida and later in the unique lineage leading to Acrasis. Meanwhile, mtDNA gene content appears to be remarkably stable in the Acrasis sister lineage leading to Naegleria and in their distant relatives Jakobida.

  • 67.
    Garcia, Sarahi L
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab. University of Wisconsin-Madison, Madison, USA.
    Stevens, Sarah L R
    University of Wisconsin-Madison, Madison, USA.
    Crary, Benjamin
    University of Wisconsin-Madison, Madison, USA.
    Martinez-Garcia, Manuel
    University of Alicante, Alicante, Spain.
    Stepanauskas, Ramunas
    Bigelow Laboratory for Ocean Sciences, East Boothbay, USA.
    Woyke, Tanja
    DOE Joint Genome Institute, Walnut Creek, USA.
    Tringe, Susannah G
    DOE Joint Genome Institute, Walnut Creek, USA.
    Andersson, Siv G E
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Bertilsson, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Malmstrom, Rex R
    DOE Joint Genome Institute, Walnut Creek, USA.
    McMahon, Katherine D
    University of Wisconsin-Madison, Madison, USA.
    Contrasting patterns of genome-level diversity across distinct co-occurring bacterial populations2018In: The ISME Journal, ISSN 1751-7362, E-ISSN 1751-7370, Vol. 12, no 3, p. 742-755Article in journal (Refereed)
    Abstract [en]

    To understand the forces driving differentiation and diversification in wild bacterial populations, we must be able to delineate and track ecologically relevant units through space and time. Mapping metagenomic sequences to reference genomes derived from the same environment can reveal genetic heterogeneity within populations, and in some cases, be used to identify boundaries between genetically similar, but ecologically distinct, populations. Here we examine population-level heterogeneity within abundant and ubiquitous freshwater bacterial groups such as the acI Actinobacteria and LD12 Alphaproteobacteria (the freshwater sister clade to the marine SAR11) using 33 single-cell genomes and a 5-year metagenomic time series. The single-cell genomes grouped into 15 monophyletic clusters (termed "tribes") that share at least 97.9% 16S rRNA identity. Distinct populations were identified within most tribes based on the patterns of metagenomic read recruitments to single-cell genomes representing these tribes. Genetically distinct populations within tribes of the acI Actinobacterial lineage living in the same lake had different seasonal abundance patterns, suggesting these populations were also ecologically distinct. In contrast, sympatric LD12 populations were less genetically differentiated. This suggests that within one lake, some freshwater lineages harbor genetically discrete (but still closely related) and ecologically distinct populations, while other lineages are composed of less differentiated populations with overlapping niches. Our results point at an interplay of evolutionary and ecological forces acting on these communities that can be observed in real time.

  • 68.
    Garcia-Pichel, Ferran
    et al.
    Arizona State Univ, Sch Life Sci, Tempe, AZ 85287 USA;Arizona State Univ, Biodesign Inst, Ctr Fundamental & Appl Microbi, Tempe, AZ 85287 USA.
    Lombard, Jonathan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Soule, Tanya
    Purdue Univ, Dept Biol, Ft Wayne, IN USA.
    Dunaj, Sean
    Purdue Univ, Dept Biol, Ft Wayne, IN USA.
    Wu, Steven H.
    Arizona State Univ, Biodesign Inst, Ctr Personalized Diagnost, Tempe, AZ USA;BioConsortia Inc, Davis, CA USA.
    Wojciechowski, Martin F.
    Arizona State Univ, Sch Life Sci, Tempe, AZ 85287 USA.
    Timing the Evolutionary Advent of Cyanobacteria and the Later Great Oxidation Event Using Gene Phylogenies of a Sunscreen2019In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 10, no 3, article id e00561-19Article in journal (Refereed)
    Abstract [en]

