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  • 101.
    James, Rory Hennell
    et al.
    Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England..
    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.
    Escasinas, Alex
    Univ Lancaster, Fac Hlth & Med, Div Biomed & Life Sci, Lancaster LA1 4YG, England..
    Alhasan, Haya
    Univ Lancaster, Fac Hlth & Med, Div Biomed & Life Sci, Lancaster LA1 4YG, England..
    Howard, Julie A.
    Univ Cambridge, Cambridge Ctr Prote, Dept Biochem, Cambridge CB2 1GA, England.;Univ Cambridge, Cambridge Ctr Prote, Cambridge Syst Biol Ctr, Cambridge CB2 1GA, England..
    Deery, Michael J.
    Univ Cambridge, Cambridge Ctr Prote, Dept Biochem, Cambridge CB2 1GA, England.;Univ Cambridge, Cambridge Ctr Prote, Cambridge Syst Biol Ctr, Cambridge CB2 1GA, England..
    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.
    Robinson, Nicholas P.
    Univ Lancaster, Fac Hlth & Med, Div Biomed & Life Sci, Lancaster LA1 4YG, England..
    Functional reconstruction of a eukaryotic-like E1/E2/(RING) E3 ubiquitylation cascade from an uncultured archaeon2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 1120Article in journal (Refereed)
    Abstract [en]

    The covalent modification of protein substrates by ubiquitin regulates a diverse range of critical biological functions. Although it has been established that ubiquitin-like modifiers evolved from prokaryotic sulphur transfer proteins it is less clear how complex eukaryotic ubiquitylation system arose and diversified from these prokaryotic antecedents. The discovery of ubiquitin, E1-like, E2-like and small-RING finger (srfp) protein components in the Aigarchaeota and the Asgard archaea superphyla has provided a substantive step toward addressing this evolutionary question. Encoded in operons, these components are likely representative of the progenitor apparatus that founded the modern eukaryotic ubiquitin modification systems. Here we report that these proteins from the archaeon Candidatus ` Caldiarchaeum subterraneum' operate together as a bona fide ubiquitin modification system, mediating a sequential ubiquitylation cascade reminiscent of the eukaryotic process. Our observations support the hypothesis that complex eukaryotic ubiquitylation signalling pathways have developed from compact systems originally inherited from an archaeal ancestor.

  • 102.
    Jerlström-Hultqvist, Jon
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Einarsson, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Xu, Feifei
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Hjort, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ek, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Steinhauf, Daniel
    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, Microbiology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Andersson, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Svärd, Staffan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Spironucleus mitochondrial remnants suggest that hydrogenosomes are ancient organellesIn: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490Article in journal (Refereed)
  • 103.
    Jerlström-Hultqvist, Jon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Einarsson, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Xu, Feifei
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Hjort, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ek, Bo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Steinhauf, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hultenby, Kjell
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Andersson, Jan O.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Hydrogenosomes in the diplomonad Spironucleus salmonicida2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 2493-Article in journal (Refereed)
    Abstract [en]

    Acquisition of the mitochondrion is a key event in the evolution of the eukaryotic cell, but diversification of the organelle has occurred during eukaryotic evolution. One example of such mitochondria-related organelles (MROs) are hydrogenosomes, which produce ATP by substrate- level phosphorylation with hydrogen as a byproduct. The diplomonad parasite Giardia intestinalis harbours mitosomes, another type of MRO. Here we identify MROs in the salmon parasite Spironucleus salmonicida with similar protein import and Fe-S cluster assembly machineries as in Giardia mitosomes. We find that hydrogen production is prevalent in the diplomonad genus Spironucleus, and that S. salmonicida MROs contain enzymes characteristic of hydrogenosomes. Evolutionary analyses of known hydrogenosomal components indicate their presence in the diplomonad ancestor, and subsequent loss in Giardia. Our results suggest that hydrogenosomes are metabolic adaptations predating the split between parabasalids and diplomonads, which is deeper than the split between animals and fungi in the eukaryotic tree.

  • 104.
    Jimenez-Gonzalez, Alejandro
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Xu, Feifei
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Andersson, Jan O.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Lateral Acquisitions Repeatedly Remodel the Oxygen Detoxification Pathway in Diplomonads and Relatives2019In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 11, no 9, p. 2542-2556Article in journal (Refereed)
    Abstract [en]

    Oxygen and reactive oxygen species (ROS) are important stress factors for cells because they can oxidize many large molecules. Fornicata, a group of flagellated protists that includes diplomonads, have anaerobic metabolism but are still able to tolerate fluctuating levels of oxygen. We identified 25 protein families putatively involved in detoxification of oxygen and ROS in this group using a bioinformatics approach and propose how these interact in an oxygen detoxification pathway. These protein families were divided into a central oxygen detoxification pathway and accessory pathways for the synthesis of nonprotein thiols. We then used a phylogenetic approach to investigate the evolutionary origin of the components of this putative pathway in Diplomonadida and other Fornicata species. Our analyses suggested that the diplomonad ancestor was adapted to low-oxygen levels, was able to reduce O-2 to H2O in a manner similar to extant diplomonads, and was able to synthesize glutathione and L-cysteine. Several genes involved in the pathway have complex evolutionary histories and have apparently been repeatedly acquired through lateral gene transfer and subsequently lost. At least seven genes were acquired independently in different Fornicata lineages, leading to evolutionary convergences. It is likely that acquiring these oxygen detoxification proteins helped anaerobic organisms (like the parasitic Giardia intestinalis) adapt to low-oxygen environments (such as the digestive tract of aerobic hosts).

  • 105.
    Kampfraath, A. A.
    et al.
    Vrije Univ Amsterdam, Dept Ecol Sci, Amsterdam, Netherlands.
    Klasson, Lisa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Anvar, S. Y.
    Leiden Univ, Dept Human Genet, Med Ctr, Leiden, Netherlands;Leiden Univ, Leiden Genome Technol Ctr, Med Ctr, Leiden, Netherlands.
    Vossen, R. H. A. M.
    Leiden Univ, Leiden Genome Technol Ctr, Med Ctr, Leiden, Netherlands.
    Roelofs, D.
    Vrije Univ Amsterdam, Dept Ecol Sci, Amsterdam, Netherlands.
    Kraaijeveld, K.
    Vrije Univ Amsterdam, Dept Ecol Sci, Amsterdam, Netherlands.
    Ellers, J.
    Vrije Univ Amsterdam, Dept Ecol Sci, Amsterdam, Netherlands.
    Genome expansion of an obligate parthenogenesis-associated Wolbachia poses an exception to the symbiont reduction model2019In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 20, article id 106Article in journal (Refereed)
    Abstract [en]

    Background: Theory predicts that dependency within host-endosymbiont interactions results in endosymbiont genome size reduction. Unexpectedly, the largest Wolbachia genome was found in the obligate, parthenogenesis-associated wFol. In this study, we investigate possible processes underlying this genome expansion by comparing a re-annotated wFol genome to other Wolbachia genomes. In addition, we also search for candidate genes related to parthenogenesis induction (PI).

    Results: Within wFol, we found five phage WO regions representing 25.4% of the complete genome, few pseudogenized genes, and an expansion of DNA-repair genes in comparison to other Wolbachia. These signs of genome conservation were mirrored in the wFol host, the springtail F. candida, which also had an expanded DNA-repair gene family and many horizontally transferred genes. Across all Wolbachia genomes, there was a strong correlation between gene numbers of Wolbachia strains and their hosts. In order to identify genes with a potential link to PI, we assembled the genome of an additional PI strain, wLcla. Comparisons between four PI Wolbachia, including wFol and wLcla, and fourteen non-PI Wolbachia yielded a small set of potential candidate genes for further investigation.

