David L. Saunders
Wellcome Trust Sanger Institute
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Featured researches published by David L. Saunders.
Nature | 2002
Stephen D. Bentley; K. F. Chater; A.-M. Cerdeño-Tárraga; Gregory L. Challis; Nicholas R. Thomson; Keith D. James; David Harris; M. A. Quail; H. Kieser; D. Harper; Alex Bateman; S. Brown; G. Chandra; Carton W. Chen; Mark O. Collins; Ann Cronin; Audrey Fraser; Arlette Goble; J. Hidalgo; T. Hornsby; S. Howarth; Chih-Hung Huang; T. Kieser; L. Larke; Lee Murphy; K. Oliver; Susan O'Neil; Ester Rabbinowitsch; Marie-Adele Rajandream; Kim Rutherford
Streptomyces coelicolor is a representative of the group of soil-dwelling, filamentous bacteria responsible for producing most natural antibiotics used in human and veterinary medicine. Here we report the 8,667,507 base pair linear chromosome of this organism, containing the largest number of genes so far discovered in a bacterium. The 7,825 predicted genes include more than 20 clusters coding for known or predicted secondary metabolites. The genome contains an unprecedented proportion of regulatory genes, predominantly those likely to be involved in responses to external stimuli and stresses, and many duplicated gene sets that may represent ‘tissue-specific’ isoforms operating in different phases of colonial development, a unique situation for a bacterium. An ancient synteny was revealed between the central ‘core’ of the chromosome and the whole chromosome of pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae. The genome sequence will greatly increase our understanding of microbial life in the soil as well as aiding the generation of new drug candidates by genetic engineering.
Nature | 2005
William C. Nierman; Arnab Pain; Michael J. Anderson; Jennifer R. Wortman; H. Stanley Kim; Javier Arroyo; Matthew Berriman; Keietsu Abe; David B. Archer; Clara Bermejo; Joan W. Bennett; Paul Bowyer; Dan Chen; Matthew Collins; Richard Coulsen; Robert Davies; Paul S. Dyer; Mark L. Farman; Nadia Fedorova; Natalie D. Fedorova; Tamara V. Feldblyum; Reinhard Fischer; Nigel Fosker; Audrey Fraser; José Luis García; María José García; Ariette Goble; Gustavo H. Goldman; Katsuya Gomi; Sam Griffith-Jones
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.
Nature | 2005
Ludwig Eichinger; J. A. Pachebat; G. Glöckner; Marie-Adele Rajandream; Richard Sucgang; Matthew Berriman; J. Song; Rolf Olsen; Karol Szafranski; Qikai Xu; Budi Tunggal; Sarah K. Kummerfeld; B. A. Konfortov; Francisco Rivero; Alan Thomas Bankier; R. Lehmann; N. Hamlin; Robert Davies; Pascale Gaudet; Petra Fey; Karen E Pilcher; Guokai Chen; David L. Saunders; Erica Sodergren; Paul Davis; Arnaud Kerhornou; X. Nie; Neil Hall; Christophe Anjard; Lisa Hemphill
The social amoebae are exceptional in their ability to alternate between unicellular and multicellular forms. Here we describe the genome of the best-studied member of this group, Dictyostelium discoideum. The gene-dense chromosomes of this organism encode approximately 12,500 predicted proteins, a high proportion of which have long, repetitive amino acid tracts. There are many genes for polyketide synthases and ABC transporters, suggesting an extensive secondary metabolism for producing and exporting small molecules. The genome is rich in complex repeats, one class of which is clustered and may serve as centromeres. Partial copies of the extrachromosomal ribosomal DNA (rDNA) element are found at the ends of each chromosome, suggesting a novel telomere structure and the use of a common mechanism to maintain both the rDNA and chromosomal termini. A proteome-based phylogeny shows that the amoebozoa diverged from the animal–fungal lineage after the plant–animal split, but Dictyostelium seems to have retained more of the diversity of the ancestral genome than have plants, animals or fungi.
