Publications by authors named "Bart Barrell"

38 Publications

Author Correction: A transcriptomic analysis of the phylum Nematoda.

Nat Genet 2020 Jul;52(7):750

School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41588-020-0658-6DOI Listing
July 2020

Genomic analysis of the causative agents of coccidiosis in domestic chickens.

Genome Res 2014 Oct 11;24(10):1676-85. Epub 2014 Jul 11.

Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, United Kingdom;

Global production of chickens has trebled in the past two decades and they are now the most important source of dietary animal protein worldwide. Chickens are subject to many infectious diseases that reduce their performance and productivity. Coccidiosis, caused by apicomplexan protozoa of the genus Eimeria, is one of the most important poultry diseases. Understanding the biology of Eimeria parasites underpins development of new drugs and vaccines needed to improve global food security. We have produced annotated genome sequences of all seven species of Eimeria that infect domestic chickens, which reveal the full extent of previously described repeat-rich and repeat-poor regions and show that these parasites possess the most repeat-rich proteomes ever described. Furthermore, while no other apicomplexan has been found to possess retrotransposons, Eimeria is home to a family of chromoviruses. Analysis of Eimeria genes involved in basic biology and host-parasite interaction highlights adaptations to a relatively simple developmental life cycle and a complex array of co-expressed surface proteins involved in host cell binding.
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http://dx.doi.org/10.1101/gr.168955.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199364PMC
October 2014

The genome sequence of ectromelia virus Naval and Cornell isolates from outbreaks in North America.

Virology 2014 Aug 5;462-463:218-26. Epub 2014 Jul 5.

Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Nicolas Cabrera 1, Campus de Cantoblanco, Madrid, Spain; Department of Medicine, University of Cambridge, United Kingdom. Electronic address:

Ectromelia virus (ECTV) is the causative agent of mousepox, a disease of laboratory mouse colonies and an excellent model for human smallpox. We report the genome sequence of two isolates from outbreaks in laboratory mouse colonies in the USA in 1995 and 1999: ECTV-Naval and ECTV-Cornell, respectively. The genome of ECTV-Naval and ECTV-Cornell was sequenced by the 454-Roche technology. The ECTV-Naval genome was also sequenced by the Sanger and Illumina technologies in order to evaluate these technologies for poxvirus genome sequencing. Genomic comparisons revealed that ECTV-Naval and ECTV-Cornell correspond to the same virus isolated from independent outbreaks. Both ECTV-Naval and ECTV-Cornell are extremely virulent in susceptible BALB/c mice, similar to ECTV-Moscow. This is consistent with the ECTV-Naval genome sharing 98.2% DNA sequence identity with that of ECTV-Moscow, and indicates that the genetic differences with ECTV-Moscow do not affect the virulence of ECTV-Naval in the mousepox model of footpad infection.
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http://dx.doi.org/10.1016/j.virol.2014.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139192PMC
August 2014

A conserved acetyl esterase domain targets diverse bacteriophages to the Vi capsular receptor of Salmonella enterica serovar Typhi.

J Bacteriol 2010 Nov 3;192(21):5746-54. Epub 2010 Sep 3.

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Sulston Building, Hinxton, Cambridge CB10 1SA, United Kingdom.

A number of bacteriophages have been identified that target the Vi capsular antigen of Salmonella enterica serovar Typhi. Here we show that these Vi phages represent a remarkably diverse set of phages belonging to three phage families, including Podoviridae and Myoviridae. Genome analysis facilitated the further classification of these phages and highlighted aspects of their independent evolution. Significantly, a conserved protein domain carrying an acetyl esterase was found to be associated with at least one tail fiber gene for all Vi phages, and the presence of this domain was confirmed in representative phage particles by mass spectrometric analysis. Thus, we provide a simple explanation and paradigm of how a diverse group of phages target a single key virulence antigen associated with this important human-restricted pathogen.
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http://dx.doi.org/10.1128/JB.00659-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953684PMC
November 2010

New insights into the blood-stage transcriptome of Plasmodium falciparum using RNA-Seq.

Mol Microbiol 2010 Apr 4;76(1):12-24. Epub 2010 Feb 4.

