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Work carried out by members of the Bioinformatics Data Science Group has been published or acknowledged in the following communications:

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  • Journal article
    Grundmann H, Glasner C, Albiger B, Aanensen DM, Tomlinson CT, Andrasević AT, Cantón R, Carmeli Y, Friedrich AW, Giske CG, Glupczynski Y, Gniadkowski M, Livermore DM, Nordmann P, Poirel L, Rossolini GM, Seifert H, Vatopoulos A, Walsh T, Woodford N, Monnet DL, European Survey of Carbapenemase-Producing Enterobacteriaceae EuSCAPE Working Groupet al., 2017,

    Occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in the European survey of carbapenemase-producing Enterobacteriaceae (EuSCAPE): a prospective, multinational study.

    , Lancet Infect Dis, Vol: 17, Pages: 153-163

    BACKGROUND: Gaps in the diagnostic capacity and heterogeneity of national surveillance and reporting standards in Europe make it difficult to contain carbapenemase-producing Enterobacteriaceae. We report the development of a consistent sampling framework and the results of the first structured survey on the occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in European hospitals. METHODS: National expert laboratories recruited hospitals with diagnostic capacities, who collected the first ten carbapenem non-susceptible clinical isolates of K pneumoniae or E coli and ten susceptible same-species comparator isolates and pertinent patient and hospital information. Isolates and data were relayed back to national expert laboratories, which made laboratory-substantiated information available for central analysis. FINDINGS: Between Nov 1, 2013, and April 30, 2014, 455 sentinel hospitals in 36 countries submitted 2703 clinical isolates (2301 [85%] K pneumoniae and 402 (15%) E coli). 850 (37%) of 2301 K pneumoniae samples and 77 (19%) of 402 E coli samples were carbapenemase (KPC, NDM, OXA-48-like, or VIM) producers. The ratio of K pneumoniae to E coli was 11:1. 1·3 patients per 10 000 hospital admissions had positive clinical specimens. Prevalence differed greatly, with the highest rates in Mediterranean and Balkan countries. Carbapenemase-producing K pneumoniae isolates showed high resistance to last-line antibiotics. INTERPRETATION: This initiative shows an encouraging commitment by all participants, and suggests that challenges in the establishment of a continent-wide enhanced sentinel surveillance for carbapenemase-producing Enterobacteriaeceae can be overcome. Strengthening infection control efforts in hospitals is crucial for controlling spread through local and national health care networks. FUNDING: European Centre for Disease Prevention and Control.

  • Journal article
    Ainsworth D, Sternberg MJE, Raczy C, Butcher SAet al., 2016,

    k-SLAM: Accurate and ultra-fast taxonomic classification and gene identification for large metagenomic datasets

    , Nucleic Acids Research, Vol: 45, Pages: 1649-1656, ISSN: 1362-4962

    k-SLAM is a highly e cient algorithm for the characterisa-tion of metagenomic data. Unlike other ultra-fast metage-nomic classi ers, full sequence alignment is performed allow-ing for gene identi cation and variant calling in addition toaccurate taxonomic classi cation. Ak-mer based methodprovides greater taxonomic accuracy than other classi ersand a three orders of magnitude speed increase over align-ment based approaches. The use of alignments to nd vari-ants and genes along with their taxonomic origins enablesnovel strains to be characterised. k-SLAM's speed allows afull taxonomic classi cation and gene identi cation to betractable on modern large datasets. A pseudo-assemblymethod is used to increase classi cation accuracy by up to40% for species which have high sequence homology withintheir genus.

  • Journal article
    Braga VMM, 2016,

    Defining functional interactions during biogenesis of epithelial junctions

    , Nature Communications, Vol: 7, ISSN: 2041-1723

    In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell-cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases.