    The biosynthesis of the unique cyanobacterial (oxyphotobacterial) indole-phenolic UVA sunscreen, scytonemin, is coded for in a conserved operon that contains both core metabolic genes and accessory, aromatic amino acid biosynthesis genes dedicated to supplying scytonemin's precursors. Comparative genomics shows conservation of this operon in many, but not all, cyanobacterial lineages. Phylogenetic analyses of the operon's aromatic amino acid genes indicate that five of them were recruited into the operon after duplication events of their respective house-keeping cyanobacterial cognates. We combined the fossil record of cyanobacteria and relaxed molecular clock models to obtain multiple estimates of these duplication events, setting a minimum age for the evolutionary advent of scytonemin at 2.1 +/- 0.3 billion years. The same analyses were used to estimate the advent of cyanobacteria as a group (and thus the appearance of oxygenic photosynthesis), at 3.6 +/- 0.2 billion years before present. Post hoc interpretation of 16S rRNA-based Bayesian analyses was consistent with these estimates. Because of physiological constraints on the use of UVA sunscreens in general, and the biochemical constraints of scytonemin in particular, scytonemin's age must postdate the time when Earth's atmosphere turned oxic, known as the Great Oxidation Event (GOE). Indeed, our biological estimate is in agreement with independent geochemical estimates for the GOE. The difference between the estimated ages of oxygenic photosynthesis and the GOE indicates the long span (on the order of a billion years) of the era of "oxygen oases," when oxygen was available locally but not globally. IMPORTANCE The advent of cyanobacteria, with their invention of oxygenic photosynthesis, and the Great Oxidation Event are arguably among the most important events in the evolutionary history of life on Earth. Oxygen is a significant toxicant to all life, but its accumulation in the atmosphere also enabled the successful development and proliferation of many aerobic organisms, especially metazoans. The currently favored dating of the Great Oxidation Event is based on the geochemical rock record. Similarly, the advent of cyanobacteria is also often drawn from the same estimates because in older rocks paleontological evidence is scarce or has been discredited. Efforts to obtain molecular evolutionary alternatives have offered widely divergent estimates. Our analyses provide a novel means to circumvent these limitations and allow us to estimate the large time gap between the two events.

  • 69.
    Gentekaki, Eleni
    et al.
    Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS, Canada.;Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Halifax, NS, Canada.;Mae Fah Luang Univ, Sch Sci, Chiang Rai, Thailand.;Mae Fah Luang Univ, Human Gut Microbiome Hlth Res Unit, Chiang Rai, Thailand..
    Curtis, Bruce A.
    Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS, Canada.;Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Halifax, NS, Canada..
    Stairs, Courtney W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS, Canada.;Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Halifax, NS, Canada..
    Klimes, Vladimir
    Univ Ostrava, Dept Biol & Ecol, Fac Sci, Ostrava, Czech Republic..
    Elias, Marek
    Univ Ostrava, Dept Biol & Ecol, Fac Sci, Ostrava, Czech Republic..
    Salas-Leiva, Dayana E.
    Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS, Canada.;Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Halifax, NS, Canada..
    Herman, Emily K.
    Univ Alberta, Dept Cell Biol, Edmonton, AB, Canada..
    Eme, Laura
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS, Canada.;Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Halifax, NS, Canada..
    Arias, Maria C.
    Univ Sci & Technol Lille, Unite Glycobiol Struct & Fonct, CNRS, UMR8576,Cite Sci, Villeneuve Dascq, France..
    Henrissat, Bernard
    Aix Marseille Univ, CNRS, UMR 7257, Marseille, France.;NRA, USC 1408, AFMB, Marseille, France.;King Abdulaziz Univ, Dept Biol Sci, Jeddah, Saudi Arabia..
    Hilliou, Frederique
    Univ Cote Azur, NRA, ISA, Sophia Antipolis, France..
    Klute, Mary J.
    Univ Alberta, Dept Cell Biol, Edmonton, AB, Canada..
    Suga, Hiroshi
    Prefectural Univ Hiroshima, Fac Life & Environm Sci, Nanatsuka 562, Shobara, Hiroshima, Japan..
    Malik, Shehre-Banoo
    Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS, Canada.;Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Halifax, NS, Canada..
    Pightling, Arthur W.
    Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS, Canada.;US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA..
    Kolisko, Martin
    Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS, Canada.;Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Halifax, NS, Canada.;Czech Acad Sci, Inst Parasitol, Ctr Biol, Ceske Budejovice, Czech Republic..
    Rachubinski, Richard A.
    Schlacht, Alexander
    Soanes, Darren M.
    Univ Exeter, Coll Life & Environm Sci, Exeter, Devon, England..
    Tsaousis, Anastasios D.
    Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS, Canada.;Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Halifax, NS, Canada.;Univ Kent, Lab Mol & Evolutionary Parasitol, RAPID Grp, Sch Biosci, Canterbury, Kent, England..
    Archibald, John M.
    Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS, Canada.;Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Halifax, NS, Canada.;Canadian Inst Adv Res, CIFAR Program Integrated Microbial Biodivers, Toronto, ON, Canada..
    Ball, Steven G.
    Dacks, Joel B.
    Univ Alberta, Dept Cell Biol, Edmonton, AB, Canada..
    Clark, C. Graham
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England..
    van der Giezen, Mark
    Univ Exeter, Biosci, Exeter, Devon, England..
    Roger, Andrew J.
    Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS, Canada.;Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Halifax, NS, Canada.;Canadian Inst Adv Res, CIFAR Program Integrated Microbial Biodivers, Toronto, ON, Canada..
    Extreme genome diversity in the hyper-prevalent parasitic eukaryote Blastocystis2017In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 15, no 9, article id e2003769Article in journal (Refereed)
    Abstract [en]