Parasite Genomics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

Recent advances in high-throughput sequencing present a new opportunity to deeply probe an organism's transcriptome. In this study, we used Illumina-based massively parallel sequencing to gain new insight into the transcriptome (RNA-Seq) of the human malaria parasite, Plasmodium falciparum. Using data collected at seven time points during the intraerythrocytic developmental cycle, we (i) detect novel gene transcripts; (ii) correct hundreds of gene models; (iii) propose alternative splicing events; and (iv) predict 5' and 3' untranslated regions. Approximately 70% of the unique sequencing reads map to previously annotated protein-coding genes. The RNA-Seq results greatly improve existing annotation of the P. falciparum genome with over 10% of gene models modified. Our data confirm 75% of predicted splice sites and identify 202 new splice sites, including 84 previously uncharacterized alternative splicing events. We also discovered 107 novel transcripts and expression of 38 pseudogenes, with many demonstrating differential expression across the developmental time series. Our RNA-Seq results correlate well with DNA microarray analysis performed in parallel on the same samples, and provide improved resolution over the microarray-based method. These data reveal new features of the P. falciparum transcriptional landscape and significantly advance our understanding of the parasite's red blood cell-stage transcriptome.
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http://dx.doi.org/10.1111/j.1365-2958.2009.07026.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859250PMC
April 2010

Characterization of a novel wood mouse virus related to murid herpesvirus 4.

J Gen Virol 2010 Apr 25;91(Pt 4):867-79. Epub 2009 Nov 25.

School of Infection and Host Defence, University of Liverpool, Liverpool L69 3GA, UK.

Two novel gammaherpesviruses were isolated, one from a field vole (Microtus agrestis) and the other from wood mice (Apodemus sylvaticus). The genome of the latter, designated wood mouse herpesvirus (WMHV), was completely sequenced. WMHV had the same genome structure and predicted gene content as murid herpesvirus 4 (MuHV4; murine gammaherpesvirus 68). Overall nucleotide sequence identity between WMHV and MuHV4 was 85 % and most of the 10 kb region at the left end of the unique region was particularly highly conserved, especially the viral tRNA-like sequences and the coding regions of genes M1 and M4. The partial sequence (71 913 bp) of another gammaherpesvirus, Brest herpesvirus (BRHV), which was isolated ostensibly from a white-toothed shrew (Crocidura russula), was also determined. The BRHV sequence was 99.2 % identical to the corresponding portion of the WMHV genome. Thus, WMHV and BRHV appeared to be strains of a new virus species. Biological characterization of WMHV indicated that it grew with similar kinetics to MuHV4 in cell culture. The pathogenesis of WMHV in wood mice was also extremely similar to that of MuHV4, except for the absence of inducible bronchus-associated lymphoid tissue at day 14 post-infection and a higher load of latently infected cells at 21 days post-infection.
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http://dx.doi.org/10.1099/vir.0.017327-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888160PMC
April 2010

Evidence for niche adaptation in the genome of the bovine pathogen Streptococcus uberis.

BMC Genomics 2009 Jan 28;10:54. Epub 2009 Jan 28.

The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

Background: Streptococcus uberis, a Gram positive bacterial pathogen responsible for a significant proportion of bovine mastitis in commercial dairy herds, colonises multiple body sites of the cow including the gut, genital tract and mammary gland. Comparative analysis of the complete genome sequence of S. uberis strain 0140J was undertaken to help elucidate the biology of this effective bovine pathogen.

Results: The genome revealed 1,825 predicted coding sequences (CDSs) of which 62 were identified as pseudogenes or gene fragments. Comparisons with related pyogenic streptococci identified a conserved core (40%) of orthologous CDSs. Intriguingly, S. uberis 0140J displayed a lower number of mobile genetic elements when compared with other pyogenic streptococci, however bacteriophage-derived islands and a putative genomic island were identified. Comparative genomics analysis revealed most similarity to the genomes of Streptococcus agalactiae and Streptococcus equi subsp. zooepidemicus. In contrast, streptococcal orthologs were not identified for 11% of the CDSs, indicating either unique retention of ancestral sequence, or acquisition of sequence from alternative sources. Functions including transport, catabolism, regulation and CDSs encoding cell envelope proteins were over-represented in this unique gene set; a limited array of putative virulence CDSs were identified.

Conclusion: S. uberis utilises nutritional flexibility derived from a diversity of metabolic options to successfully occupy a discrete ecological niche. The features observed in S. uberis are strongly suggestive of an opportunistic pathogen adapted to challenging and changing environmental parameters.
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http://dx.doi.org/10.1186/1471-2164-10-54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2657157PMC
January 2009

The genome of Burkholderia cenocepacia J2315, an epidemic pathogen of cystic fibrosis patients.

J Bacteriol 2009 Jan 17;191(1):261-77. Epub 2008 Oct 17.

The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, United Kingdom.