Nature Genetics | 2003
Julian Parkhill; Mohammed Sebaihia; Andrew Preston; Lee Murphy; Nicholas R. Thomson; David Harris; Matthew T. G. Holden; Carol Churcher; Stephen D. Bentley; Karen Mungall; Ana Cerdeño-Tárraga; Louise M. Temple; Keith James; Barbara Harris; Michael A. Quail; Mark Achtman; Rebecca Atkin; Steven Baker; David Basham; Nathalie Bason; Inna Cherevach; Tracey Chillingworth; Matthew Collins; Anne Cronin; Paul Davis; Jonathan Doggett; Theresa Feltwell; Arlette Goble; N. Hamlin; Heidi Hauser
Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica are closely related Gram-negative β-proteobacteria that colonize the respiratory tracts of mammals. B. pertussis is a strict human pathogen of recent evolutionary origin and is the primary etiologic agent of whooping cough. B. parapertussis can also cause whooping cough, and B. bronchiseptica causes chronic respiratory infections in a wide range of animals. We sequenced the genomes of B. bronchiseptica RB50 (5,338,400 bp; 5,007 predicted genes), B. parapertussis 12822 (4,773,551 bp; 4,404 genes) and B. pertussis Tohama I (4,086,186 bp; 3,816 genes). Our analysis indicates that B. parapertussis and B. pertussis are independent derivatives of B. bronchiseptica-like ancestors. During the evolution of these two host-restricted species there was large-scale gene loss and inactivation; host adaptation seems to be a consequence of loss, not gain, of function, and differences in virulence may be related to loss of regulatory or control functions.
PLOS Genetics | 2006
Stephen D. Bentley; David M. Aanensen; Angeliki Mavroidi; David L. Saunders; Ester Rabbinowitsch; Matthew Collins; Kathy Donohoe; David Harris; Lee Murphy; Michael A. Quail; Gabby Samuel; Ian C. Skovsted; Margit S. Kaltoft; Bart Barrell; Peter R. Reeves; Julian Parkhill; Brian G. Spratt
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.
Genome Biology | 2008
Lisa Crossman; Virginia C. Gould; J. Maxwell Dow; Georgios S. Vernikos; Aki Okazaki; Mohammed Sebaihia; David L. Saunders; Claire Arrowsmith; Tim Carver; Nicholas Peters; Ellen Adlem; Arnaud Kerhornou; Angela Lord; Lee Murphy; Katharine Seeger; R. Squares; Simon Rutter; Michael A. Quail; Mari Adele Rajandream; David Harris; Carol Churcher; Stephen D. Bentley; Julian Parkhill; Nicholas R. Thomson; Matthew B. Avison
BackgroundStenotrophomonas maltophilia is a nosocomial opportunistic pathogen of the Xanthomonadaceae. The organism has been isolated from both clinical and soil environments in addition to the sputum of cystic fibrosis patients and the immunocompromised. Whilst relatively distant phylogenetically, the closest sequenced relatives of S. maltophilia are the plant pathogenic xanthomonads.ResultsThe genome of the bacteremia-associated isolate S. maltophilia K279a is 4,851,126 bp and of high G+C content. The sequence reveals an organism with a remarkable capacity for drug and heavy metal resistance. In addition to a number of genes conferring resistance to antimicrobial drugs of different classes via alternative mechanisms, nine resistance-nodulation-division (RND)-type putative antimicrobial efflux systems are present. Functional genomic analysis confirms a role in drug resistance for several of the novel RND efflux pumps. S. maltophilia possesses potentially mobile regions of DNA and encodes a number of pili and fimbriae likely to be involved in adhesion and biofilm formation that may also contribute to increased antimicrobial drug resistance.ConclusionThe panoply of antimicrobial drug resistance genes and mobile genetic elements found suggests that the organism can act as a reservoir of antimicrobial drug resistance determinants in a clinical environment, which is an issue of considerable concern.
Nature Genetics | 2013
Olivo Miotto; Jacob Almagro-Garcia; Magnus Manske; Bronwyn MacInnis; Susana Campino; Kirk A. Rockett; Chanaki Amaratunga; Pharath Lim; Seila Suon; Sokunthea Sreng; Jennifer M. Anderson; Socheat Duong; Chea Nguon; Char Meng Chuor; David L. Saunders; Youry Se; Chantap Lon; Mark M. Fukuda; Lucas Amenga-Etego; Abraham Hodgson; Victor Asoala; Mallika Imwong; Shannon Takala-Harrison; François Nosten; Xin-Zhuan Su; Pascal Ringwald; Frédéric Ariey; Christiane Dolecek; Tran Tinh Hien; Maciej F. Boni
We describe an analysis of genome variation in 825 P. falciparum samples from Asia and Africa that identifies an unusual pattern of parasite population structure at the epicenter of artemisinin resistance in western Cambodia. Within this relatively small geographic area, we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to artemisinin, which have skewed allele frequency spectra and high levels of haplotype homozygosity, indicative of founder effects and recent population expansion. We provide a catalog of SNPs that show high levels of differentiation in the artemisinin-resistant subpopulations, including codon variants in transporter proteins and DNA mismatch repair proteins. These data provide a population-level genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular markers to assist in its elimination.