    Blastocystis is the most prevalent eukaryotic microbe colonizing the human gut, infecting approximately 1 billion individuals worldwide. Although Blastocystis has been linked to intestinal disorders, its pathogenicity remains controversial because most carriers are asymptomatic. Here, the genome sequence of Blastocystis subtype (ST) 1 is presented and compared to previously published sequences for ST4 and ST7. Despite a conserved core of genes, there is unexpected diversity between these STs in terms of their genome sizes, guanine-cytosine (GC) content, intron numbers, and gene content. ST1 has 6,544 protein-coding genes, which is several hundred more than reported for ST4 and ST7. The percentage of proteins unique to each ST ranges from 6.2% to 20.5%, greatly exceeding the differences observed within parasite genera. Orthologous proteins also display extreme divergence in amino acid sequence identity between STs (i.e., 59%-61% median identity), on par with observations of the most distantly related species pairs of parasite genera. The STs also display substantial variation in gene family distributions and sizes, especially for protein kinase and protease gene families, which could reflect differences in virulence. It remains to be seen to what extent these inter-ST differences persist at the intra-ST level. A full 26% of genes in ST1 have stop codons that are created on the mRNA level by a novel polyadenylation mechanism found only in Blastocystis. Reconstructions of pathways and organellar systems revealed that ST1 has a relatively complete membrane-trafficking system and a near-complete meiotic toolkit, possibly indicating a sexual cycle. Unlike some intestinal protistan parasites, Blastocystis ST1 has near-complete de novo pyrimidine, purine, and thiamine biosynthesis pathways and is unique amongst studied stramenopiles in being able to metabolize alpha-glucans rather than beta-glucans. It lacks all genes encoding heme-containing cytochrome P450 proteins. Predictions of the mitochondrion-related organelle (MRO) proteome reveal an expanded repertoire of functions, including lipid, cofactor, and vitamin biosynthesis, as well as proteins that may be involved in regulating mitochondrial morphology and MRO/endoplasmic reticulum (ER) interactions. In sharp contrast, genes for peroxisome-associated functions are absent, suggesting Blastocystis STs lack this organelle. Overall, this study provides an important window into the biology of Blastocystis, showcasing significant differences between STs that can guide future experimental investigations into differences in their virulence and clarifying the roles of these organisms in gut health and disease.

  • 70. Gerardo, Nicole M
    et al.
    Altincicek, Boran
    Anselme, Caroline
    Atamian, Hagop
    Barribeau, Seth M
    de Vos, Martin
    Duncan, Elizabeth J
    Evans, Jay D
    Gabaldón, Toni
    Ghanim, Murad
    Heddi, Adelaziz
    Kaloshian, Isgouhi
    Latorre, Amparo
    Moya, Andres
    Nakabachi, Atsushi
    Parker, Benjamin J
    Pérez-Brocal, Vincente
    Pignatelli, Miguel
    Rahbé, Yvan
    Ramsey, John S
    Spragg, Chelsea J
    Tamames, Javier
    Tamarit, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Tamborindeguy, Cecilia
    Vincent-Monegat, Caroline
    Vilcinskas, Andreas
    Immunity and other defenses in pea aphids, Acyrthosiphon pisum.2010In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 11, no 2Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Recent genomic analyses of arthropod defense mechanisms suggest conservation of key elements underlying responses to pathogens, parasites and stresses. At the center of pathogen-induced immune responses are signaling pathways triggered by the recognition of fungal, bacterial and viral signatures. These pathways result in the production of response molecules, such as antimicrobial peptides and lysozymes, which degrade or destroy invaders. Using the recently sequenced genome of the pea aphid (Acyrthosiphon pisum), we conducted the first extensive annotation of the immune and stress gene repertoire of a hemipterous insect, which is phylogenetically distantly related to previously characterized insects models.