Bacterial infections of the lungs of cystic fibrosis (CF) patients cause major complications in the treatment of this common genetic disease. Burkholderia cenocepacia infection is particularly problematic since this organism has high levels of antibiotic resistance, making it difficult to eradicate; the resulting chronic infections are associated with severe declines in lung function and increased mortality rates. B. cenocepacia strain J2315 was isolated from a CF patient and is a member of the epidemic ET12 lineage that originated in Canada or the United Kingdom and spread to Europe. The 8.06-Mb genome of this highly transmissible pathogen comprises three circular chromosomes and a plasmid and encodes a broad array of functions typical of this metabolically versatile genus, as well as numerous virulence and drug resistance functions. Although B. cenocepacia strains can be isolated from soil and can be pathogenic to both plants and man, J2315 is representative of a lineage of B. cenocepacia rarely isolated from the environment and which spreads between CF patients. Comparative analysis revealed that ca. 21% of the genome is unique in comparison to other strains of B. cenocepacia, highlighting the genomic plasticity of this species. Pseudogenes in virulence determinants suggest that the pathogenic response of J2315 may have been recently selected to promote persistence in the CF lung. The J2315 genome contains evidence that its unique and highly adapted genetic content has played a significant role in its success as an epidemic CF pathogen.
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http://dx.doi.org/10.1128/JB.01230-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612433PMC
January 2009

Genome-wide discovery and verification of novel structured RNAs in Plasmodium falciparum.

Genome Res 2008 Feb 20;18(2):281-92. Epub 2007 Dec 20.

Ancient DNA and Evolution Group, Department of Biology, University of Copenhagen, Copenhagen DK-2100, Denmark.

We undertook a genome-wide search for novel noncoding RNAs (ncRNA) in the malaria parasite Plasmodium falciparum. We used the RNAz program to predict structures in the noncoding regions of the P. falciparum 3D7 genome that were conserved with at least one of seven other Plasmodium spp. genome sequences. By using Northern blot analysis for 76 high-scoring predictions and microarray analysis for the majority of candidates, we have verified the expression of 33 novel ncRNA transcripts including four members of a ncRNA family in the asexual blood stage. These transcripts represent novel structured ncRNAs in P. falciparum and are not represented in any RNA databases. We provide supporting evidence for purifying selection acting on the experimentally verified ncRNAs by comparing the nucleotide substitutions in the predicted ncRNA candidate structures in P. falciparum with the closely related chimp malaria parasite P. reichenowi. The high confirmation rate within a single parasite life cycle stage suggests that many more of the predictions may be expressed in other stages of the organism's life cycle.
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http://dx.doi.org/10.1101/gr.6836108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2203626PMC
February 2008

Genome plasticity of BCG and impact on vaccine efficacy.

Proc Natl Acad Sci U S A 2007 Mar 19;104(13):5596-601. Epub 2007 Mar 19.

Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, 28 Rue du Docteur Roux, 75724 Paris Cedex 15, France.

To understand the evolution, attenuation, and variable protective efficacy of bacillus Calmette-Guérin (BCG) vaccines, Mycobacterium bovis BCG Pasteur 1173P2 has been subjected to comparative genome and transcriptome analysis. The 4,374,522-bp genome contains 3,954 protein-coding genes, 58 of which are present in two copies as a result of two independent tandem duplications, DU1 and DU2. DU1 is restricted to BCG Pasteur, although four forms of DU2 exist; DU2-I is confined to early BCG vaccines, like BCG Japan, whereas DU2-III and DU2-IV occur in the late vaccines. The glycerol-3-phosphate dehydrogenase gene, glpD2, is one of only three genes common to all four DU2 variants, implying that BCG requires higher levels of this enzyme to grow on glycerol. Further amplification of the DU2 region is ongoing, even within vaccine preparations used to immunize humans. An evolutionary scheme for BCG vaccines was established by analyzing DU2 and other markers. Lesions in genes encoding sigma-factors and pleiotropic transcriptional regulators, like PhoR and Crp, were also uncovered in various BCG strains; together with gene amplification, these affect gene expression levels, immunogenicity, and, possibly, protection against tuberculosis. Furthermore, the combined findings suggest that early BCG vaccines may even be superior to the later ones that are more widely used.
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http://dx.doi.org/10.1073/pnas.0700869104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1838518PMC
March 2007

Meningococcal genetic variation mechanisms viewed through comparative analysis of serogroup C strain FAM18.

PLoS Genet 2007 Feb 21;3(2):e23. Epub 2006 Dec 21.

Wellcome Trust Sanger Institute, Hinxton, United Kingdom.