    Conclusions: The strong similarities in genome content of wFol and its host, as well as the correlation between host and Wolbachia gene numbers suggest that there may be some form of convergent evolution between endosymbiont and host genomes. If such convergent evolution would be strong enough to overcome the evolutionary forces causing genome reduction, it would enable expanded genomes within long-term obligate endosymbionts.

  • 106.
    Kee, Nigel
    et al.
    Ludwig Inst Canc Res, Box 240, S-17177 Stockholm, Sweden.;Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden..
    Volakakis, Nikolaos
    Ludwig Inst Canc Res, Box 240, S-17177 Stockholm, Sweden..
    Kirkeby, Agnete
    Lund Univ, Dept Expt Med Sci, Lund Stem Cell Ctr, S-22184 Lund, Sweden..
    Dahl, Lina
    Ludwig Inst Canc Res, Box 240, S-17177 Stockholm, Sweden..
    Storvall, Helena
    Ludwig Inst Canc Res, Box 240, S-17177 Stockholm, Sweden..
    Nolbrant, Sara
    Lund Univ, Dept Expt Med Sci, Lund Stem Cell Ctr, S-22184 Lund, Sweden..
    Lahti, Laura
    Ludwig Inst Canc Res, Box 240, S-17177 Stockholm, Sweden..
    Björklund, Åsa K.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gillberg, Linda
    Ludwig Inst Canc Res, Box 240, S-17177 Stockholm, Sweden..
    Joodmardi, Eliza
    Ludwig Inst Canc Res, Box 240, S-17177 Stockholm, Sweden..
    Sandberg, Rickard
    Ludwig Inst Canc Res, Box 240, S-17177 Stockholm, Sweden.;Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden..
    Parmar, Malin
    Lund Univ, Dept Expt Med Sci, Lund Stem Cell Ctr, S-22184 Lund, Sweden..
    Perlmann, Thomas
    Ludwig Inst Canc Res, Box 240, S-17177 Stockholm, Sweden.;Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden..
    Single-Cell Analysis Reveals a Close Relationship between Differentiating Dopamine and Subthalamic Nucleus Neuronal Lineages2017In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 20, no 1, p. 29-40Article in journal (Refereed)
    Abstract [en]

    Stem cell engineering and grafting of mesencephalic dopamine (mesDA) neurons is a promising strategy for brain repair in Parkinson's disease (PD). Refinement of differentiation protocols to optimize this approach will require deeper understanding of mesDA neuron development. Here, we studied this process using transcriptome-wide single-cell RNA sequencing of mouse neural progenitors expressing the mesDA neuron determinant Lmx1a. This approach resolved the differentiation of mesDA and neighboring neuronal lineages and revealed a remarkably close relationship between developing mesDA and subthalamic nucleus (STN) neurons, while also highlighting a distinct transcription factor set that can distinguish between them. While previous hESC mesDA differentiation protocols have relied on markers that are shared between the two lineages, we found that application of these highlighted markers can help to refine current stem cell engineering protocols, increasing the proportion of appropriately patterned mesDA progenitors. Our results, therefore, have important implications for cell replacement therapy in PD.

  • 107.
    Klasson, Lisa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    The unpredictable road to reduction2017In: Nature ecology and evolution, ISSN 2397-334X, Vol. 1, p. 1062-1063Article in journal (Other academic)
  • 108.
    Klasson, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Kumar, Nikhil
    Bromley, Robin
    Sieber, Karsten
    Flowers, Melissa
    Ott, Sandra H.
    Tallon, Luke J.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Hotopp, Julie C. Dunning
    Extensive duplication of the Wolbachia DNA in chromosome four of Drosophila ananassae2014In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, p. 1097-Article in journal (Refereed)
    Abstract [en]

    Background: Lateral gene transfer (LGT) from bacterial Wolbachia endosymbionts has been detected in similar to 20% of arthropod and nematode genome sequencing projects. Many of these transfers are large and contain a substantial part of the Wolbachia genome. Results: Here, we re-sequenced three D. ananassae genomes from Asia and the Pacific that contain large LGTs from Wolbachia. We find that multiple copies of the Wolbachia genome are transferred to the Drosophila nuclear genome in all three lines. In the D. ananassae line from Indonesia, the copies of Wolbachia DNA in the nuclear genome are nearly identical in size and sequence yielding an even coverage of mapped reads over the Wolbachia genome. In contrast, the D. ananassae lines from Hawaii and India show an uneven coverage of mapped reads over the Wolbachia genome suggesting that different parts of these LGTs are present in different copy numbers. In the Hawaii line, we find that this LGT is underrepresented in third instar larvae indicative of being heterochromatic. Fluorescence in situ hybridization of mitotic chromosomes confirms that the LGT in the Hawaii line is heterochromatic and represents similar to 20% of the sequence on chromosome 4 (dot chromosome, Muller element F). Conclusions: This collection of related lines contain large lateral gene transfers composed of multiple Wolbachia genomes that constitute >2% of the D. ananassae genome (similar to 5 Mbp) and partially explain the abnormally large size of chromosome 4 in D. ananassae.

  • 109.
    Klinger, Christen M.
    et al.
    Univ Alberta, Dept Cell Biol, Edmonton, AB, Canada..
    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.
    Dacks, Joel B.
    Univ Alberta, Dept Cell Biol, Edmonton, AB, Canada..
    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.
    Tracing the Archaeal Origins of Eukaryotic Membrane-Trafficking System Building Blocks2016In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 33, no 6, p. 1528-1541Article in journal (Refereed)
    Abstract [en]

    In contrast to prokaryotes, eukaryotic cells are characterized by a complex set of internal membrane-bound compartments. A subset of these, and the protein machineries that move material between them, define the membrane-trafficking system (MTS), the emergence of which represents a landmark in eukaryotic evolution. Unlike mitochondria and plastids, MTS organelles have autogenous origins. Much of the MTS machinery is composed of building blocks, including small GTPase, coiled-coil, beta-propeller + alpha-solenoid, and longin domains. Despite the identification of prokaryotic proteins containing these domains, only few represent direct orthologues, leaving the origins and early evolution of the MTS poorly understood. Here, we present an in-depth analysis of MTS building block homologues in the composite genome of Lokiarchaeum, the recently discovered archaeal sister clade of eukaryotes, yielding several key insights. We identify two previously unreported Eukaryotic Signature Proteins; orthologues of the Gtr/Rag family GTPases, involved in target of rapamycin complex signaling, and of the RLC7 dynein component. We could not identify golgin or SNARE (coiled-coil) or beta-propeller + alpha-solenoid orthologues, nor typical MTS domain fusions, suggesting that these either were lost from Lokiarchaeum or emerged later in eukaryotic evolution. Furthermore, our phylogenetic analyses of lokiarchaeal GTPases support a split into Ras-like and Arf-like superfamilies, with different prokaryotic antecedents, before the advent of eukaryotes. While no GTPase activating proteins or exchange factors were identified, we show that Lokiarchaeum encodes numerous roadblock domain proteins and putative longin domain proteins, confirming the latter's origin from Archaea. Altogether, our study provides new insights into the emergence and early evolution of the eukaryotic membrane-trafficking system.