    RESULTS: Strikingly, pea aphids appear to be missing genes present in insect genomes characterized to date and thought critical for recognition, signaling and killing of microbes. In line with results of gene annotation, experimental analyses designed to characterize immune response through the isolation of RNA transcripts and proteins from immune-challenged pea aphids uncovered few immune-related products. Gene expression studies, however, indicated some expression of immune and stress-related genes.

    CONCLUSIONS: The absence of genes suspected to be essential for the insect immune response suggests that the traditional view of insect immunity may not be as broadly applicable as once thought. The limitations of the aphid immune system may be representative of a broad range of insects, or may be aphid specific. We suggest that several aspects of the aphid life style, such as their association with microbial symbionts, could facilitate survival without strong immune protection.

  • 71.
    Giacomello, Stefania
    et al.
    Stockholm Univ, Dept Biochemestry & Biophys, Stockholm, Sweden; SciLifeLab, Royal Inst Technol, Dept Gene Technol, Stockholm, Sweden.
    Asp, Michaela
    SciLifeLab, Royal Inst Technol, Dept Gene Technol, Stockholm, Sweden.
    Wärdell, Eva
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Reimegård, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Salmén, Fredrik
    SciLifeLab, Royal Inst Technol, Dept Gene Technol, Stockholm, Sweden.
    Grinnemo, Karl-Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Månsson-Broberg, Agneta
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Corbascio, Cecilia Österholm
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Sylvén, Christer
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Ståhl, Patrik
    SciLifeLab, Royal Inst Technol, Dept Gene Technol, Stockholm, Sweden.
    Corbascio, Matthias
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Lundeberg, Joakim
    SciLifeLab, Royal Inst Technol, Dept Gene Technol, Stockholm, Sweden.
    New insights into the human heart development using a combined spatial and single-cell transcriptomics approach2018In: HUMAN GENOMICS, ISSN 1473-9542, Vol. 12, no Suppl 1, p. 50-51Article in journal (Other academic)
  • 72.
    Giacomello, Stefania
    et al.
    KTH Royal Inst Technol, Sch Biotechnol, Div Gene Technol, Sci Life Lab, S-17165 Solna, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, S-17165 Solna, Sweden..
    Salmen, Fredrik
    Terebieniec, Barbara K.
    Umea Univ, Dept Plant Physiol, Umea Plant Sci Ctr, S-90736 Umea, Sweden..
    Vickovic, Sanja
    Navarro, Jose Fernandez
    Karolinska Inst, Dept Cell & Mol Biol, S-17165 Solna, Sweden..
    Alexeyenko, Andrey
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, S-17165 Solna, Sweden.;Sci Life Lab, Natl Bioinformat Infrastruct Sweden, S-17121 Solna, Sweden..
    Reimegård, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    McKee, Lauren S.
    KTH Royal Inst Technol, AlbaNova Univ Ctr, Sch Biotechnol, Div Glycosci, S-11421 Stockholm, Sweden..
    Mannapperuma, Chanaka
    Umea Univ, Dept Plant Physiol, Umea Plant Sci Ctr, S-90736 Umea, Sweden..
    Bulone, Vincent
    KTH Royal Inst Technol, AlbaNova Univ Ctr, Sch Biotechnol, Div Glycosci, S-11421 Stockholm, Sweden.;Univ Adelaide, ARC Ctr Excellence Plant & Cell Walls, Waite Campus, Adelaide, SA 5064, Australia.;Univ Adelaide, Sch Agr Food & Wine, Waite Campus, Adelaide, SA 5064, Australia..
    Stahl, Patrik L.
    Karolinska Inst, Dept Cell & Mol Biol, S-17165 Solna, Sweden..
    Sundstrom, Jens F.
    Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala BioCtr, Dept Plant Biol, S-75007 Uppsala, Sweden..
    Street, Nathaniel R.
    Umea Univ, Dept Plant Physiol, Umea Plant Sci Ctr, S-90736 Umea, Sweden..
    Lundeberg, Joakim
    KTH Royal Inst Technol, Sch Biotechnol, Div Gene Technol, Sci Life Lab, S-17165 Solna, Sweden..
    Spatially resolved transcriptome profiling in model plant species2017In: NATURE PLANTS, ISSN 2055-026X, Vol. 3, no 6, article id 17061Article in journal (Refereed)
    Abstract [en]

