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Bacterial epidemiology and biology - lessons from genome sequencing
Julian Parkhill, Brendan W Wren
Genome Biology , 2011, DOI: 10.1186/gb-2011-12-10-230
Abstract: The application of whole-genome sequencing affords the opportunity to generate bacterial nucleic acid sequence data of extraordinary resolution, making it possible to identify single base changes within entire genomes. The development of second (and third) generation sequencing technology has largely been driven by the desire to assess human genetic variation rapidly by mapping genome-wide single-nucleotide polymorphisms (SNPs). Several recent studies have applied similar analyses at the whole-genome level to the much smaller genomes of bacteria, providing data of very fine-scale resolution and enabling the evolutionary history of multiple strains within a clonal lineage to be determined [1-8]. Not surprisingly, these studies have focused on bacterial pathogens because of their importance in disease.Distinguishing individual bacterial lineages within a species, initially by phenotypic and subsequently by genotypic typing techniques, has been the cornerstone of infectious disease epidemiology, allowing the identification and tracking of the organisms responsible for infection and disease. On a wider scale, molecular typing is central to determining the population structure and understanding the evolution of bacterial pathogens. To date, sequence-based typing approaches, such as multilocus sequence typing (MLST), have relied on variation within a few genes [9]. Although such techniques are highly informative, they have limited resolution when applied to closely related isolates. Thus, they are often unsuitable for identifying fine-grained evolutionary events or for distinguishing clonal strains within a recent epidemic [10]. This situation has now been improved by the application of next-generation sequencing to bacterial collections of known origin and provenance. We review recent examples in which such studies have informed our understanding of the epidemiology and evolution of bacterial pathogens.Studies of the phylogeny of a species or of a clonal lineage within a
Genomic information infrastructure after the deluge
Julian Parkhill, Ewan Birney, Paul Kersey
Genome Biology , 2010, DOI: 10.1186/gb-2010-11-7-402
Abstract: The advent of next-generation sequencing technology has led to a profound shift in the economics of genomics. Sequencing costs have fallen more than a hundredfold over the past four years, and this rate of reduction is likely to continue for the foreseeable future. The availability of cheap DNA sequencing has changed the cost of a variety of experiments - gaining a near-complete bacterial sequence costs a few hundred dollars in consumables, whereas mid-size genomes are amenable to a single grant proposal. A number of large genomes, such as those of vertebrates (for example, the turkey) have been undertaken by small consortia of interested laboratories. In addition, there are a variety of novel assays, such as RNA sequencing (RNA-seq), transposon mutagenesis and chromatin immunoprecipitation and sequencing (ChIP-seq) in which low-cost sequencing has replaced other readout platforms such as nucleic acid hybridization. Understanding these data rests fundamentally on well curated, up-to-date annotation for reference genomes, which can be leveraged for other species. However, the ability of the scientific community to maintain such resources is failing as a result of the onslaught of new data and the disconnect between the archival DNA databases and the new types of information and analysis being reported in the scientific literature. In this article, we propose a new structure for genomic information resources to address this problem.Dramatic falls in the consumable costs of DNA sequencing have not fundamentally changed the need for computational analysis to process and interpret the information produced. Indeed, the need has increased as the volume and complexity of the data have risen. There has, therefore, been a profound shift towards a higher intensity of informatics in biological research, with bioinformatics becoming a necessary component of many, if not most, molecular biology groups. The analysis of new genome-wide experiments typically requires the presence of
Genetic flux over time in the Salmonella lineage
Georgios S Vernikos, Nicholas R Thomson, Julian Parkhill
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-6-r100