  • 110. Krzewinska, Maja
    et al.
    Bjornstad, Gro
    Skoglund, Pontus
    Ólason, Páll Isolfur
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Bill, Jan
    Gotherstrom, Anders
    Hagelberg, Erika
    Mitochondrial DNA variation in the Viking age population of Norway2015In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 370, no 1660, p. 20130384-Article in journal (Refereed)
    Abstract [en]

    The medieval Norsemen or Vikings had an important biological and cultural impact on many parts of Europe through raids, colonization and trade, from about AD 793 to 1066. To help understand the genetic affinities of the ancient Norsemen, and their genetic contribution to the gene pool of other Europeans, we analysed DNA markers in Late Iron Age skeletal remains from Norway. DNA was extracted from 80 individuals, and mitochondrial DNA polymorphisms were detected by next-generation sequencing. The sequences of 45 ancient Norwegians were verified as genuine through the identification of damage patterns characteristic of ancient DNA. The ancient Norwegians were genetically similar to previously analysed ancient Icelanders, and to present-day Shetland and Orkney Islanders, Norwegians, Swedes, Scots, English, German and French. The Viking Age population had higher frequencies of K*, U*, V* and I* haplogroups than their modern counterparts, but a lower proportion of T* and H* haplogroups. Three individuals carried haplotypes that are rare in Norway today (U5b1b1, Hg A* and an uncommon variant of H*). Our combined analyses indicate that Norse women were important agents in the overseas expansion and settlement of the Vikings, and that women from the Orkneys and Western Isles contributed to the colonization of Iceland.

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

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

  • 112. Lall, Gurdeep K.
    et al.
    Darby, Alistair C.
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Molecular Evolution.
    MacLeod, Ewan T.
    Bishop, Richard P.
    Welburn, Susan C.
    Amplified fragment length polymorphism (AFLP) analysis of closely related wild and captive tsetse fly (Glossina morsitans morsitans) populations2010In: Parasites & Vectors, ISSN 1756-3305, Vol. 3, p. 47-Article in journal (Refereed)
    Abstract [en]

    Background: Tsetse flies (Diptera: Glossinidae) are vectors of trypanosomes that cause sleeping sickness in humans and nagana in livestock across sub-Saharan Africa. Tsetse control strategies rely on a detailed understanding of the epidemiology and ecology of tsetse together with genetic variation within and among populations. High-resolution nuclear genetic markers are useful tools for elucidation of the genetic basis of phenotypic traits. In this study amplified fragment length polymorphism (AFLP) markers were developed to analyze genetic variation in Glossina morsitans morsitans from laboratory and field-collected populations from Zimbabwe. Results: A total of seven hundred and fifty one loci from laboratory and field populations of G. m. morsitans from Zimbabwe were genotyped using AFLP with seven primer combinations. Analysis identified 335 polymorphic loci. The two populations could be distinguished by cluster and principal components analysis (PCA) analysis, indicating that AFLP markers can be used to separate genetically similar populations; at the same time differences observed between laboratory and field populations were not very great. Among the techniques investigated, the use of acetone was the most reliable method of preservation of tsetse for subsequent extraction of high molecular weight DNA. An interesting finding was that AFLP also enabled robust within-population discrimination of male and female tsetse flies due to their different X chromosome DNA complements. Conclusions: AFLP represents a useful additional tool to add to the suite of techniques currently available for the genetic analysis of tsetse populations and represents a useful resource for identification of the genetic basis of important phenotypic traits.

  • 113.
    Lax, Gordon
    et al.
    Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Dept Biol, Halifax, NS, Canada.
    Eglit, Yana
    Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Dept Biol, Halifax, NS, Canada.
    Eme, Laura
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab. Dalhousie Univ, Dept Biochem & Mol Biol, Ctr Comparat Genom & Evolutionary Bioinformat, Halifax, NS, Canada.
    Bertrand, Erin M.
    Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Dept Biol, Halifax, NS, Canada.
    Roger, Andrew J.
    Dalhousie Univ, Dept Biochem & Mol Biol, Ctr Comparat Genom & Evolutionary Bioinformat, Halifax, NS, Canada.
    Simpson, Alastair G. B.
    Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Dept Biol, Halifax, NS, Canada.
    Hemimastigophora is a novel supra-kingdom-level lineage of eukaryotes2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 564, no 7736, p. 410-414Article in journal (Refereed)
    Abstract [en]

    Almost all eukaryote life forms have now been placed within one of five to eight supra-kingdom-level groups using molecular phylogenetics(1-4). The 'phylum' Hemimastigophora is probably the most distinctive morphologically defined lineage that still awaits such a phylogenetic assignment. First observed in the nineteenth century, hemimastigotes are free-living predatory protists with two rows of flagella and a unique cell architecture(5-7); to our knowledge, no molecular sequence data or cultures are currently available for this group. Here we report phylogenomic analyses based on high-coverage, cultivation-independent transcriptomics that place Hemimastigophora outside of all established eukaryote supergroups. They instead comprise an independent supra-kingdom-level lineage that most likely forms a sister clade to the 'Diaphoretickes' half of eukaryote diversity (that is, the 'stramenopiles, alveolates and Rhizaria' supergroup (Sar), Archaeplastida and Cryptista, as well as other major groups). The previous ranking of Hemimastigophora as a phylum understates the evolutionary distinctiveness of this group, which has considerable importance for investigations into the deep-level evolutionary history of eukaryotic life-ranging from understanding the origins of fundamental cell systems to placing the root of the tree. We have also established the first culture of a hemimastigote (Hemimastix kukwesjijk sp. nov.), which will facilitate future genomic and cellbiological investigations into eukaryote evolution and the last eukaryotic common ancestor.

  • 114.
    Le Rhun, Anais
    et al.
    Umea Univ, Lab Mol Infect Sweden MIMS, UCMR, Dept Mol Biol, S-90187 Umea, Sweden.;Helmholtz Ctr Infect Res HZI, Dept Regulat Infect Biol, D-38124 Braunschweig, Germany..
    Beer, Yan Yan
    Helmholtz Ctr Infect Res HZI, Dept Regulat Infect Biol, D-38124 Braunschweig, Germany..
    Reimegård, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Chylinski, Krzysztof
    Umea Univ, Lab Mol Infect Sweden MIMS, UCMR, Dept Mol Biol, S-90187 Umea, Sweden.;Univ Vienna, MFPL, A-1030 Vienna, Austria..
    Charpentier, Emmanuelle
    Umea Univ, Lab Mol Infect Sweden MIMS, UCMR, Dept Mol Biol, S-90187 Umea, Sweden.;Helmholtz Ctr Infect Res HZI, Dept Regulat Infect Biol, D-38124 Braunschweig, Germany.;Hannover Med Sch MHH, D-30625 Hannover, Germany.;Max Planck Inst Infect Biol, Dept Regulat Infect Biol, D-10117 Berlin, Germany..
    RNA sequencing uncovers antisense RNAs and novel small RNAs in Streptococcus pyogenes2016In: RNA Biology, ISSN 1547-6286, E-ISSN 1555-8584, Vol. 13, no 2, p. 177-195Article in journal (Refereed)
    Abstract [en]

    Streptococcus pyogenes is a human pathogen responsible for a wide spectrum of diseases ranging from mild to life-threatening infections. During the infectious process, the temporal and spatial expression of pathogenicity factors is tightly controlled by a complex network of protein and RNA regulators acting in response to various environmental signals. Here, we focus on the class of small RNA regulators (sRNAs) and present the first complete analysis of sRNA sequencing data in S. pyogenes. In the SF370 clinical isolate (M1 serotype), we identified 197 and 428 putative regulatory RNAs by visual inspection and bioinformatics screening of the sequencing data, respectively. Only 35 from the 197 candidates identified by visual screening were assigned a predicted function (T-boxes, ribosomal protein leaders, characterized riboswitches or sRNAs), indicating how little is known about sRNA regulation in S. pyogenes. By comparing our list of predicted sRNAs with previous S. pyogenes sRNA screens using bioinformatics or microarrays, 92 novel sRNAs were revealed, including antisense RNAs that are for the first time shown to be expressed in this pathogen. We experimentally validated the expression of 30 novel sRNAs and antisense RNAs. We show that the expression profile of 9 sRNAs including 2 predicted regulatory elements is affected by the endoribonucleases RNase III and/or RNase Y, highlighting the critical role of these enzymes in sRNA regulation.