    Understanding complex biological systems requires functional characterization of specialized tissue domains. However, existing strategies for generating and analysing high-throughput spatial expression profiles were developed for a limited range of organisms, primarily mammals. Here we present the first available approach to generate and study highresolution, spatially resolved functional profiles in a broad range of model plant systems. Our process includes highthroughput spatial transcriptome profiling followed by spatial gene and pathway analyses. We first demonstrate the feasibility of the technique by generating spatial transcriptome profiles from model angiosperms and gymnosperms microsections. In Arabidopsis thaliana we use the spatial data to identify differences in expression levels of 141 genes and 189 pathways in eight inflorescence tissue domains. Our combined approach of spatial transcriptomics and functional profiling offers a powerful new strategy that can be applied to a broad range of plant species, and is an approach that will be pivotal to answering fundamental questions in developmental and evolutionary biology.

  • 73.
    Gomez-Velazquez, Melisa
    et al.
    CNIC, Madrid, Spain..
    Badia-Careaga, Claudio
    CNIC, Madrid, Spain..
    Victoria Lechuga-Vieco, Ana
    CNIC, Madrid, Spain..
    Nieto-Arellano, Rocio
    CNIC, Madrid, Spain..
    Tena, Juan J.
    Univ Pablo de Olavide Junta de Andalucia, CSIC, CABD, Seville, Spain..
    Rollan, Isabel
    CNIC, Madrid, Spain..
    Alvarez, Alba
    CNIC, Madrid, Spain..
    Torroja, Carlos
    CNIC, Madrid, Spain..
    Caceres, Eva F.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab. CNIC, Madrid, Spain..
    Roy, Anna
    Hosp Sick Children, Translat Med, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Galjart, Niels
    Erasmus MC, Dept Cell Biol & Genet, Rotterdam, Netherlands..
    Delgado-Olguin, Paul
    Hosp Sick Children, Translat Med, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.;Heart & Stroke Richard Lewar Ctr Excellence, Toronto, ON, Canada..
    Sanchez-Cabo, Fatima
    CNIC, Madrid, Spain..
    Antonio Enriquez, Jose
    CNIC, Madrid, Spain..
    Luis Gomez-Skarmeta, Jose
    Univ Pablo de Olavide Junta de Andalucia, CSIC, CABD, Seville, Spain..
    Manzanares, Miguel
    CNIC, Madrid, Spain..
    CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 8, article id e1006985Article in journal (Refereed)
    Abstract [en]

    Cardiac progenitors are specified early in development and progressively differentiate and mature into fully functional cardiomyocytes. This process is controlled by an extensively studied transcriptional program. However, the regulatory events coordinating the progression of such program from development to maturation are largely unknown. Here, we show that the genome organizer CTCF is essential for cardiogenesis and that it mediates genomic interactions to coordinate cardiomyocyte differentiation and maturation in the developing heart. Inactivation of Ctcf in cardiac progenitor cells and their derivatives in vivo during development caused severe cardiac defects and death at embryonic day 12.5. Genome wide expression analysis in Ctcf mutant hearts revealed that genes controlling mitochondrial function and protein production, required for cardiomyocyte maturation, were upregulated. However, mitochondria from mutant cardiomyocytes do not mature properly. In contrast, multiple development regulatory genes near predicted heart enhancers, including genes in the IrxA cluster, were downregulated in Ctcf mutants, suggesting that CTCF promotes cardiomyocyte differentiation by facilitating enhancer-promoter interactions. Accordingly, loss of CTCF disrupts gene expression and chromatin interactions as shown by chromatin conformation capture followed by deep sequencing. Furthermore, CRISPR-mediated deletion of an intergenic CTCF site within the IrxA cluster alters gene expression in the developing heart. Thus, CTCF mediates local regulatory interactions to coordinate transcriptional programs controlling transitions in morphology and function during heart development.