  • Journal article
    Giotis ES, Robey RC, Skinner NG, Tomlinson CD, Goodbourn S, Skinner MAet al., 2016,

    Chicken interferome: avian interferon-stimulated genes identified by microarray and RNA-seq of primary chick embryo fibroblasts treated with a chicken type I interferon (IFN-α)

    , Veterinary Research, Vol: 47, ISSN: 1297-9716

    Viruses that infect birds pose major threats—to the global supply of chicken, the major, universally-acceptable meat, and as zoonotic agents (e.g. avian influenza viruses H5N1 and H7N9). Controlling these viruses in birds as well as understanding their emergence into, and transmission amongst, humans will require considerable ingenuity and understanding of how different species defend themselves. The type I interferon-coordinated response constitutes the major antiviral innate defence. Although interferon was discovered in chicken cells, details of the response, particularly the identity of hundreds of stimulated genes, are far better described in mammals. Viruses induce interferon-stimulated genes but they also regulate the expression of many hundreds of cellular metabolic and structural genes to facilitate their replication. This study focusses on the potentially anti-viral genes by identifying those induced just by interferon in primary chick embryo fibroblasts. Three transcriptomic technologies were exploited: RNA-seq, a classical 3′-biased chicken microarray and a high density, “sense target”, whole transcriptome chicken microarray, with each recognising 120–150 regulated genes (curated for duplication and incorrect assignment of some microarray probesets). Overall, the results are considered robust because 128 of the compiled, curated list of 193 regulated genes were detected by two, or more, of the technologies.

  • Journal article
    Florea M, Hagemann H, Santosa G, Abbott J, Micklem CN, Spencer-Milnes X, de Arroyo Garcia L, Paschou D, Lazenbatt C, Kong D, Chughtai H, Jensen K, Freemont P, Kitney RI, Reeve B, Ellis Tet al., 2016,

    Engineering control of bacterial cellulose production using a genetic toolkit and a new cellulose-producing strain

    , Proceedings of the National Academy of Sciences of the United States of America, Vol: 113, Pages: E3431-E3440, ISSN: 1091-6490

    Bacterial cellulose is a strong and ultrapure form of cellulose produced naturally by several species of the Acetobacteraceae. Its high strength, purity and biocompatibility make it of great interest to materials science, however precise control of its biosynthesis has remained a challenge for biotechnology. Here we isolate a new strain of Komagataeibacter rhaeticus (Komagataeibacter rhaeticus iGEM) that can produce cellulose at high yields, grow in low nitrogen conditions, and is highly resistant to toxic chemicals. We achieve external control over its bacterial cellulose production through development of a modular genetic toolkit that enables rational reprogramming of the cell. To further its use as an organism for biotechnology, we sequenced its genome and demonstrate genetic circuits that enable functionalization and patterning of heterologous gene expression within the cellulose matrix. This work lays the foundations for using genetic engineering to produce cellulose-based materials, with numerous applications in basic science, materials engineering and biotechnology.

  • Journal article
    Florea M, Reeve B, Abbott J, Freemont PS, Ellis Tet al., 2016,

    Genome sequence and plasmid transformation of the model high-yield bacterial cellulose producer Gluconacetobacter hansenii ATCC 53582.

    , Scientific Reports, Vol: 6, ISSN: 2045-2322

    Bacterial cellulose is a strong, highly pure form of cellulose that is used in a range of applications in industry, consumer goods and medicine. Gluconacetobacter hansenii ATCC 53582 is one of the highest reported bacterial cellulose producing strains and has been used as a model organism in numerous studies of bacterial cellulose production and studies aiming to increased cellulose productivity. Here we present a high-quality draft genome sequence for G. hansenii ATCC 53582 and find that in addition to the previously described cellulose synthase operon, ATCC 53582 contains two additional cellulose synthase operons and several previously undescribed genes associated with cellulose production. In parallel, we also develop optimized protocols and identify plasmid backbones suitable for transformation of ATCC 53582, albeit with low efficiencies. Together, these results provide important information for further studies into cellulose synthesis and for future studies aiming to genetically engineer G. hansenii ATCC 53582 for increased cellulose productivity.

