Pathogen genomics

Research

Genome sequencing and analysis

The Pathogen genomics team's approach to pathogen genome analysis is "broad and deep". "Broad" means that we are interested in a wide variety of human and animal pathogens, in order to study the wide diversity of mechanisms that are used to infect a host and cause disease. These broad analyses include, for example, related members of a group of organisms that can cause disease in humans, animals and even plants, and those that live in a host without causing disease. These comparisons allow us to identify genes that are of key importance for specifying common functions, and those that are accessory for example responsible for interaction with specific hosts, or for causing specific pathologies. We have carried out analyses on a range of species including the enteric bacteria Salmonella, Escherichia, Yersinia and Erwinia, and others such as Streptococcus and Staphylococcus. Broad investigations also allow us to find the novel and unexpected in less well-studied pathogens, and to lay the foundations for investigating neglected diseases.

"Deep" refers to multiple comparisons between very closely related strains within a species, or group of species. Such comparisons allow us to look at the fine detail of how or why organisms specialise on particular hosts for example the host-restricted pathogen Salmonella Typhi, how they have evolved for example Bordetella pertussis or Yersinia pestis and how variation in DNA sequence corresponds to the degree to which the organism can cause disease (or virulence) for example Streptococcus pneumoniae or Neisseria meningitidis. Fine detail comparisons also give us DNA markers that allow studies following transmission, virulence or drug resistance in related families of organisms such as Mycobacterium tuberculosis or Staphylococcus aureus.

Laboratory studies

For some of the organisms we are studying in depth, we also move beyond sequencing into lab-based studies. These include transcriptomics using microarrays and high-throughput sequencing, proteomics, and saturation mutagenesis studies.

Another area of growing interest is the contribution to the health and development of the host by bacteria. We are studying bacterial populations, primarily in the gut, in both humans and mice. Looking at how these populations vary between individuals, and between diseased and healthy organs, should shed light on the role of microorganisms in these processes.

Informatics

To support assigning function to pieces of the DNA sequence (annotation) in pathogens, and to present our data to the scientific community, we have a group of software programmes available. These include our analysis tool Artemis, which is designed to be an intuitive and portable sequence viewer, and an extension of this, a powerful analysis tool called ACT, which allows an interactive view of full genome comparisons. We also provide a set of web pages, GeneDB, which serve as a repository and source for our annotation and analysis.

Collaborations

Internal collaborations

To pursue these studies effectively we have built up very strong collaborations with the other groups within the Institute, particularly Gordon Dougan, Paul Kellam, Trevor Lawley, Matthew Berriman and Dominic Kwiatkowski, and we intend to expand these collaborations to include new pathogen faculty members. We also rely heavily on the support of the core sequencing and informatics teams.

External collaborations

Along with providing our data to the scientific community, we believe it is important to enable scientists to utilise the information provided to its fullest extent, especially in the developing world, where these diseases are most prevalent. In collaboration with the Wellcome Trust Advanced Courses group, we have established a series of bioinformatics training workshops in developing countries, most recently in Vietnam, Malawi, Uraguay and Kenya.

We collaborate on specific projects with a broad section of the scientific community, in the UK, Europe, the US and the wider world, and we always welcome new collaborations.

Selected Publications

• Artemis: an integrated platform for visualization and analysis of high-throughput sequence-based experimental data.

  Carver T, Harris SR, Berriman M, Parkhill J and McQuillan JA

  Bioinformatics (Oxford, England) 2012;28;4;464-9

  PUBMED: 22199388; PMC: 3278759; DOI: 10.1093/bioinformatics/btr703

• Evidence for several waves of global transmission in the seventh cholera pandemic.

  Mutreja A, Kim DW, Thomson NR, Connor TR, Lee JH, Kariuki S, Croucher NJ, Choi SY, Harris SR, Lebens M, Niyogi SK, Kim EJ, Ramamurthy T, Chun J, Wood JL, Clemens JD, Czerkinsky C, Nair GB, Holmgren J, Parkhill J and Dougan G

  Nature 2011;477;7365;462-5

  PUBMED: 21866102; DOI: 10.1038/nature10392

• Meticillin-resistant Staphylococcus aureus with a novel mecA homologue in human and bovine populations in the UK and Denmark: a descriptive study.

  García-Álvarez L, Holden MT, Lindsay H, Webb CR, Brown DF, Curran MD, Walpole E, Brooks K, Pickard DJ, Teale C, Parkhill J, Bentley SD, Edwards GF, Girvan EK, Kearns AM, Pichon B, Hill RL, Larsen AR, Skov RL, Peacock SJ, Maskell DJ and Holmes MA

  The Lancet infectious diseases 2011;11;8;595-603

  PUBMED: 21641281; DOI: 10.1016/S1473-3099(11)70126-8

• Salmonella bongori provides insights into the evolution of the Salmonellae.