  • 115.
    Le Rhun, Anais
    et al.
    Umea Univ, UCMR, Dept Mol Biol, Lab Mol Infect Sweden MIMS, S-90187 Umea, Sweden.;Max Planck Inst Infect Biol, Dept Regulat Infect Biol, D-10117 Berlin, Germany.;Helmholtz Ctr Infect Res, Dept Regulat Infect Biol, D-38124 Braunschweig, Germany..
    Lecrivain, Anne-Laure
    Umea Univ, UCMR, Dept Mol Biol, Lab Mol Infect Sweden MIMS, S-90187 Umea, Sweden.;Max Planck Inst Infect Biol, Dept Regulat Infect Biol, D-10117 Berlin, Germany..
    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.
    Proux-Wera, Estelle
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Box 1031, SE-17121 Solna, Sweden..
    Broglia, Laura
    Max Planck Inst Infect Biol, Dept Regulat Infect Biol, D-10117 Berlin, Germany.;Helmholtz Ctr Infect Res, Dept Regulat Infect Biol, D-38124 Braunschweig, Germany..
    Della Beffa, Cristina
    Helmholtz Ctr Infect Res, Dept Regulat Infect Biol, D-38124 Braunschweig, Germany..
    Charpentier, Emmanuelle
    Umea Univ, UCMR, Dept Mol Biol, Lab Mol Infect Sweden MIMS, S-90187 Umea, Sweden.;Max Planck Inst Infect Biol, Dept Regulat Infect Biol, D-10117 Berlin, Germany.;Helmholtz Ctr Infect Res, Dept Regulat Infect Biol, D-38124 Braunschweig, Germany.;Humboldt Univ, D-10115 Berlin, Germany..
    Identification of endoribonuclease specific cleavage positions reveals novel targets of RNase III in Streptococcus pyogenes2017In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 5, p. 2329-2340Article in journal (Refereed)
    Abstract [en]

    A better understanding of transcriptional and post-transcriptional regulation of gene expression in bacteria relies on studying their transcriptome. RNA sequencing methods are used not only to assess RNA abundance but also the exact boundaries of primary and processed transcripts. Here, we developed a method, called identification of specific cleavage position (ISCP), which enables the identification of direct endoribonuclease targets in vivo by comparing the 5' and 3' ends of processed transcripts between wild type and RNase deficient strains. To demonstrate the ISCP method, we used as a model the double-stranded specific RNase III in the human pathogen Streptococcus pyogenes. We mapped 92 specific cleavage positions (SCPs) among which, 48 were previously described and 44 are new, with the characteristic 2 nucleotides 3' overhang of RNase III. Most SCPs were located in untranslated regions of RNAs. We screened for RNase III targets using transcriptomic differential expression analysis (DEA) and compared those with the RNase III targets identified using the ISCP method. Our study shows that in S. pyogenes, under standard growth conditions, RNase III has a limited impact both on antisense transcripts and on global gene expression with the expression of most of the affected genes being downregulated in an RNase III deletion mutant.

  • 116. Lebbad, Marianne
    et al.
    Mattsson, Jens G
    Christensson, Bodil
    Ljungström, Bitte
    Backhans, Annette
    Andersson, Jan O.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Molecular Evolution.
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    From mouse to moose: multilocus genotyping of Giardia isolates from various animal species.2010In: Veterinary parasitology, ISSN 0304-4017, E-ISSN 1873-2550, Vol. 168, no 3-4, p. 231-239Article in journal (Refereed)
    Abstract [en]

    Giardia intestinalis is a protozoan parasite that consists of seven genetically distinct assemblages (A to G). Assemblage A and B parasites have been detected in a wide range of animals including humans, while the other assemblages (C to G) appear to have a narrower host range. However, the knowledge about zoonotic transmission of G. intestinalis is limited. To address this question, 114 Giardia isolates from various animals in Sweden including pets, livestock, wildlife and captive non-human primates were investigated by a sequence-based analysis of three genes (beta-giardin, glutamate dehydrogenase and triose phosphate isomerase). Assemblage A infections were detected in nine ruminants, five cats and one dog, while three sheep were infected with both assemblages A and E. Multilocus genotypes (MLGs) were defined for assemblage A, and three of these MLGs have previously been detected in Giardia isolates from humans. The newly described sub-assemblage AIII, until now reported mainly in wild hoofed animals, was found in one cat isolate. Assemblage B occurred in three monkeys, one guinea pig and one rabbit. The rabbit isolate exhibited sequences at all three loci previously detected in human isolates. The non-zoonotic assemblages C, D, E, F or G were found in the remaining 83 G. intestinalis isolates, which were successfully amplified and genotyped, generating a wide variety of both novel and known sub-genotypes. Double peaks in chromatograms were seen in assemblage B, C, D and E isolates but were never observed in assemblage A, F and G isolates, which can reflect differences in allelic sequence divergence. No evidence of genetic exchange between assemblages was detected. The study shows that multilocus genotyping of G. intestinalis is a highly discriminatory and useful tool in the determination of zoonotic sub-groups within assemblage A, but less valuable for subtyping assemblages B, C, D and E due to the high frequency of double peaks in the chromatograms. The obtained data also suggest that zoonotic transmission of assemblages A and B might occur to a limited extent in Sweden.

  • 117. Lebbad, Marianne
    et al.
    Petersson, Ingvor
    Karlsson, Lillemor
    Botero-Kleiven, Silvia
    Andersson, Jan O.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Svenungsson, Bo
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Multilocus Genotyping of Human Giardia Isolates Suggests Limited Zoonotic Transmission and Association between Assemblage B and Flatulence in Children2011In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, Vol. 5, no 8, p. e1262-Article in journal (Refereed)
    Abstract [en]

    Background: Giardia intestinalis is one of the most common diarrhea-related parasites in humans, where infection ranges from asymptomatic to acute or chronic disease. G. intestinalis consists of eight genetically distinct genotypes or assemblages, designated A-H, and assemblages A and B can infect humans. Giardiasis has been classified as a possible zoonotic disease but the role of animals in human disease transmission still needs to be proven. We tried to link different assemblages and sub-assemblages of G. intestinalis isolates from Swedish human patients to clinical symptoms and zoonotic transmission. Methodology/Principal Findings: Multilocus sequence-based genotyping of 207 human Giardia isolates using three gene loci: beta-giardin, glutamate dehydrogenase (gdh), and triose phosphate isomerase (tpi) was combined with assemblage-specific tpi PCRs. This analysis identified 73 patients infected with assemblage A, 128 with assemblage B, and six with mixed assemblages A+B. Multilocus genotypes (MLGs) were easily determined for the assemblage A isolates, and most patients with this genotype had apparently been infected through anthroponotic transmission. However, we also found evidence of limited zoonotic transmission of Giardia in Sweden, since a few domestic human infections involved the same assemblage A MLGs previously reported in Swedish cats and ruminants. Assemblage B was detected more frequently than assemblage A and it was also more common in patients with suspected treatment failure. However, a large genetic variability made determination of assemblage B MLGs problematic. Correlation between symptoms and assemblages was found only for flatulence, which was significantly more common in children less than six years of age infected with assemblage B. Conclusions/Significance: This study shows that certain assemblage A subtypes are potentially zoonotic and that flatulence is connected to assemblage B infections in young children. Determination of MLGs from assemblages A and B can be a valuable tool in outbreak situations and to help identify possible zoonotic transmission.