  • Journal article
    Stanford NJ, Tomlinson CD, et al, 2015,

    The evolution of standards and data management practices in systems biology

    , Molecular Systems Biology, Vol: 11, ISSN: 1744-4292
  • Journal article
    Kato N, Loh M, Takeuchi F, Verweij N, Wang X, Zhang W, Kelly TN, Saleheen D, Lehne B, Leach IM, Drong AW, Abbott J, Wahl S, Tan S-T, Scott WR, Campanella G, Chadeau-Hyam M, Afzal U, Ahluwalia TS, Bonder MJ, Chen P, Dehghan A, Edwards TL, Esko T, Go MJ, Harris SE, Hartiala J, Kasela S, Kasturiratne A, Khor C-C, Kleber ME, Li H, Mok ZY, Nakatochi M, Sapari NS, Saxena R, Stewart AFR, Stolk L, Tabara Y, Teh AL, Wu Y, Wu J-Y, Zhang Y, Aits I, Alves ADSC, Das S, Dorajoo R, Hopewell JC, Kim YK, Koivula RW, Luan J, Lyytikainen L-P, Nguyen QN, Pereira MA, Postmus I, Raitakari OT, Bryan MS, Scott RA, Sorice R, Tragante V, Traglia M, White J, Yamamoto K, Zhang Y, Adair LS, Ahmed A, Akiyama K, Asif R, Aung T, Barroso I, Bjonnes A, Braun TR, Cai H, Chang L-C, Chen C-H, Cheng C-Y, Chong Y-S, Collins R, Courtney R, Davies G, Delgado G, Do LD, Doevendans PA, Gansevoort RT, Gao Y-T, Grammer TB, Grarup N, Grewal J, Gu D, Wander GS, Hartikainen A-L, Hazen SL, He J, Heng C-K, Hixson JE, Hofman A, Hsu C, Huang W, Husemoen LLN, Hwang J-Y, Ichihara S, Igase M, Isono M, Justesen JM, Katsuy T, Kibriya MG, Kim YJ, Kishimoto M, Koh W-P, Kohara K, Kumari M, Kwek K, Lee NR, Lee J, Liao J, Lieb W, Liewald DCM, Matsubara T, Matsushita Y, Meitinger T, Mihailov E, Milani L, Mills R, Mononen N, Mueller-Nurasyid M, Nabika T, Nakashima E, Ng HK, Nikus K, Nutile T, Ohkubo T, Ohnaka K, Parish S, Paternoster L, Peng H, Peters A, Pham ST, Pinidiyapathirage MJ, Rahman M, Rakugi H, Rolandsson O, Rozario MA, Ruggiero D, Sala CF, Sarju R, Shimokawa K, Snieder H, Sparso T, Spiering W, Starr JM, Stott DJ, Stram DO, Sugiyama T, Szymczak S, Tang WHW, Tong L, Trompet S, Turjanmaa V, Ueshima H, Uitterlinden AG, Umemura S, Vaarasmaki M, van Dam RM, van Gilst WH, van Veldhuisen DJ, Viikari JS, Waldenberger M, Wang Y, Wang A, Wilson R, Wong T-Y, Xiang Y-B, Yamaguchi S, Ye X, Young RD, Young TL, Yuan J-M, Zhou X, Asselbergs FW, Ciullo M, Clarke R, Deloukas P, Franke A, Franks PW, Franks S, Friedlander Y, Gross MD, Guoet al., 2015,

    Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

    , Nature Genetics, Vol: 47, Pages: 1282-1293, ISSN: 1546-1718

    We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

  • Journal article
    Turner CE, Abbott J, Lamagni T, Holden MTG, David S, Jones MD, Game L, Efstratiou A, Sriskandan Set al., 2015,

    Emergence of a new highly successful acapsular group A Streptococcus clade of the genotype emm89 in the United Kingdom