  Fookes M, Schroeder GN, Langridge GC, Blondel CJ, Mammina C, Connor TR, Seth-Smith H, Vernikos GS, Robinson KS, Sanders M, Petty NK, Kingsley RA, Bäumler AJ, Nuccio SP, Contreras I, Santiviago CA, Maskell D, Barrow P, Humphrey T, Nastasi A, Roberts M, Frankel G, Parkhill J, Dougan G and Thomson NR

  PLoS pathogens 2011;7;8;e1002191

  PUBMED: 21876672; PMC: 3158058; DOI: 10.1371/journal.ppat.1002191

• The impact of recombination on dN/dS within recently emerged bacterial clones.

  Castillo-Ramírez S, Harris SR, Holden MT, He M, Parkhill J, Bentley SD and Feil EJ

  PLoS pathogens 2011;7;7;e1002129

  PUBMED: 21779170; PMC: 3136474; DOI: 10.1371/journal.ppat.1002129

• Enterotypes of the human gut microbiome.

  Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto JM, Bertalan M, Borruel N, Casellas F, Fernandez L, Gautier L, Hansen T, Hattori M, Hayashi T, Kleerebezem M, Kurokawa K, Leclerc M, Levenez F, Manichanh C, Nielsen HB, Nielsen T, Pons N, Poulain J, Qin J, Sicheritz-Ponten T, Tims S, Torrents D, Ugarte E, Zoetendal EG, Wang J, Guarner F, Pedersen O, de Vos WM, Brunak S, Doré J, MetaHIT Consortium, Antolín M, Artiguenave F, Blottiere HM, Almeida M, Brechot C, Cara C, Chervaux C, Cultrone A, Delorme C, Denariaz G, Dervyn R, Foerstner KU, Friss C, van de Guchte M, Guedon E, Haimet F, Huber W, van Hylckama-Vlieg J, Jamet A, Juste C, Kaci G, Knol J, Lakhdari O, Layec S, Le Roux K, Maguin E, Mérieux A, Melo Minardi R, M'rini C, Muller J, Oozeer R, Parkhill J, Renault P, Rescigno M, Sanchez N, Sunagawa S, Torrejon A, Turner K, Vandemeulebrouck G, Varela E, Winogradsky Y, Zeller G, Weissenbach J, Ehrlich SD and Bork P

  Nature 2011;473;7346;174-80

  PUBMED: 21508958; DOI: 10.1038/nature09944

• Partitioning core and satellite taxa from within cystic fibrosis lung bacterial communities.

  van der Gast CJ, Walker AW, Stressmann FA, Rogers GB, Scott P, Daniels TW, Carroll MP, Parkhill J and Bruce KD

  The ISME journal 2011;5;5;780-91

  PUBMED: 21151003; PMC: 3105771; DOI: 10.1038/ismej.2010.175

• Rapid pneumococcal evolution in response to clinical interventions.

  Croucher NJ, Harris SR, Fraser C, Quail MA, Burton J, van der Linden M, McGee L, von Gottberg A, Song JH, Ko KS, Pichon B, Baker S, Parry CM, Lambertsen LM, Shahinas D, Pillai DR, Mitchell TJ, Dougan G, Tomasz A, Klugman KP, Parkhill J, Hanage WP and Bentley SD

  Science (New York, N.Y.) 2011;331;6016;430-4

  PUBMED: 21273480; DOI: 10.1126/science.1198545

• Bacterial epidemiology and biology--lessons from genome sequencing.

  Parkhill J and Wren BW

  Genome biology 2011;12;10;230

  PUBMED: 22027015; PMC: 3333767; DOI: 10.1186/gb-2011-12-10-230

• Evolutionary dynamics of Clostridium difficile over short and long time scales.

  He M, Sebaihia M, Lawley TD, Stabler RA, Dawson LF, Martin MJ, Holt KE, Seth-Smith HM, Quail MA, Rance R, Brooks K, Churcher C, Harris D, Bentley SD, Burrows C, Clark L, Corton C, Murray V, Rose G, Thurston S, van Tonder A, Walker D, Wren BW, Dougan G and Parkhill J

  Proceedings of the National Academy of Sciences of the United States of America 2010;107;16;7527-32

  PUBMED: 20368420; PMC: 2867753; DOI: 10.1073/pnas.0914322107

• Evolution of MRSA during hospital transmission and intercontinental spread.

  Harris SR, Feil EJ, Holden MT, Quail MA, Nickerson EK, Chantratita N, Gardete S, Tavares A, Day N, Lindsay JA, Edgeworth JD, de Lencastre H, Parkhill J, Peacock SJ and Bentley SD

  Science (New York, N.Y.) 2010;327;5964;469-74

  PUBMED: 20093474; PMC: 2821690; DOI: 10.1126/science.1182395

Team

No team members listed

Background

In 1995 the Wellcome Trust took the decision to set up a Pathogen sequencing unit (PSU) at what was then the Sanger Centre, to sequence the genomes of organisms relevant to human and animal health. It was initially funded through individual grants and later through the Wellcome Trust Beowulf Genomics Panel. The Beowulf panel now no longer operates and the PSU has been renamed to Pathogen genomics. This is now funded through the Sanger Institute Wellcome Trust envelope funding.