  • 118.
    Leger, Michelle M.
    et al.
    UPF, CSIC, Inst Evolutionary Biol, Barcelona, Spain.
    Eme, Laura
    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.
    Roger, Andrew J.
    Dalhousie Univ, Ctr Comparat Genom & Evolutionary Bioinformat, Dept Biochem & Mol Biol, Halifax, NS, Canada.
    Demystifying Eukaryote Lateral Gene Transfer2018In: Bioessays, ISSN 0265-9247, E-ISSN 1521-1878, Vol. 40, no 5, article id 1700242Article in journal (Refereed)
    Abstract [en]

    In a recent BioEssays paper [W. F. Martin, BioEssays 2017, 39, 1700115], William Martin sharply criticizes evolutionary interpretations that involve lateral gene transfer (LGT) into eukaryotic genomes. Most published examples of LGTs in eukaryotes, he suggests, are in fact contaminants, ancestral genes that have been lost from other extant lineages, or the result of artefactual phylogenetic inferences. Martin argues that, except for transfers that occurred from endosymbiotic organelles, eukaryote LGT is insignificant. Here, in reviewing this field, we seek to correct some of the misconceptions presented therein with regard to the evidence for LGT in eukaryotes.

  • 119.
    Leger, Michelle M.
    et al.
    Dalhousie Univ, Dept Biochem & Mol Biol, 5850 Coll St,POB 15000, Halifax, NS B3H 4R2, Canada.;Univ Pompeu Fabra, CSIC, Inst Evolutionary Biol, Passeig Maritim de la Barceloneta 37-49, Barcelona 08003, Spain..
    Kolisko, Martin
    Dalhousie Univ, Dept Biochem & Mol Biol, 5850 Coll St,POB 15000, Halifax, NS B3H 4R2, Canada.;Czech Acad Sci, Biol Ctr, Inst Parasitol, Branisovska 1160-31, Ceske Budejovice 37005, Czech Republic..
    Kamikawa, Ryoma
    Kyoto Univ, Grad Sch Global Environm Studies, Grad Sch Human & Environm Studies, Sakyo Ku, Yoshida Honmachi, Kyoto 6068501, Japan..
    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, 5850 Coll St,POB 15000, Halifax, NS B3H 4R2, Canada.
    Kume, Keitaro
    Univ Tsukuba, Ctr Computat Sci, Grad Sch Life & Environm Sci, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058572, Japan..
    Cepicka, Ivan
    Charles Univ Prague, Fac Sci, Dept Zool, Vinicna 7, CR-12844 Prague 2, Czech Republic..
    Silberman, Jeffrey D.
    Univ Arkansas, Dept Biol Sci, Fayetteville, AR 72701 USA..
    Andersson, Jan O.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Xu, Feifei
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Yabuki, Akinori
    Japan Agcy Marine Earth Sci & Technol JAMSTEC, 2-15 Natsushima Cho, Yokosuka, Kanagawa 2370061, Japan..
    Eme, Laura
    Dalhousie Univ, Dept Biochem & Mol Biol, 5850 Coll St,POB 15000, Halifax, NS B3H 4R2, Canada.
    Zhang, Qianqian
    Chinese Acad Sci, Yantai Inst Coastal Zone Res, 17 Chunhui Rd, Yantai 264003, Shandong, Peoples R China..
    Takishita, Kiyotaka
    Japan Agcy Marine Earth Sci & Technol JAMSTEC, 2-15 Natsushima Cho, Yokosuka, Kanagawa 2370061, Japan..
    Inagaki, Yuji
    Univ Tsukuba, Ctr Computat Sci, Grad Sch Life & Environm Sci, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058572, Japan.;Univ Tsukuba, Ctr Computat Sci, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058577, Japan..
    Simpson, Alastair G. B.
    Dalhousie Univ, Dept Biol, 1355 Oxford St,POB 15000, Halifax, NS B3H 4R2, Canada..
    Hashimoto, Tetsuo
    Univ Tsukuba, Ctr Computat Sci, Grad Sch Life & Environm Sci, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058572, Japan.;Univ Tsukuba, Ctr Computat Sci, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058577, Japan..
    Roger, Andrew J.
    Dalhousie Univ, Dept Biochem & Mol Biol, 5850 Coll St,POB 15000, Halifax, NS B3H 4R2, Canada..
    Organelles that illuminate the origins of Trichomonas hydrogenosomes and Giardia mitosomes2017In: NATURE ECOLOGY & EVOLUTION, ISSN 2397-334X, Vol. 1, no 4, article id UNSP 0092Article in journal (Refereed)
    Abstract [en]

    Many anaerobic microbial parasites possess highly modified mitochondria known as mitochondrion-related organelles (MROs). The best-studied of these are the hydrogenosomes of Trichomonas vaginalis and Spironucleus salmonicida, which produce ATP anaerobically through substrate-level phosphorylation with concomitant hydrogen production; and the mitosomes of Giardia intestinalis, which are functionally reduced and lack any role in ATP production. Howewer, to understand the metabolic specializations that these MROs underwent in adaptation to parasitism, data from their free-living relatives are needed. Here, we present a large-scale comparative transcriptomic study of MROs across a major eukaryotic group, Metamonada, examining lineage-specific gain and loss of metabolic functions in the MROs of Trichomonas, Giardia, Spironucleus and their free-living relatives. Our analyses uncover a complex history of ATP production machinery in diplomonads such as Giardia, and their closest relative, Dysnectes; and a correlation between the glycine cleavage machinery and lifestyles. Our data further suggest the existence of a previously undescribed biochemical class of MRO that generates hydrogen but is incapable of ATP synthesis.

  • 120.
    Li, Daniel Y.
    et al.
    Tech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany.
    Busch, Albert
    Tech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany.
    Jin, Hong
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Chernogubova, Ekaterina
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Pelisek, Jaroslav
    Tech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany.
    Karlsson, Joakim
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Gothenburg, Sweden.
    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.
    Liu, Shengliang
    Tech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany.
    Lao, Shen
    Hofmann, Patrick
    Univ Hosp Frankfurt, Inst Cardiovasc Regenerat, Frankfurt, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Rhein Main, Frankfurt, Germany.
    Baecklund, Alexandra
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Eken, Suzanne M.
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Roy, Joy
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Eriksson, Per
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Dacken, Brian
    Exemplar Genet, Sioux Ctr, IA USA.
    Ramanujam, Deepak
    Tech Univ Munich, Inst Pharmacol & Toxicol, Munich, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich, Munich, Germany.
    Dueck, Anne
    Tech Univ Munich, Inst Pharmacol & Toxicol, Munich, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich, Munich, Germany.
    Engelhardt, Stefan
    Tech Univ Munich, Inst Pharmacol & Toxicol, Munich, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich, Munich, Germany.
    Boon, Reinier A.
    Univ Hosp Frankfurt, Inst Cardiovasc Regenerat, Frankfurt, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Rhein Main, Frankfurt, Germany.
    Eckstein, Hans-Henning
    Tech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany.
    Spin, Joshua M.
    Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA.
    Tsao, Philip S.
    Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA.
    Maegdefessel, Lars
    Tech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany;Karolinska Inst, Dept Med, Stockholm, Sweden.
    H19 Induces Abdominal Aortic Aneurysm Development and Progression2018In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 138, no 15, p. 1551-1568Article in journal (Refereed)
    Abstract [en]

    Background: Long noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development. Methods: We profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E-deficient (ApoE(-/-)) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization. Results: Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue samples, and in a novel preclinical LDLR-/- (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1 as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1 and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1 via recruiting the transcription factor specificity protein 1 to the promoter region. Conclusions: The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.