The bacterium Neisseria meningitidis is commonly found harmlessly colonising the mucosal surfaces of the human nasopharynx. Occasionally strains can invade host tissues causing septicaemia and meningitis, making the bacterium a major cause of morbidity and mortality in both the developed and developing world. The species is known to be diverse in many ways, as a product of its natural transformability and of a range of recombination and mutation-based systems. Previous work on pathogenic Neisseria has identified several mechanisms for the generation of diversity of surface structures, including phase variation based on slippage-like mechanisms and sequence conversion of expressed genes using information from silent loci. Comparison of the genome sequences of two N. meningitidis strains, serogroup B MC58 and serogroup A Z2491, suggested further mechanisms of variation, including C-terminal exchange in specific genes and enhanced localised recombination and variation related to repeat arrays. We have sequenced the genome of N. meningitidis strain FAM18, a representative of the ST-11/ET-37 complex, providing the first genome sequence for the disease-causing serogroup C meningococci; it has 1,976 predicted genes, of which 60 do not have orthologues in the previously sequenced serogroup A or B strains. Through genome comparison with Z2491 and MC58 we have further characterised specific mechanisms of genetic variation in N. meningitidis, describing specialised loci for generation of cell surface protein variants and measuring the association between noncoding repeat arrays and sequence variation in flanking genes. Here we provide a detailed view of novel genetic diversification mechanisms in N. meningitidis. Our analysis provides evidence for the hypothesis that the noncoding repeat arrays in neisserial genomes (neisserial intergenic mosaic elements) provide a crucial mechanism for the generation of surface antigen variants. Such variation will have an impact on the interaction with the host tissues, and understanding these mechanisms is important to aid our understanding of the intimate and complex relationship between the human nasopharynx and the meningococcus.
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http://dx.doi.org/10.1371/journal.pgen.0030023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797815PMC
February 2007

Complete genome of acute rheumatic fever-associated serotype M5 Streptococcus pyogenes strain manfredo.

J Bacteriol 2007 Feb 29;189(4):1473-7. Epub 2006 Sep 29.

The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.

Comparisons of the 1.84-Mb genome of serotype M5 Streptococcus pyogenes strain Manfredo with previously sequenced genomes emphasized the role of prophages in diversification of S. pyogenes and the close relationship between strain Manfredo and MGAS8232, another acute rheumatic fever-associated strain.
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http://dx.doi.org/10.1128/JB.01227-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797351PMC
February 2007

Common inheritance of chromosome Ia associated with clonal expansion of Toxoplasma gondii.

Genome Res 2006 Sep 10;16(9):1119-25. Epub 2006 Aug 10.

Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Toxoplasma gondii is a globally distributed protozoan parasite that can infect virtually all warm-blooded animals and humans. Despite the existence of a sexual phase in the life cycle, T. gondii has an unusual population structure dominated by three clonal lineages that predominate in North America and Europe, (Types I, II, and III). These lineages were founded by common ancestors approximately10,000 yr ago. The recent origin and widespread distribution of the clonal lineages is attributed to the circumvention of the sexual cycle by a new mode of transmission-asexual transmission between intermediate hosts. Asexual transmission appears to be multigenic and although the specific genes mediating this trait are unknown, it is predicted that all members of the clonal lineages should share the same alleles. Genetic mapping studies suggested that chromosome Ia was unusually monomorphic compared with the rest of the genome. To investigate this further, we sequenced chromosome Ia and chromosome Ib in the Type I strain, RH, and the Type II strain, ME49. Comparative genome analyses of the two chromosomal sequences revealed that the same copy of chromosome Ia was inherited in each lineage, whereas chromosome Ib maintained the same high frequency of between-strain polymorphism as the rest of the genome. Sampling of chromosome Ia sequence in seven additional representative strains from the three clonal lineages supports a monomorphic inheritance, which is unique within the genome. Taken together, our observations implicate a specific combination of alleles on chromosome Ia in the recent origin and widespread success of the clonal lineages of T. gondii.
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http://dx.doi.org/10.1101/gr.5318106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1557770PMC
September 2006

The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome.

Nat Genet 2006 Jul 25;38(7):779-86. Epub 2006 Jun 25.

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.

We determined the complete genome sequence of Clostridium difficile strain 630, a virulent and multidrug-resistant strain. Our analysis indicates that a large proportion (11%) of the genome consists of mobile genetic elements, mainly in the form of conjugative transposons. These mobile elements are putatively responsible for the acquisition by C. difficile of an extensive array of genes involved in antimicrobial resistance, virulence, host interaction and the production of surface structures. The metabolic capabilities encoded in the genome show multiple adaptations for survival and growth within the gut environment. The extreme genome variability was confirmed by whole-genome microarray analysis; it may reflect the organism's niche in the gut and should provide information on the evolution of virulence in this organism.
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http://dx.doi.org/10.1038/ng1830DOI Listing
July 2006

Genetic analysis of the capsular biosynthetic locus from all 90 pneumococcal serotypes.

PLoS Genet 2006 Mar 10;2(3):e31. Epub 2006 Mar 10.

Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.