  • 74. Gottlieb, Yuval
    et al.
    Lalzar, Itai
    Klasson, Lisa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Distinctive Genome Reduction Rates Revealed by Genomic Analyses of Two Coxiella-Like Endosymbionts in Ticks2015In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 7, no 6, p. 1779-1796Article in journal (Refereed)
    Abstract [en]

    Genome reduction is a hallmark of symbiotic genomes, and the rate and patterns of gene loss associated with this process have been investigated in several different symbiotic systems. However, in long-term host-associated coevolving symbiont clades, the genome size differences between strains are normally quite small and hence patterns of large-scale genome reduction can only be inferred from distant relatives. Here we present the complete genome of a Coxiella-like symbiont from Rhipicephalus turanicus ticks (CRt), and compare it with other genomes from the genus Coxiella in order to investigate the process of genome reduction in a genus consisting of intracellular host-associated bacteria with variable genome sizes. The 1.7-Mb CRt genome is larger than the genomes of most obligate mutualists but has a very low protein-coding content (48.5%) and an extremely high number of identifiable pseudogenes, indicating that it is currently undergoing genome reduction. Analysis of encoded functions suggests that CRt is an obligate tick mutualist, as indicated by the possible provisioning of the tick with biotin (B7), riboflavin (B2) and other cofactors, and by the loss of most genes involved in host cell interactions, such as secretion systems. Comparative analyses between CRt and the 2.5 times smaller genome of Coxiella from the lonestar tick Amblyomma americanum (CLEAA) show that many of the same gene functions are lost and suggest that the large size difference might be due to a higher rate of genome evolution in CLEAA generated by the loss of the mismatch repair genes mutSL. Finally, sequence polymorphisms in the CRt population sampled from field collected ticks reveal up to one distinct strain variant per tick, and analyses of mutational patterns within the population suggest that selection might be acting on synonymous sites. The CRt genome is an extreme example of a symbiont genome caught in the act of genome reduction, and the comparison between CLEAA and CRt indicates that losses of particular genes early on in this process can potentially greatly influence the speed of this process.

  • 75.
    Grabherr, Manfred
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala Univ, Natl Bioinformat Infrastruct Sweden, S-75236 Uppsala, Sweden.
    Kaminska, Bozena
    Polish Acad Sci, Nencki Inst Expt Biol, PL-02093 Warsaw, Poland;Guangzhou Med Univ, Affiliated Canc Hosp & Inst, Guangzhou 510095, Guangdong, Peoples R China.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Polish Acad Sci, Inst Comp Sci, PL-02093 Warsaw, Poland.
    Special Issue Introduction: The Wonders and Mysteries Next Generation Sequencing Technologies Help Reveal2018In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 9, no 10, article id 505Article in journal (Other academic)
  • 76. Grogan, Dennis W
    et al.
    Ozarzak, Melissa A
    Bernander, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Molecular Evolution.
    Variation in gene content among geographically diverse Sulfolobus isolates2008In: Environmental Microbiology, ISSN 1462-2912, E-ISSN 1462-2920, Vol. 10, no 1, p. 137-146Article in journal (Refereed)
    Abstract [en]

    The ability of competitive (i.e., comparative) genomic hybridization (CGH) to assess similarity across entire microbial genomes suggests that it should reveal diversification within and between natural populations of free-living prokaryotes. We used CGH to measure relatedness of genomes drawn from Sulfolobus populations that had been shown in a previous study to be diversified along geographical lines. Eight isolates representing a wide range of spatial separation were compared with respect to gene-specific tags based on a closely related reference strain (Sulfolobus solfataricus P2). For the purpose of assessing genetic divergence, 232 loci identified as polymorphic were assigned one of two alleles based on the corresponding fluorescence intensities from the arrays. Clustering of these binary genotypes was stable with respect to changes in the threshold and similarity criteria, and most of the groupings were consistent with an isolation-by-distance model of diversification. These results indicate that increasing spatial separation of geothermal sites correlates not only with minor sequence polymorphisms in conserved genes of Sulfolobus (demonstrated in the previous study), but also with the regions of difference (RDs) that occur between genomes of conspecifics. In view of the abundance of RDs in prokaryotic genomes and the relevance that some RDs may have for ecological adaptation, the results further suggest that CGH on microarrays may have advantages for investigating patterns of diversification in other free-living archaea and bacteria.