  • 121. Lin, Yao-Cheng
    et al.
    Wang, Jing
    Delhomme, Nicolas
    Schiffthaler, Bastian
    Sundström, Görel
    Zuccolo, Andrea
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hvidsten, Torgeir R.
    de la Torre, Amanda
    Cossu, Rosa M.
    Höppner, Marc P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lantz, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Scofield, Douglas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Zamani, Neda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Anna C. V.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mannapperuma, Chanaka
    Robinson, Kathryn M.
    Mähler, Niklas
    Leitch, Ilia J.
    Pellicer, Jaume
    Park, Eung-Jun
    Van Montagu, Marc
    Van de Peer, Yves
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jansson, Stefan
    Ingvarsson, Pär K.
    Street, Nathaniel R.
    Functional and evolutionary genomic inferences in Populus through genome and population sequencing of American and European aspen2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 46, p. E10970-E10978Article in journal (Refereed)
  • 122. Lind, Anders E
    et al.
    Lewis, William H
    Spang, Anja
    Guy, Lionel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Embley, Martin T
    Ettema, Thijs JG
    Genomic insights into two independent events of archaeal endosymbiosisIn: Article in journal (Other academic)
  • 123.
    Lind, Anders E.
    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.
    Lewis, William H
    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.
    Guy, Lionel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Embley, T Martin
    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.
    Genomes of two archaeal endosymbionts show convergent adaptations to an intracellular lifestyle.2018In: The ISME Journal, ISSN 1751-7362, E-ISSN 1751-7370, Vol. 12, no 11, p. 2655-2667Article in journal (Refereed)
    Abstract [en]

    Endosymbiosis is a widespread phenomenon in the microbial world and can be based on diverse interactions between endosymbiont and host cell. The vast majority of the known endosymbiotic interactions involve bacteria that have invaded eukaryotic host cells. However, methanogenic archaea have been found to thrive in anaerobic, hydrogenosome-containing protists and it was suggested that this symbiosis is based on the transfer of hydrogen. Here, we used culture-independent genomics approaches to sequence the genomes of two distantly related methanogenic endosymbionts that have been acquired in two independent events by closely related anaerobic ciliate hosts Nyctotherus ovalis and Metopus contortus, respectively. The sequences obtained were then validated as originating from the ciliate endosymbionts by in situ probing experiments. Comparative analyses of these genomes and their closest free-living counterparts reveal that the genomes of both endosymbionts are in an early stage of adaptation towards endosymbiosis as evidenced by the large number of genes undergoing pseudogenization. For instance, the observed loss of genes involved in amino acid biosynthesis in both endosymbiont genomes indicates that the endosymbionts rely on their hosts for obtaining several essential nutrients. Furthermore, the endosymbionts appear to have gained significant amounts of genes of potentially secreted proteins, providing targets for future studies aiming to elucidate possible mechanisms underpinning host-interactions. Altogether, our results provide the first genomic insights into prokaryotic endosymbioses from the archaeal domain of life.

  • 124.
    Lind, Peter A.
    et al.
    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 Organismal Biology, Molecular Evolution.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mutational robustness of ribosomal protein genes2010In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 330, no 6005, p. 825-827Article in journal (Refereed)
    Abstract [en]

    The distribution of fitness effects (DFE) of mutations is of fundamental importance for understanding evolutionary dynamics and complex diseases and for conserving threatened species. DFEs estimated from DNA sequences have rarely been subject to direct experimental tests. We used a bacterial system in which the fitness effects of a large number of defined single mutations in two ribosomal proteins were measured with high sensitivity. The obtained DFE appears to be unimodal, where most mutations (120 out of 126) are weakly deleterious and the remaining ones are potentially neutral. The DFEs for synonymous and nonsynonymous substitutions are similar, suggesting that in some genes, strong fitness constraints are present at the level of the messenger RNA.

  • 125.
    Lind, Peter A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tobin, Christina
    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 Organismal Biology, Molecular Evolution.
    Kurland, Charles G
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Compensatory gene amplification restores fitness after inter-species gene replacements2010In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 75, no 5, p. 1078-1089Article in journal (Refereed)
    Abstract [en]

    Genes introduced by gene replacements and other types of horizontal gene transfer (HGT) represent a significant presence in many archaeal and eubacterial genomes. Most alien genes are likely to be neutral or deleterious upon arrival and their long-term persistence may require a mechanism that improves their selective contribution. To examine the fate of inter-species gene replacements, we exchanged three native S. typhimurium genes encoding ribosomal proteins with orthologues from various other microbes. The results show that replacement of each of these three genes reduces fitness to such an extent that it would provide an effective barrier against inter-species gene replacements in eubacterial populations. However, these fitness defects could be partially ameliorated by gene amplification that augmented the dosage of the heterologous proteins. This suggests that suboptimal expression is a common fitness constraint for inter-species gene replacements, with fitness costs conferred by either a lower expression level of the alien protein compared with the native protein or a requirement for an increased amount of the alien protein to maintain proper function. Our findings can explain the observation that duplicated genes are over-represented among horizontally transferred genes, and suggest a potential coupling between compensatory gene amplification after HGT and the evolution of new genes.

  • 126.
    Lindqvist, C Mårten
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ekman, Diana
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Sweden.
    Johansson, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Moghadam, Behrooz Torabi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Raine, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Övernäs, Elin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Dahlberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wahlberg, Per
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Henriksson, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abrahamsson, Jonas
    Department of Pediatrics, Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Grandér, Dan
    Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Heyman, Mats
    Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Palle, Josefine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Söderhäll, Stefan
    Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Forestier, Erik
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berglund, Eva C
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    The Mutational Landscape in Pediatric Acute Lymphoblastic Leukemia Deciphered by Whole Genome Sequencing2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 1, p. 118-128Article in journal (Refereed)
    Abstract [en]

    Genomic characterization of pediatric acute lymphoblastic leukemia (ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21)ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T-ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications.

  • 127.
    Lindqvist, Carl Mårten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Raine, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Övernäs, Elin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Ekman, Diana
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frost, B M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Grandér, Dan
    Karolinska Institutet, Dept. Oncology and Pathology, Stockholm, Sweden.
    Forestier, Erik
    Dept. of Medical Biosciences, University of Umeå, Umeå, Sweden.
    Lönnerholm, G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berglund, Eva Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Identification of somatic single nucleotide variants inleukemia by targeted sequencing of non-indexed overlapping poolsManuscript (preprint) (Other academic)
  • 128.
    Ling, Jiaxin
    et al.
    Univ Helsinki, Med, Dept Virol, Helsinki, Finland..
    Smura, Teemu
    Univ Helsinki, Med, Dept Virol, Helsinki, Finland..
    Tamarit, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Huitu, Otso
    Nat Resources Inst Finland, Forest & Anim Ecol, Tampere, Finland..
    Voutilainen, Liina
    Univ Helsinki, Med, Dept Virol, Helsinki, Finland.;Nat Resources Inst Finland, Forest & Anim Ecol, Helsinki, Finland..
    Henttonen, Heikki
    Nat Resources Inst Finland, Forest & Anim Ecol, Helsinki, Finland..
    Vaheri, Antti
    Univ Helsinki, Med, Dept Virol, Helsinki, Finland..
    Vapalahti, Olli
    Univ Helsinki, Med, Dept Virol, Helsinki, Finland.;Univ Helsinki, Dept Vet Biosci, Helsinki, Finland.;Univ Helsinki, Helsinki Univ Hosp, Helsinki, Finland..
    Sironen, Tarja
    Univ Helsinki, Med, Dept Virol, Helsinki, Finland.;Univ Helsinki, Dept Vet Biosci, Helsinki, Finland..
    Evolution and postglacial colonization of Seewis hantavirus with Sorex araneus in Finland2018In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 57, p. 88-97Article in journal (Refereed)
    Abstract [en]