    , mBio, Vol: 6, ISSN: 2161-2129
  • Journal article
    Chambers JC, Loh M, Lehne B, Drong A, Kriebel J, Motta V, Wahl S, Elliott HR, Rota F, Scott WR, Zhang W, Tan S-T, Campanella G, Chadeau-Hyam M, Yengo L, Richmond RC, Adamowicz-Brice M, Afzal U, Bozaoglu K, Mok ZY, Ng HK, Pattou F, Prokisch H, Rozario MA, Tarantini L, Abbott J, Ala-Korpela M, Albetti B, Ammerpohl O, Bertazzi PA, Blancher C, Caiazzo R, Danesh J, Gaunt TR, de Lusignan S, Gieger C, Illig T, Jha S, Jones S, Jowett J, Kangas AJ, Kasturiratne A, Kato N, Kotea N, Kowlessur S, Pitkaeniemi J, Punjabi P, Saleheen D, Schafmayer C, Soininen P, Tai E-S, Thorand B, Tuomilehto J, Wickremasinghe AR, Kyrtopoulos SA, Aitman TJ, Herder C, Hampe J, Cauchi S, Relton CL, Froguel P, Soong R, Vineis P, Jarvelin M-R, Scott J, Grallert H, Bollati V, Elliott P, McCarthy MI, Kooner JSet al., 2015,

    Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study

    , The Lancet Diabetes & Endocrinology, Vol: 3, Pages: 526-534, ISSN: 2213-8587

    BackgroundIndian Asians, who make up a quarter of the world's population, are at high risk of developing type 2 diabetes. We investigated whether DNA methylation is associated with future type 2 diabetes incidence in Indian Asians and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes.MethodsWe did a nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. Patients were recruited between May 1, 2002, and Sept 12, 2008. We did epigenome-wide association analysis using samples from Indian Asians with incident type 2 diabetes and age-matched and sex-matched Indian Asian controls, followed by replication testing of top-ranking signals in Europeans. For both discovery and replication, DNA methylation was measured in the baseline blood sample, which was collected before the onset of type 2 diabetes. Epigenome-wide significance was set at p<1 × 10−7. We compared methylation levels between Indian Asian and European controls without type 2 diabetes at baseline to estimate the potential contribution of DNA methylation to increased risk of future type 2 diabetes incidence among Indian Asians.Findings1608 (11·9%) of 13 535 Indian Asians and 306 (4·3%) of 7066 Europeans developed type 2 diabetes over a mean of 8·5 years (SD 1·8) of follow-up. The age-adjusted and sex-adjusted incidence of type 2 diabetes was 3·1 times (95% CI 2·8–3·6; p<0·0001) higher among Indian Asians than among Europeans, and remained 2·5 times (2·1–2·9; p<0·0001) higher after adjustment for adiposity, physical activity, family history of type 2 diabetes, and baselin

  • Journal article
    Chambers JC, Abbott J, Zhang W, Turro E, Scott WR, Tan S-T, Afzal U, Afaq S, Loh M, Lehne B, O'Reilly P, Gaulton KJ, Pearson RD, Li X, Lavery A, Vandrovcova J, Wass MN, Miller K, Sehmi J, Oozageer L, Kooner IK, Al-Hussaini A, Mills R, Grewal J, Panoulas V, Lewin AM, Northwood K, Wander GS, Geoghegan F, Li Y, Wang J, Aitman TJ, McCarthy MI, Scott J, Butcher S, Elliott P, Kooner JSet al., 2014,

    The South Asian Genome

    , PLOS One, Vol: 9, ISSN: 1932-6203

    The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.

  • Conference paper
    Shand B, Thomas GA, Blaveri E, Rashbass J, Farrimond J, Chapman M, Tomlinson Cet al., 2014,

    BiobankLink: automating data exchange between the cancer registry and human biosample collections

    , Cancer Outcomes Conference 2014
  • Journal article
    Harries P, Davies M, Gilhooley K, Gilhooley M, Tomlinson CDet al., 2014,

    Educating novice practitioners to detect elder financial abuse: a randomised controlled trial

    , BMC Medical Education, Vol: 14
  • Journal article
    Woodbridge M, Fagiolo G, O'Regan DP, 2013,

    MRIdb: Medical Image Management for Biobank Research

    , JOURNAL OF DIGITAL IMAGING, Vol: 26, Pages: 886-890, ISSN: 0897-1889
  • Journal article
    Filippis I, Lopez-Cobollo R, Abbott J, Butcher S, Bishop GJet al., 2013,