Several major invasive bacterial pathogens are encapsulated. Expression of a polysaccharide capsule is essential for survival in the blood, and thus for virulence, but also is a target for host antibodies and the basis for effective vaccines. Encapsulated species typically exhibit antigenic variation and express one of a number of immunochemically distinct capsular polysaccharides that define serotypes. We provide the sequences of the capsular biosynthetic genes of all 90 serotypes of Streptococcus pneumoniae and relate these to the known polysaccharide structures and patterns of immunological reactivity of typing sera, thereby providing the most complete understanding of the genetics and origins of bacterial polysaccharide diversity, laying the foundations for molecular serotyping. This is the first time, to our knowledge, that a complete repertoire of capsular biosynthetic genes has been available, enabling a holistic analysis of a bacterial polysaccharide biosynthesis system. Remarkably, the total size of alternative coding DNA at this one locus exceeds 1.8 Mbp, almost equivalent to the entire S. pneumoniae chromosomal complement.
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http://dx.doi.org/10.1371/journal.pgen.0020031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1391919PMC
March 2006

Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus.

Nature 2005 Dec;438(7071):1151-6

The Institute for Genomic Research, Rockville, Maryland 20850, USA.

Aspergillus fumigatus is exceptional among microorganisms in being both a primary and opportunistic pathogen as well as a major allergen. Its conidia production is prolific, and so human respiratory tract exposure is almost constant. A. fumigatus is isolated from human habitats and vegetable compost heaps. In immunocompromised individuals, the incidence of invasive infection can be as high as 50% and the mortality rate is often about 50% (ref. 2). The interaction of A. fumigatus and other airborne fungi with the immune system is increasingly linked to severe asthma and sinusitis. Although the burden of invasive disease caused by A. fumigatus is substantial, the basic biology of the organism is mostly obscure. Here we show the complete 29.4-megabase genome sequence of the clinical isolate Af293, which consists of eight chromosomes containing 9,926 predicted genes. Microarray analysis revealed temperature-dependent expression of distinct sets of genes, as well as 700 A. fumigatus genes not present or significantly diverged in the closely related sexual species Neosartorya fischeri, many of which may have roles in the pathogenicity phenotype. The Af293 genome sequence provides an unparalleled resource for the future understanding of this remarkable fungus.
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http://dx.doi.org/10.1038/nature04332DOI Listing
December 2005

Complete genome sequence and lytic phase transcription profile of a Coccolithovirus.

Science 2005 Aug;309(5737):1090-2

Plymouth Marine Laboratory, Prospect Place, The Hoe, Plymouth, PL1 3DH, UK.

The genus Coccolithovirus is a recently discovered group of viruses that infect the globally important marine calcifying microalga Emiliania huxleyi. Among the 472 predicted genes of the 407,339-base pair genome are a variety of unexpected genes, most notably those involved in biosynthesis of ceramide, a sphingolipid known to induce apoptosis. Uniquely for algal viruses, it also contains six RNA polymerase subunits and a novel promoter, suggesting this virus encodes its own transcription machinery. Microarray transcriptomic analysis reveals that 65% of the predicted virus-encoded genes are expressed during lytic infection of E. huxleyi.
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http://dx.doi.org/10.1126/science.1113109DOI Listing
August 2005

The genome of the kinetoplastid parasite, Leishmania major.

Science 2005 Jul;309(5733):436-42

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.

Leishmania species cause a spectrum of human diseases in tropical and subtropical regions of the world. We have sequenced the 36 chromosomes of the 32.8-megabase haploid genome of Leishmania major (Friedlin strain) and predict 911 RNA genes, 39 pseudogenes, and 8272 protein-coding genes, of which 36% can be ascribed a putative function. These include genes involved in host-pathogen interactions, such as proteolytic enzymes, and extensive machinery for synthesis of complex surface glycoconjugates. The organization of protein-coding genes into long, strand-specific, polycistronic clusters and lack of general transcription factors in the L. major, Trypanosoma brucei, and Trypanosoma cruzi (Tritryp) genomes suggest that the mechanisms regulating RNA polymerase II-directed transcription are distinct from those operating in other eukaryotes, although the trypanosomatids appear capable of chromatin remodeling. Abundant RNA-binding proteins are encoded in the Tritryp genomes, consistent with active posttranscriptional regulation of gene expression.
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http://dx.doi.org/10.1126/science.1112680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1470643PMC
July 2005

Genome of the host-cell transforming parasite Theileria annulata compared with T. parva.