Journal of Bacteriology | 2009
Atsushi Iguchi; Nicholas R. Thomson; Yoshitoshi Ogura; David L. Saunders; Tadasuke Ooka; Ian R. Henderson; David J. Harris; M. Asadulghani; Ken Kurokawa; Paul Dean; Brendan Kenny; Michael A. Quail; Scott Thurston; Gordon Dougan; Tetsuya Hayashi; Julian Parkhill; Gad Frankel
Enteropathogenic Escherichia coli (EPEC) was the first pathovar of E. coli to be implicated in human disease; however, no EPEC strain has been fully sequenced until now. Strain E2348/69 (serotype O127:H6 belonging to E. coli phylogroup B2) has been used worldwide as a prototype strain to study EPEC biology, genetics, and virulence. Studies of E2348/69 led to the discovery of the locus of enterocyte effacement-encoded type III secretion system (T3SS) and its cognate effectors, which play a vital role in attaching and effacing lesion formation on gut epithelial cells. In this study, we determined the complete genomic sequence of E2348/69 and performed genomic comparisons with other important E. coli strains. We identified 424 E2348/69-specific genes, most of which are carried on mobile genetic elements, and a number of genetic traits specifically conserved in phylogroup B2 strains irrespective of their pathotypes, including the absence of the ETT2-related T3SS, which is present in E. coli strains belonging to all other phylogroups. The genome analysis revealed the entire gene repertoire related to E2348/69 virulence. Interestingly, E2348/69 contains only 21 intact T3SS effector genes, all of which are carried on prophages and integrative elements, compared to over 50 effector genes in enterohemorrhagic E. coli O157. As E2348/69 is the most-studied pathogenic E. coli strain, this study provides a genomic context for the vast amount of existing experimental data. The unexpected simplicity of the E2348/69 T3SS provides the first opportunity to fully dissect the entire virulence strategy of attaching and effacing pathogens in the genomic context.
Genome Research | 2008
Craig Winstanley; Morgan G. I. Langille; Joanne L. Fothergill; Irena Kukavica-Ibrulj; Catherine Paradis-Bleau; François Sanschagrin; Nicholas R. Thomson; Geoff Winsor; Michael A. Quail; Nicola Lennard; Alexandra Bignell; Louise Clarke; Kathy Seeger; David L. Saunders; David J. Harris; Julian Parkhill; Robert E. W. Hancock; Fiona S. L. Brinkman; Roger C. Levesque
Pseudomonas aeruginosa isolates have a highly conserved core genome representing up to 90% of the total genomic sequence with additional variable accessory genes, many of which are found in genomic islands or islets. The identification of the Liverpool Epidemic Strain (LES) in a childrens cystic fibrosis (CF) unit in 1996 and its subsequent observation in several centers in the United Kingdom challenged the previous widespread assumption that CF patients acquire only unique strains of P. aeruginosa from the environment. To learn about the forces that shaped the development of this important epidemic strain, the genome of the earliest archived LES isolate, LESB58, was sequenced. The sequence revealed the presence of many large genomic islands, including five prophage clusters, one defective (pyocin) prophage cluster, and five non-phage islands. To determine the role of these clusters, an unbiased signature tagged mutagenesis study was performed, followed by selection in the chronic rat lung infection model. Forty-seven mutants were identified by sequencing, including mutants in several genes known to be involved in Pseudomonas infection. Furthermore, genes from four prophage clusters and one genomic island were identified and in direct competition studies with the parent isolate; four were demonstrated to strongly impact on competitiveness in the chronic rat lung infection model. This strongly indicates that enhanced in vivo competitiveness is a major driver for maintenance and diversifying selection of these genomic prophage genes.
The Journal of Infectious Diseases | 2015
Shannon Takala-Harrison; Christopher G. Jacob; Cesar Arze; Michael P. Cummings; Joana C. Silva; Arjen M. Dondorp; Mark M. Fukuda; Tran Tinh Hien; Mayfong Mayxay; Harald Noedl; François Nosten; Myat Phone Kyaw; Nguyen Thanh Thuy Nhien; Mallika Imwong; Delia Bethell; Youry Se; Chanthap Lon; Stuart D. Tyner; David L. Saunders; Frédéric Ariey; Odile Mercereau-Puijalon; Didier Ménard; Paul N. Newton; Maniphone Khanthavong; Bouasy Hongvanthong; Peter Starzengruber; Hans-Peter Fuehrer; Paul Swoboda; Wasif Ali Khan; Aung Pyae Phyo
BACKGROUND The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia. METHODS P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently. RESULTS The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P = 1.97 × 10(-12)). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas. CONCLUSIONS K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.