    Using a periclinal chimera to unravel layer-specific gene expression in plants

    , PLANT JOURNAL, Vol: 75, Pages: 1039-1049, ISSN: 0960-7412
  • Journal article
    Williams KJ, Bryant WA, Jenkins VA, Barton GR, Witney AA, Pinney JW, Robertson BDet al., 2013,

    Deciphering the response of Mycobacterium smegmatis to nitrogen stress using bipartite active modules

    , BMC Genomics, Vol: 14, ISSN: 1471-2164

    BackgroundThe ability to adapt to environments with fluctuating nutrient availability is vital for bacterial survival. Although essential for growth, few nitrogen metabolism genes have been identified or fully characterised in mycobacteria and nitrogen stress survival mechanisms are unknown.ResultsA global transcriptional analysis of the mycobacterial response to nitrogen stress, showed a significant change in the differential expression of 16% of the Mycobacterium smegmatis genome. Gene expression changes were mapped onto the metabolic network using Active Modules for Bipartite Networks (AMBIENT) to identify metabolic pathways showing coordinated transcriptional responses to the stress. AMBIENT revealed several key features of the metabolic response not identified by KEGG enrichment alone. Down regulated reactions were associated with the general reduction in cellular metabolism as a consequence of reduced growth rate. Up-regulated modules highlighted metabolic changes in nitrogen assimilation and scavenging, as well as reactions involved in hydrogen peroxide metabolism, carbon scavenging and energy generation.ConclusionsApplication of an Active Modules algorithm to transcriptomic data identified key metabolic reactions and pathways altered in response to nitrogen stress, which are central to survival under nitrogen limiting environments.

  • Journal article
    Jenkins VA, Barton GR, Robertson BD, Williams KJet al., 2013,

    Genome wide analysis of the complete GlnR nitrogen-response regulon in Mycobacterium smegmatis

    , BMC Genomics, Vol: 14, ISSN: 1471-2164

    BackgroundNitrogen is an essential element for bacterial growth and an important component of biological macromolecules. Consequently, responding to nitrogen limitation is critical for bacterial survival and involves the interplay of signalling pathways and transcriptional regulation of nitrogen assimilation and scavenging genes. In the soil dwelling saprophyte Mycobacterium smegmatis the OmpR-type response regulator GlnR is thought to mediate the transcriptomic response to nitrogen limitation. However, to date only ten genes have been shown to be in the GlnR regulon, a vastly reduced number compared to other organisms.ResultsWe investigated the role of GlnR in the nitrogen limitation response and determined the entire GlnR regulon, by combining expression profiling of M. smegmatis wild type and glnR deletion mutant, with GlnR-specific chromatin immunoprecipitation and high throughput sequencing. We identify 53 GlnR binding sites during nitrogen limitation that control the expression of over 100 genes, demonstrating that GlnR is the regulator controlling the assimilation and utilisation of nitrogen. We also determine a consensus GlnR binding motif and identify key residues within the motif that are required for specific GlnR binding.ConclusionsWe have demonstrated that GlnR is the global nitrogen response regulator in M. smegmatis, directly regulating the expression of more than 100 genes. GlnR controls key nitrogen stress survival processes including primary nitrogen metabolism pathways, the ability to utilise nitrate and urea as alternative nitrogen sources, and the potential to use cellular components to provide a source of ammonium. These studies further our understanding of how mycobacteria survive nutrient limiting conditions.

  • Journal article
    Sheppard C, James E, Barton G, Matthews S, Severinov K, Wigneshweraraj Set al., 2013,

    A non-bacterial transcription factor inhibits bacterial transcription by a multipronged mechanism

    , RNA BIOLOGY, Vol: 10, Pages: 495-501, ISSN: 1547-6286
  • Journal article
    Williams KJ, Bennett MH, Barton GR, Jenkins VA, Robertson BDet al., 2013,

    Adenylylation of mycobacterial Glnk (PII) protein is induced by nitrogen limitation

    , TUBERCULOSIS, Vol: 93, Pages: 198-206, ISSN: 1472-9792
  • Journal article
    Tomlinson CD, Barton GR, Woodbridge M, Butcher SAet al., 2013,

    XperimentR: painless annotation of a biological experiment for the laboratory scientist

    , Bmc Bioinformatics

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