Science 2005 Jul;309(5731):131-3

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

Theileria annulata and T. parva are closely related protozoan parasites that cause lymphoproliferative diseases of cattle. We sequenced the genome of T. annulata and compared it with that of T. parva to understand the mechanisms underlying transformation and tropism. Despite high conservation of gene sequences and synteny, the analysis reveals unequally expanded gene families and species-specific genes. We also identify divergent families of putative secreted polypeptides that may reduce immune recognition, candidate regulators of host-cell transformation, and a Theileria-specific protein domain [frequently associated in Theileria (FAINT)] present in a large number of secreted proteins.
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http://dx.doi.org/10.1126/science.1110418DOI Listing
July 2005

The Chlamydophila abortus genome sequence reveals an array of variable proteins that contribute to interspecies variation.

Genome Res 2005 May 18;15(5):629-40. Epub 2005 Apr 18.

The Pathogen Sequencing Unit, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.

The obligate intracellular bacterial pathogen Chlamydophila abortus strain S26/3 (formerly the abortion subtype of Chlamydia psittaci) is an important cause of late gestation abortions in ruminants and pigs. Furthermore, although relatively rare, zoonotic infection can result in acute illness and miscarriage in pregnant women. The complete genome sequence was determined and shows a high level of conservation in both sequence and overall gene content in comparison to other Chlamydiaceae. The 1,144,377-bp genome contains 961 predicted coding sequences, 842 of which are conserved with those of Chlamydophila caviae and Chlamydophila pneumoniae. Within this conserved Cp. abortus core genome we have identified the major regions of variation and have focused our analysis on these loci, several of which were found to encode highly variable protein families, such as TMH/Inc and Pmp families, which are strong candidates for the source of diversity in host tropism and disease causation in this group of organisms. Significantly, Cp. abortus lacks any toxin genes, and also lacks genes involved in tryptophan metabolism and nucleotide salvaging (guaB is present as a pseudogene), suggesting that the genetic basis of niche adaptation of this species is distinct from those previously proposed for other chlamydial species.
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http://dx.doi.org/10.1101/gr.3684805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1088291PMC
May 2005

Integration of tools and resources for display and analysis of genomic data for protozoan parasites.

Int J Parasitol 2005 Apr;35(5):481-93

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

Centralisation of tools for analysis of genomic data is paramount in ensuring that research is always carried out on the latest currently available data. As such, World Wide Web sites providing a range of online analyses and displays of data can play a crucial role in guaranteeing consistency of in silico work. In this respect, the protozoan parasite research community is served by several resources, either focussing on data and tools for one species or taking a broader view and providing tools for analysis of data from many species, thereby facilitating comparative studies. In this paper, we give a broad overview of the online resources available. We then focus on the GeneDB project, detailing the features and tools currently available through it. Finally, we discuss data curation and its importance in keeping genomic data 'relevant' to the research community.
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http://dx.doi.org/10.1016/j.ijpara.2005.01.011DOI Listing
April 2005

Extensive DNA inversions in the B. fragilis genome control variable gene expression.

Science 2005 Mar;307(5714):1463-5

Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.

The obligately anaerobic bacterium Bacteroides fragilis, an opportunistic pathogen and inhabitant of the normal human colonic microbiota, exhibits considerable within-strain phase and antigenic variation of surface components. The complete genome sequence has revealed an unusual breadth (in number and in effect) of DNA inversion events that potentially control expression of many different components, including surface and secreted components, regulatory molecules, and restriction-modification proteins. Invertible promoters of two different types (12 group 1 and 11 group 2) were identified. One group has inversion crossover (fix) sites similar to the hix sites of Salmonella typhimurium. There are also four independent intergenic shufflons that potentially alter the expression and function of varied genes. The composition of the 10 different polysaccharide biosynthesis gene clusters identified (7 with associated invertible promoters) suggests a mechanism of synthesis similar to the O-antigen capsules of Escherichia coli.
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http://dx.doi.org/10.1126/science.1107008DOI Listing
March 2005

The genome of the protist parasite Entamoeba histolytica.

Nature 2005 Feb;433(7028):865-8

TIGR, 9712 Medical Center Drive, Rockville, Maryland 20850, USA.

Entamoeba histolytica is an intestinal parasite and the causative agent of amoebiasis, which is a significant source of morbidity and mortality in developing countries. Here we present the genome of E. histolytica, which reveals a variety of metabolic adaptations shared with two other amitochondrial protist pathogens: Giardia lamblia and Trichomonas vaginalis. These adaptations include reduction or elimination of most mitochondrial metabolic pathways and the use of oxidative stress enzymes generally associated with anaerobic prokaryotes. Phylogenomic analysis identifies evidence for lateral gene transfer of bacterial genes into the E. histolytica genome, the effects of which centre on expanding aspects of E. histolytica's metabolic repertoire. The presence of these genes and the potential for novel metabolic pathways in E. histolytica may allow for the development of new chemotherapeutic agents. The genome encodes a large number of novel receptor kinases and contains expansions of a variety of gene families, including those associated with virulence. Additional genome features include an abundance of tandemly repeated transfer-RNA-containing arrays, which may have a structural function in the genome. Analysis of the genome provides new insights into the workings and genome evolution of a major human pathogen.
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http://dx.doi.org/10.1038/nature03291DOI Listing
February 2005

A selenocysteine tRNA and SECIS element in Plasmodium falciparum.