  • 77.
    Gullberg, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cao, Sha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berg, Otto G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Ilbäck, Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Selection of Resistant Bacteria at Very Low Antibiotic Concentrations2011In: PLoS pathogens, ISSN 1553-7366, Vol. 7, no 7, p. e1002158-Article in journal (Refereed)
    Abstract [en]

    The widespread use of antibiotics is selecting for a variety of resistance mechanisms that seriously challenge our ability to treat bacterial infections. Resistant bacteria can be selected at the high concentrations of antibiotics used therapeutically, but what role the much lower antibiotic concentrations present in many environments plays in selection remains largely unclear. Here we show using highly sensitive competition experiments that selection of resistant bacteria occurs at extremely low antibiotic concentrations. Thus, for three clinically important antibiotics, drug concentrations up to several hundred-fold below the minimal inhibitory concentration of susceptible bacteria could enrich for resistant bacteria, even when present at a very low initial fraction. We also show that de novo mutants can be selected at sub-MIC concentrations of antibiotics, and we provide a mathematical model predicting how rapidly such mutants would take over in a susceptible population. These results add another dimension to the evolution of resistance and suggest that the low antibiotic concentrations found in many natural environments are important for enrichment and maintenance of resistance in bacterial populations.

  • 78.
    Guy, Lionel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Ettema, Thijs J. G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    The archaeal ‘TACK’ superphylum and the origin of eukaryotes2011In: Trends in Microbiology, ISSN 0966-842X, E-ISSN 1878-4380, Vol. 19, no 12, p. 580-587Article, review/survey (Refereed)
    Abstract [en]

    Although most hypotheses to explain the emergence of the eukaryotic lineage are conflicting, some consensus exists concerning the requirement of a genomic fusion between archaeal and bacterial components. Recent phylogenomic studies have provided support for eocyte-like scenarios in which the alleged ‘archaeal parent’ of the eukaryotic cell emerged from the Crenarchaeota/Thaumarchaeota. Here, we provide evidence for a scenario in which this archaeal parent emerged from within the ‘TACK’ superphylum that comprises the Thaumarchaeota, Crenarchaeota and Korarchaeota, as well as the recently proposed phylum ‘Aigarchaeota’. In support of this view, functional and comparative genomics studies have unearthed an increasing number of features that are uniquely shared by the TACK superphylum and eukaryotes, including proteins involved in cytokinesis, membrane remodeling, cell shape determination and protein recycling.

  • 79.
    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.
    Jernberg, Cecilia
    Ivarsson, Sofie
    Hedenstrom, Ingela
    Engstrand, Lars
    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.
    Genomic diversity of the 2011 European outbreaks of Escherichia coli O104:H42012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 52, p. E3627-E3628Article in journal (Refereed)
  • 80.
    Guy, Lionel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Jernberg, Cecilia
    Norling, Jenny Arven
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Ivarsson, Sofie
    Hedenstrom, Ingela
    Melefors, Ojar
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Engstrand, Lars
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Adaptive Mutations and Replacements of Virulence Traits in the Escherichia coli O104:H4 Outbreak Population2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e63027-Article in journal (Refereed)
    Abstract [en]

    The sequencing of highly virulent Escherichia coli O104:H4 strains isolated during the outbreak of bloody diarrhea and hemolytic uremic syndrome in Europe in 2011 revealed a genome that contained a Shiga toxin encoding prophage and a plasmid encoding enteroaggregative fimbriae. Here, we present the draft genome sequence of a strain isolated in Sweden from a patient who had travelled to Tunisia in 2010 (E112/10) and was found to differ from the outbreak strains by only 38 SNPs in non-repetitive regions, 16 of which were mapped to the branch to the outbreak strain. We identified putatively adaptive mutations in genes for transporters, outer surface proteins and enzymes involved in the metabolism of carbohydrates. A comparative analysis with other historical strains showed that E112/10 contained Shiga toxin prophage genes of the same genotype as the outbreak strain, while these genes have been replaced by a different genotype in two otherwise very closely related strains isolated in the Republic of Georgia in 2009. We also present the genome sequences of two enteroaggregative E. coli strains affiliated with phylogroup A (C43/90 and C48/93) that contain the agg genes for the AAF/I-type fimbriae characteristic of the outbreak population. Interestingly, C43/90 also contained a tet/mer antibiotic resistance island that was nearly identical in sequence to that of the outbreak strain, while the corresponding island in the Georgian strains was most similar to E. coli strains of other serotypes. We conclude that the pan-genome of the outbreak population is shared with strains of the A phylogroup and that its evolutionary history is littered with gene replacement events, including most recently independent acquisitions of antibiotic resistance genes in the outbreak strains and its nearest neighbors. The results are summarized in a refined evolutionary model for the emergence of the O104:H4 outbreak population.

  • 81.