    Hantaviruses have co-existed with their hosts for millions of years. Seewis virus (SWSV), a soricomorph-borne hantavirus, is widespread in Eurasia, ranging from Central Siberia to Western Europe. To gain insight into the phylogeography and evolutionary history of SWSV in Finland, lung tissue samples of 225 common shrews (Sorex araneus) trapped from different parts of Finland were screened for the presence of SWSV RNA. Forty-two of the samples were positive. Partial small (S), medium (M) and large (L) segments of the virus were sequenced, and analyzed together with all SWSV sequences available in Genbank. The phylogenetic analysis of the partial S-segment sequences suggested that all Finnish SWSV strains shared their most recent common ancestor with the Eastern European strains, while the L-segment suggested multiple introductions. The difference between the Land S-segment phylogenies implied that reassortment events play a role in the evolution of SWSV. Of the Finnish strains, variants from Eastern Finland occupied the root position in the phylogeny, and had the highest genetic diversity, supporting the hypothesis that SWSV reached Finland first form the east. During the spread in Finland, the virus has formed three separate lineages, identified here by correlation analysis of genetic versus geographic distance combined with median-joining network analysis. These results support the hypothesis that Finnish SWSV recolonized Finland with its host, the common shrew, from east after the last ice age 12,000-8000 years ago, and then subsequently spread along emerging land bridges towards west or north with the migration and population expansion of its host.

  • 129. Llorens, Carlos
    et al.
    Futami, Ricardo
    Covelli, Laura
    Domínguez-Escribá, Laura
    Viu, Jose M
    Tamarit, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Aguilar-Rodríguez, Jose
    Vicente-Ripolles, Miguel
    Fuster, Gonzalo
    Bernet, Guillermo P
    Maumus, Florian
    Munoz-Pomer, Alfonso
    Sempere, Jose M
    Latorre, Amparo
    Moya, Andres
    The Gypsy Database (GyDB) of mobile genetic elements: release 2.0.2011In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 39, no Database issueArticle in journal (Refereed)
    Abstract [en]

    This article introduces the second release of the Gypsy Database of Mobile Genetic Elements (GyDB 2.0): a research project devoted to the evolutionary dynamics of viruses and transposable elements based on their phylogenetic classification (per lineage and protein domain). The Gypsy Database (GyDB) is a long-term project that is continuously progressing, and that owing to the high molecular diversity of mobile elements requires to be completed in several stages. GyDB 2.0 has been powered with a wiki to allow other researchers participate in the project. The current database stage and scope are long terminal repeats (LTR) retroelements and relatives. GyDB 2.0 is an update based on the analysis of Ty3/Gypsy, Retroviridae, Ty1/Copia and Bel/Pao LTR retroelements and the Caulimoviridae pararetroviruses of plants. Among other features, in terms of the aforementioned topics, this update adds: (i) a variety of descriptions and reviews distributed in multiple web pages; (ii) protein-based phylogenies, where phylogenetic levels are assigned to distinct classified elements; (iii) a collection of multiple alignments, lineage-specific hidden Markov models and consensus sequences, called GyDB collection; (iv) updated RefSeq databases and BLAST and HMM servers to facilitate sequence characterization of new LTR retroelement and caulimovirus queries; and (v) a bibliographic server. GyDB 2.0 is available at http://gydb.org.

  • 130.
    Lundgren, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Molecular Evolution.
    Malandrin, Laurence
    Eriksson, Stefan
    Huber, Harald
    Bernander, Rolf
    Cell Cycle Characteristics of Crenarchaea: Unity among DiversityManuscript (Other academic)
  • 131.
    Ma'ayeh, Showgy Y.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Liu, Jingyi
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Peirasmaki, Dimitra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Hörnaeus, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergström Lind, Sara K.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Svärd, Staffan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Characterization of the Giardia intestinalis secretome during interaction with human intestinal epithelial cells: The impact on host cells2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 12, article id e0006120Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Giardia intestinalis is a non-invasive protozoan parasite that causes giardiasis in humans, the most common form of parasite-induced diarrhea. Disease mechanisms are not completely defined and very few virulence factors are known.

    METHODOLOGY:

    To identify putative virulence factors and elucidate mechanistic pathways leading to disease, we have used proteomics to identify the major excretory-secretory products (ESPs) when Giardia trophozoites of WB and GS isolates (assemblages A and B, respectively) interact with intestinal epithelial cells (IECs) in vitro.

    FINDINGS:

    The main parts of the IEC and parasite secretomes are constitutively released proteins, the majority of which are associated with metabolism but several proteins are released in response to their interaction (87 and 41 WB and GS proteins, respectively, 76 and 45 human proteins in response to the respective isolates). In parasitized IECs, the secretome profile indicated effects on the cell actin cytoskeleton and the induction of immune responses whereas that of Giardia showed anti-oxidation, proteolysis (protease-associated) and induction of encystation responses. The Giardia secretome also contained immunodominant and glycosylated proteins as well as new candidate virulence factors and assemblage-specific differences were identified. A minor part of Giardia ESPs had signal peptides (29% for both isolates) and extracellular vesicles were detected in the ESPs fractions, suggesting alternative secretory pathways. Microscopic analyses showed ESPs binding to IECs and partial internalization. Parasite ESPs reduced ERK1/2 and P38 phosphorylation and NF-κB nuclear translocation. Giardia ESPs altered gene expression in IECs, with a transcriptional profile indicating recruitment of immune cells via chemokines, disturbances in glucose homeostasis, cholesterol and lipid metabolism, cell cycle and induction of apoptosis.

    CONCLUSIONS:

    This is the first study identifying Giardia ESPs and evaluating their effects on IECs. It highlights the importance of host and parasite ESPs during interactions and reveals the intricate cellular responses that can explain disease mechanisms and attenuated inflammatory responses during giardiasis.

  • 132.
    Mahajan, Mayank
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Evolution of cellular complexity and other remarkable features in Gemmataceae: Complex bacterial lineages defy prokaryotic trends2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Bacteria of the family Gemmataceae belong the phylum Planctomycetes and are remarkable because of their complex cellular architectures, previously considered to be traits exclusive to eukaryotes. This thesis provides clues to the atypical cell envelope, the enhanced radiotolerance and the amazing cellular complexity of these bacteria.

    A comparative genomics study of these bacteria revealed massive duplications and new combinations of structural domains that are highly abundant in eukaryotes but rare in bacteria. These domains are known to facilitate signalling and protein interactions. The proteins of these bacteria also contain long regions with no predicted domains. On average, eukaryotic proteins are longer and more disordered than prokaryotic proteins. Intriguingly, the length and fraction of disordered regions in proteins of some bacteria are higher than in many other prokaryotes, and these bacteria also have complex lifestyles. Many bacteria in the Planctomycetes, including the Gemmataceae, are among these few bacteria. This suggests that there is no sharp boundary between prokaryotes and eukaryotes with respect to protein length and domain composition patterns, as previously thought.

    A bioinformatics analysis revealed the loss of genes for the peptidoglycan cell wall in some lineages of the Planctomycetes. Loss of the gene for the FtsZ protein, the major cell division protein in bacteria, may have facilitated the evolution of budding in the Planctomycetales and led to the gradual loss of the cell wall and cell division gene cluster. These changes may have enabled the expansion of the inner membrane and triggered adaptive changes in conserved membrane proteins and transport systems. The loss of the peptidoglycan cell wall may also explain the altered cell morphology. A subcellular proteomics study showed that the DNA replication and repair proteins are associated with the cell envelope, which supports the cell factory model of DNA replication.

    T. immobilis, which has the simplest genome of all members of the Gemmataceae, was found to be naturally competent and most suitable for transformation experiments. T. immobilis was transformed to produce mutants in which the gene for DdrA, a double stranded break DNA repair protein, has been inactivated. The DdrA-null mutant showed a major loss in radiotolerance.