RNA 2005 Feb;11(2):119-22

The molecular machinery for incorporating selenocysteine into proteins is present in both prokaryotes and eukaryotes. Although selenocysteine insertion has been reported in animals, plants, and protozoans, known eukaryotic selenocysteine tRNA sequences and selenocysteine insertion sequences are limited to animals and plants. Here we present clear indications of the presence of selenocysteine-tRNA and a selenocysteine insertion sequence in Plasmodium falciparum. To our knowledge, this is the first report of an identification of protozoan selenocysteine insertion machinery at the sequence level.
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http://dx.doi.org/10.1261/rna.7185605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1370700PMC
February 2005

A comprehensive survey of the Plasmodium life cycle by genomic, transcriptomic, and proteomic analyses.

Science 2005 Jan;307(5706):82-6

Pathogen Sequencing Unit, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

Plasmodium berghei and Plasmodium chabaudi are widely used model malaria species. Comparison of their genomes, integrated with proteomic and microarray data, with the genomes of Plasmodium falciparum and Plasmodium yoelii revealed a conserved core of 4500 Plasmodium genes in the central regions of the 14 chromosomes and highlighted genes evolving rapidly because of stage-specific selective pressures. Four strategies for gene expression are apparent during the parasites' life cycle: (i) housekeeping; (ii) host-related; (iii) strategy-specific related to invasion, asexual replication, and sexual development; and (iv) stage-specific. We observed posttranscriptional gene silencing through translational repression of messenger RNA during sexual development, and a 47-base 3' untranslated region motif is implicated in this process.
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http://dx.doi.org/10.1126/science.1103717DOI Listing
January 2005

A transcriptomic analysis of the phylum Nematoda.

Nat Genet 2004 Dec 14;36(12):1259-67. Epub 2004 Nov 14.

Hospital for Sick Children, 555 University Avenue, Departments of Biochemistry and Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada.

The phylum Nematoda occupies a huge range of ecological niches, from free-living microbivores to human parasites. We analyzed the genomic biology of the phylum using 265,494 expressed-sequence tag sequences, corresponding to 93,645 putative genes, from 30 species, including 28 parasites. From 35% to 70% of each species' genes had significant similarity to proteins from the model nematode Caenorhabditis elegans. More than half of the putative genes were unique to the phylum, and 23% were unique to the species from which they were derived. We have not yet come close to exhausting the genomic diversity of the phylum. We identified more than 2,600 different known protein domains, some of which had differential abundances between major taxonomic groups of nematodes. We also defined 4,228 nematode-specific protein families from nematode-restricted genes: this class of genes probably underpins species- and higher-level taxonomic disparity. Nematode-specific families are particularly interesting as drug and vaccine targets.
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http://dx.doi.org/10.1038/ng1472DOI Listing
December 2004

A genome sequence survey of the filarial nematode Brugia malayi: repeats, gene discovery, and comparative genomics.

Mol Biochem Parasitol 2004 Oct;137(2):215-27

Ashworth Laboratories, Institution of Cell, Animal and Polulation Biology, School of Biological Sciences, University of Edinburgh, King's Buildings, Edinburgh EH9 3JT, UK.

Comparative nematode genomics has thus far been largely constrained to the genus Caenorhabditis, but a huge diversity of other nematode species, and genomes, exist. The Brugia malayi genome is approximately 100 Mb in size, and distributed across five chromosome pairs. Previous genomic investigations have included definition of major repeat classes and sequencing of selected genes. We have generated over 18,000 sequences from the ends of large-insert clones from bacterial artificial chromosome libraries. These end sequences, totalling over 10 Mb of sequence, contain just under 8 Mb of unique sequence. We identified the known Mbo I and Hha I repeat families in the sequence data, and also identified several new repeats based on their abundance. Genomic copies of 17% of B. malayi genes defined by expressed sequence tags have been identified. Nearly one quarter of end sequences can encode peptides with significant similarity to protein sequences in the public databases, and we estimate that we have identified more than 2700 new B. malayi genes. Importantly, 459 end sequences had homologues in other organisms, but lacked a match in the completely sequenced genomes of Caenorhabditis briggsae and Caenorhabditis elegans, emphasising the role of gene loss in genome evolution. B. malayi is estimated to have over 18,500 protein-coding genes.
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http://dx.doi.org/10.1016/j.molbiopara.2004.05.013DOI Listing
October 2004

Genomic plasticity of the causative agent of melioidosis, Burkholderia pseudomallei.

