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      Dominant Role of Nucleotide Substitution in the Diversification of Serotype 3 Pneumococci over Decades and during a Single Infection


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          Streptococcus pneumoniae of serotype 3 possess a mucoid capsule and cause disease associated with high mortality rates relative to other pneumococci. Phylogenetic analysis of a complete reference genome and 81 draft sequences from clonal complex 180, the predominant serotype 3 clone in much of the world, found most sampled isolates belonged to a clade affected by few diversifying recombinations. However, other isolates indicate significant genetic variation has accumulated over the clonal complex's entire history. Two closely related genomes, one from the blood and another from the cerebrospinal fluid, were obtained from a patient with meningitis. The pair differed in their behaviour in a mouse model of disease and in their susceptibility to antimicrobials, with at least some of these changes attributable to a mutation that up-regulated the patAB efflux pump. This indicates clinically important phenotypic variation can accumulate rapidly through small alterations to the genotype.

          Author Summary

          Streptococcus pneumoniae (‘the pneumococcus’) is a bacterium commonly found asymptomatically in the human nasopharynx that represents a common cause of diseases such as pneumonia, bacteraemia and meningitis. Some strains have been found to exchange DNA with other bacteria at a high rate. However, serotype 3 pneumococci are unusual both in not exhibiting much genetic variation and causing disease with a comparatively high relative rate of mortality. Here we used whole genome sequencing to characterise 82 serotype 3 pneumococci, finding that the majority of the population accumulate variation very slowly. However, comparing two isolates from a single case of disease revealed a small number of mutations had occurred over a short period of time. These resulted in differences in the activity of several genes, including two encoding a drug efflux pump. The pair of isolates was found to differ in their tolerance of different antimicrobial compounds and their behaviour in a mouse model of disease. However, moving the mutation that caused the change in resistance into a distantly-related pneumococcus failed to fully replicate the other changes in behaviour, which indicates that interpretation of the impact of mutations in different strains of diverse bacterial species will be difficult.

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          Vienna RNA secondary structure server.

          The Vienna RNA secondary structure server provides a web interface to the most frequently used functions of the Vienna RNA software package for the analysis of RNA secondary structures. It currently offers prediction of secondary structure from a single sequence, prediction of the consensus secondary structure for a set of aligned sequences and the design of sequences that will fold into a predefined structure. All three services can be accessed via the Vienna RNA web server at http://rna.tbi.univie.ac.at/.
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            Artemis and ACT: viewing, annotating and comparing sequences stored in a relational database

            Motivation: Artemis and Artemis Comparison Tool (ACT) have become mainstream tools for viewing and annotating sequence data, particularly for microbial genomes. Since its first release, Artemis has been continuously developed and supported with additional functionality for editing and analysing sequences based on feedback from an active user community of laboratory biologists and professional annotators. Nevertheless, its utility has been somewhat restricted by its limitation to reading and writing from flat files. Therefore, a new version of Artemis has been developed, which reads from and writes to a relational database schema, and allows users to annotate more complex, often large and fragmented, genome sequences. Results: Artemis and ACT have now been extended to read and write directly to the Generic Model Organism Database (GMOD, http://www.gmod.org) Chado relational database schema. In addition, a Gene Builder tool has been developed to provide structured forms and tables to edit coordinates of gene models and edit functional annotation, based on standard ontologies, controlled vocabularies and free text. Availability: Artemis and ACT are freely available (under a GPL licence) for download (for MacOSX, UNIX and Windows) at the Wellcome Trust Sanger Institute web sites: http://www.sanger.ac.uk/Software/Artemis/ http://www.sanger.ac.uk/Software/ACT/ Contact: artemis@sanger.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.
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              Whole-genome sequencing for analysis of an outbreak of meticillin-resistant Staphylococcus aureus: a descriptive study

              Summary Background The emergence of meticillin-resistant Staphylococcus aureus (MRSA) that can persist in the community and replace existing hospital-adapted lineages of MRSA means that it is necessary to understand transmission dynamics in terms of hospitals and the community as one entity. We assessed the use of whole-genome sequencing to enhance detection of MRSA transmission between these settings. Methods We studied a putative MRSA outbreak on a special care baby unit (SCBU) at a National Health Service Foundation Trust in Cambridge, UK. We used whole-genome sequencing to validate and expand findings from an infection-control team who assessed the outbreak through conventional analysis of epidemiological data and antibiogram profiles. We sequenced isolates from all colonised patients in the SCBU, and sequenced MRSA isolates from patients in the hospital or community with the same antibiotic susceptibility profile as the outbreak strain. Findings The hospital infection-control team identified 12 infants colonised with MRSA in a 6 month period in 2011, who were suspected of being linked, but a persistent outbreak could not be confirmed with conventional methods. With whole-genome sequencing, we identified 26 related cases of MRSA carriage, and showed transmission occurred within the SCBU, between mothers on a postnatal ward, and in the community. The outbreak MRSA type was a new sequence type (ST) 2371, which is closely related to ST22, but contains genes encoding Panton-Valentine leucocidin. Whole-genome sequencing data were used to propose and confirm that MRSA carriage by a staff member had allowed the outbreak to persist during periods without known infection on the SCBU and after a deep clean. Interpretation Whole-genome sequencing holds great promise for rapid, accurate, and comprehensive identification of bacterial transmission pathways in hospital and community settings, with concomitant reductions in infections, morbidity, and costs. Funding UK Clinical Research Collaboration Translational Infection Research Initiative, Wellcome Trust, Health Protection Agency, and the National Institute for Health Research Cambridge Biomedical Research Centre.

                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                October 2013
                October 2013
                10 October 2013
                : 9
                : 10
                : e1003868
                [1 ]Pathogen Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
                [2 ]Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
                [3 ]Institute of Microbiology and Infection and School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
                [4 ]Bacterial Microarray Group, Division of Clinical Sciences, St. George's Hospital, University of London, London, United Kingdom
                [5 ]Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
                [6 ]Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
                [7 ]Dept. of Laboratory Medicine, Division of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden
                [8 ]National Institute of Public Health, Prague, Czech Republic
                [9 ]Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
                Inserm U722, France
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: NJC DI JP SN BHN TJM SDB. Performed the experiments: NJC AMM KAG DI TF MCF SJS SB HZ JH. Analyzed the data: NJC AMM DI LB SRH JD JH. Contributed reagents/materials/analysis tools: SB HZ SN BHN TJM DI. Wrote the paper: NJC SDB JP TJM.

                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                : 7 May 2013
                : 24 August 2013
                Page count
                Pages: 14
                This work was funded by Wellcome Trust grant numbers 098051 and 086547, and EU grant HEALTH-F3-2009-223111 CAREPNEUMO, and by grants from the Swedish Research Council, ALF grant from Stockholm County Council, EU commission (PREVIS), Swedish Foundation for Strategic Research, Swedish Foundation for Strategic Research, and Knut and Alice Wallenberg foundation. NJC was funded by an AXA Foundation post-doctoral fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article



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