    List of papers
    1. Comparative genomics reveals massive paralogization and a role for protein interactions in the Gemmataceae, bacteria with complex cell structures
    Open this publication in new window or tab >>Comparative genomics reveals massive paralogization and a role for protein interactions in the Gemmataceae, bacteria with complex cell structures
    Show others...
    2019 (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    National Category
    Evolutionary Biology
    Research subject
    Biology with specialization in Molecular Evolution
    Identifiers
    urn:nbn:se:uu:diva-378565 (URN)
    Available from: 2019-03-06 Created: 2019-03-06 Last updated: 2019-03-22
    2. Independent losses of gene clusters for cell wall and cell division complexes in the Planctomycetes: clues to the evolution of cellular complexity
    Open this publication in new window or tab >>Independent losses of gene clusters for cell wall and cell division complexes in the Planctomycetes: clues to the evolution of cellular complexity
    Show others...
    2019 (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    National Category
    Evolutionary Biology
    Research subject
    Biology with specialization in Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-378566 (URN)
    Available from: 2019-03-06 Created: 2019-03-06 Last updated: 2019-03-22
    3. Natural competence in the Planctomycetes and its use in transforming the Gemmata-related species Tuwongella immobilis
    Open this publication in new window or tab >>Natural competence in the Planctomycetes and its use in transforming the Gemmata-related species Tuwongella immobilis
    Show others...
    2019 (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    National Category
    Evolutionary Biology
    Research subject
    Biology with specialization in Molecular Evolution
    Identifiers
    urn:nbn:se:uu:diva-378567 (URN)
    Available from: 2019-03-06 Created: 2019-03-06 Last updated: 2019-03-22
    4. The subcellular proteome suggests that the replication machinery is located distinct from other information processing systems in the Gemmata-related bacterium Tuwongella immobilis.
    Open this publication in new window or tab >>The subcellular proteome suggests that the replication machinery is located distinct from other information processing systems in the Gemmata-related bacterium Tuwongella immobilis.
    2019 (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    National Category
    Evolutionary Biology
    Research subject
    Biology with specialization in Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-378568 (URN)
    Available from: 2019-03-06 Created: 2019-03-06 Last updated: 2019-03-22
    5. Comparative proteomics identify the core proteome of growing bacterial cells of the family Gemmataceae
    Open this publication in new window or tab >>Comparative proteomics identify the core proteome of growing bacterial cells of the family Gemmataceae
    2019 (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    National Category
    Evolutionary Biology
    Research subject
    Biology with specialization in Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-378569 (URN)
    Available from: 2019-03-06 Created: 2019-03-06 Last updated: 2019-03-22
  • 133.
    Maric, Jovana
    et al.
    Med Univ Graz, Inst Expt & Clin Pharmacol, Graz, Austria;Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden.
    Ravindran, Avinash
    Karolinska Inst, Dept Med, Immunol & Allergy Unit, Stockholm, Sweden.
    Mazzurana, Luca
    Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden.
    Björklund, Åsa K.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Van Acker, Aline
    Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden.
    Rao, Anna
    Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden.
    Friberg, Danielle
    Karolinska Univ Hosp, Dept Otorhinolaryngol, Stockholm, Sweden;Karolinska Inst, CLINTEC, Stockholm, Sweden.
    Dahlen, Sven-Erik
    Karolinska Inst, Inst Environm Med, Expt Asthma & Allergy Res, Stockholm, Sweden.
    Heinemann, Akos
    Med Univ Graz, Inst Expt & Clin Pharmacol, Graz, Austria.
    Konya, Viktoria
    Med Univ Graz, Inst Expt & Clin Pharmacol, Graz, Austria;Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden.
    Mjösberg, Jenny
    Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Prostaglandin E-2 suppresses human group 2 innate lymphoid cell function2018In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 141, no 5, p. 1761-1773.e6Article in journal (Refereed)
    Abstract [en]

    Background: Group 2 innate lymphoid cells (ILC2s) are involved in the initial phase of type 2 inflammation and can amplify allergic immune responses by orchestrating other type 2 immune cells. Prostaglandin (PG) E-2 is a bioactive lipid that plays protective roles in the lung, particularly during allergic inflammation.

    Objective: We set out to investigate how PGE(2) regulates human ILC2 function.

    Methods: The effects of PGE(2) on human ILC2 proliferation and intracellular cytokine and transcription factor expression were assessed by means of flow cytometry. Cytokine production was measured by using ELISA, and real-time quantitative PCR was performed to detect PGE(2) receptor expression.

    Results: PGE(2) inhibited GATA-3 expression, as well as production of the type 2 cytokines IL-5 and IL-13, from human tonsillar and blood ILC2s in response to stimulation with a combination of IL-25, IL-33, thymic stromal lymphopoietin, and IL-2. Furthermore, PGE(2) downregulated the expression of IL-2 receptor alpha (CD25). In line with this observation, PGE(2) decreased ILC2 proliferation. These effects were mediated by the combined action of E-type prostanoid receptor (EP) 2 and EP4 receptors, which were specifically expressed on ILC2s.

    Conclusion: Our findings reveal that PGE(2) limits ILC2 activation and propose that selective EP2 and EP4 receptor agonists might serve as a promising therapeutic approach in treating allergic diseases by suppressing ILC2 function.

  • 134.
    Marques, Sueli
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    van Bruggen, David
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Vanichkina, Darya Pavlovna
    Univ Sydney, Centenary Inst, Gene & Stem Cell Therapy Program, Camperdown, NSW 2050, Australia;Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4067, Australia.
    Floriddia, Elisa Mariagrazia
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Munguba, Hermany
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Väremo, Leif
    Chalmers Univ Technol, Dept Biol & Biol Engn, Sci Life Lab, Kemivagen 10, S-41296 Gothenburg, Sweden.
    Giacomello, Stefania
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Box 1031, S-17121 Solna, Sweden.
    Falcao, Ana Mendanha
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Meijer, Mandy
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Björklund, Åsa K.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hjerling-Leffler, Jens
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Taft, Ryan James
    Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4067, Australia;Illumina Inc, San Diego, CA 92122 USA.
    Castelo-Branco, Goncalo
    Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, Biomedicum, S-17177 Stockholm, Sweden.
    Transcriptional Convergence of Oligodendrocyte Lineage Progenitors during Development2018In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 46, no 4, p. 504-517Article in journal (Refereed)
    Abstract [en]

    Pdgfra+ oligodendrocyte precursor cells (OPCs) arise in distinct specification waves during embryogenesis in the central nervous system (CNS). It is unclear whether there is a correlation between these waves and different oligodendrocyte (OL) states at adult stages. Here, we present bulk and single-cell transcriptomics resources providing insights on how transitions between these states occur. We found that post-natal OPCs from brain and spinal cord present similar transcriptional signatures. Moreover, post-natal OPC progeny of E13.5 Pdgfra+ cells present electrophysiological and transcriptional profiles similar to OPCs derived from subsequent specification waves, indicating that Pdgfra+ pre-OPCs rewire their transcriptional network during development. Single-cell RNA-seq and lineage tracing indicates that a subset of E13.5 Pdgfra+ cells originates cells of the pericyte lineage. Thus, our results indicate that embryonic Pdgfra+ cells in the CNS give rise to distinct post-natal cell lineages, including OPCs with convergent transcriptional profiles in different CNS regions.

  • 135.
    Marshall, Ian P. G.
    et al.
    Aarhus Univ, Microbiol Sect, Dept Biosci, Geomicrobiol, Aarhus, Denmark.;Aarhus Univ Hosp, Dept Mol Med, Aarhus, Denmark..
    Starnawski, Piotr </