Proc Natl Acad Sci U S A 2004 Sep 17;101(39):14240-5. Epub 2004 Sep 17.

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.

Burkholderia pseudomallei is a recognized biothreat agent and the causative agent of melioidosis. This Gram-negative bacterium exists as a soil saprophyte in melioidosis-endemic areas of the world and accounts for 20% of community-acquired septicaemias in northeastern Thailand where half of those affected die. Here we report the complete genome of B. pseudomallei, which is composed of two chromosomes of 4.07 megabase pairs and 3.17 megabase pairs, showing significant functional partitioning of genes between them. The large chromosome encodes many of the core functions associated with central metabolism and cell growth, whereas the small chromosome carries more accessory functions associated with adaptation and survival in different niches. Genomic comparisons with closely and more distantly related bacteria revealed a greater level of gene order conservation and a greater number of orthologous genes on the large chromosome, suggesting that the two replicons have distinct evolutionary origins. A striking feature of the genome was the presence of 16 genomic islands (GIs) that together made up 6.1% of the genome. Further analysis revealed these islands to be variably present in a collection of invasive and soil isolates but entirely absent from the clonally related organism B. mallei. We propose that variable horizontal gene acquisition by B. pseudomallei is an important feature of recent genetic evolution and that this has resulted in a genetically diverse pathogenic species.
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http://dx.doi.org/10.1073/pnas.0403302101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC521101PMC
September 2004

Complete genomes of two clinical Staphylococcus aureus strains: evidence for the rapid evolution of virulence and drug resistance.

Proc Natl Acad Sci U S A 2004 Jun 22;101(26):9786-91. Epub 2004 Jun 22.

The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.

Staphylococcus aureus is an important nosocomial and community-acquired pathogen. Its genetic plasticity has facilitated the evolution of many virulent and drug-resistant strains, presenting a major and constantly changing clinical challenge. We sequenced the approximately 2.8-Mbp genomes of two disease-causing S. aureus strains isolated from distinct clinical settings: a recent hospital-acquired representative of the epidemic methicillin-resistant S. aureus EMRSA-16 clone (MRSA252), a clinically important and globally prevalent lineage; and a representative of an invasive community-acquired methicillin-susceptible S. aureus clone (MSSA476). A comparative-genomics approach was used to explore the mechanisms of evolution of clinically important S. aureus genomes and to identify regions affecting virulence and drug resistance. The genome sequences of MRSA252 and MSSA476 have a well conserved core region but differ markedly in their accessory genetic elements. MRSA252 is the most genetically diverse S. aureus strain sequenced to date: approximately 6% of the genome is novel compared with other published genomes, and it contains several unique genetic elements. MSSA476 is methicillin-susceptible, but it contains a novel Staphylococcal chromosomal cassette (SCC) mec-like element (designated SCC(476)), which is integrated at the same site on the chromosome as SCCmec elements in MRSA strains but encodes a putative fusidic acid resistance protein. The crucial role that accessory elements play in the rapid evolution of S. aureus is clearly illustrated by comparing the MSSA476 genome with that of an extremely closely related MRSA community-acquired strain; the differential distribution of large mobile elements carrying virulence and drug-resistance determinants may be responsible for the clinically important phenotypic differences in these strains.
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http://dx.doi.org/10.1073/pnas.0402521101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC470752PMC
June 2004

Insight into the genome of Aspergillus fumigatus: analysis of a 922 kb region encompassing the nitrate assimilation gene cluster.

Fungal Genet Biol 2004 Apr;41(4):443-53

The Pathogen Sequencing Unit, The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

Aspergillus fumigatus is the most ubiquitous opportunistic filamentous fungal pathogen of human. As an initial step toward sequencing the entire genome of A. fumigatus, which is estimated to be approximately 30 Mb in size, we have sequenced a 922 kb region, contained within 16 overlapping bacterial artificial chromosome (BAC) clones. Fifty-four percent of the DNA is predicted to be coding with 341 putative protein coding genes. Functional classification of the proteins showed the presence of a higher proportion of enzymes and membrane transporters when compared to those of Saccharomyces cerevisiae. In addition to the nitrate assimilation gene cluster, the quinate utilisation gene cluster is also present on this 922 kb genomic sequence. We observed large scale synteny between A. fumigatus and Aspergillus nidulans by comparing this sequence to the A. nidulans genetic map of linkage group VIII.
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http://dx.doi.org/10.1016/j.fgb.2003.12.003DOI Listing
April 2004
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