Abstract: From a whole-genome comparative analysis of eleven Salmonella, three Escherichia coli and one Shigella strain, we inferred the relative time of insertion of putative horizontally acquired (PHA) genes in three Salmonella strains on different branches of the S. enterica phylogenetic tree. Compositional analysis suggests that most of the PHA genes are still undergoing an amelioration process and shows a clear correlation between time of insertion and the level of amelioration.The results show that older insertions include almost all functional classes. However, very recent horizontal transfer events in the Salmonella lineage involve primarily prophage elements that are shared only between very recently diverged lineages; despite this, the prophage sequence composition is close to that of the host, indicating that host adaptation, rather than amelioration, is likely to be the source of the compositional similarity. Almost half of the PHA genes were acquired at the base of the Salmonella lineage, whereas nearly three-quarters are shared between most S. enterica subspecies. The numerical distribution of PHA genes in the Salmonella tree topology correlates well with the divergence of the major Salmonella species, highlighting the major impact of horizontal transfer on the evolution of the salmonellae.The divergence of Salmonella and Escherichia coli lineages from their common ancestor has been estimated to have occurred approximately 100-140 million years (Myr) ago [1,2]. Using models of amelioration to estimate the time of horizontal gene transfer (HGT) events it has been previously shown [3] that the entire E. coli chromosome contains more than 600 kb of horizontally transferred, protein-coding DNA. The same authors estimated the HGT rate to be 31 kb per million years, which is close to the point mutation frequency. Under this assumption the E. coli and Salmonella enterica lineages have each gained and lost more than 3 megabases (Mb) of novel DNA since their divergence.D
Investigations into genome diversity of Haemophilus influenzae using whole genome sequencing of clinical isolates and laboratory transformants
Power Peter M,Bentley Stephen D,Parkhill Julian,Moxon E
BMC Microbiology , 2012, DOI: 10.1186/1471-2180-12-273
Abstract: Background Haemophilus influenzae is an important human commensal pathogen associated with significant levels of disease. High-throughput DNA sequencing was used to investigate differences in genome content within this species. Results Genomic DNA sequence was obtained from 85 strains of H. influenzae and from other related species, selected based on geographical site of isolation, disease association and documented genotypic and phenotypic differences. When compared by Mauve alignment these indicated groupings of H. influenzae that were consistent with previously published analyses; capsule expressing strains fell into two distinct groups and those of serotype b (Hib) were found in two closely positioned lineages. For 18 Hib strains representing both lineages we found many discrete regions (up to 40% of the total genome) displaying sequence variation when compared to a common reference strain. Evidence that this naturally occurring pattern of inter-strain variation in H. influenzae can be mediated by transformation was obtained through sequencing DNA obtained from a pool of 200 independent transformants of a recipient (strain Rd) using donor DNA from a heterologous Hib strain (Eagan). Conclusion Much of the inter-strain variation in genome sequence in H. influenzae is likely the result of inter-strain exchanges of DNA, most plausibly through transformation.
A High-Resolution View of Genome-Wide Pneumococcal Transformation
Nicholas J. Croucher ,Simon R. Harris,Lars Barquist,Julian Parkhill,Stephen D. Bentley
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002745
Abstract: Transformation is an important mechanism of microbial evolution through which bacteria have been observed to rapidly adapt in response to clinical interventions; examples include facilitating vaccine evasion and the development of penicillin resistance in the major respiratory pathogen Streptococcus pneumoniae. To characterise the process in detail, the genomes of 124 S. pneumoniae isolates produced through in vitro transformation were sequenced and recombination events detected. Those recombinations importing the selected marker were independent of unselected events elsewhere in the genome, the positions of which were not significantly affected by local sequence similarity between donor and recipient or mismatch repair processes. However, both types of recombinations were sometimes mosaic, with multiple non-contiguous segments originating from the same molecule of donor DNA. The lengths of the unselected events were exponentially distributed with a mean of 2.3 kb, implying that recombinations are stochastically resolved with a fixed per base probability of 4.4×10?4 bp?1. This distribution of recombination sizes, coupled with an observed under representation of large insertions within transferred sequence, suggests transformation has the potential to reduce the size of bacterial genomes, and is unlikely to act as an efficient mechanism for the uptake of accessory genomic loci.
Identification, variation and transcription of pneumococcal repeat sequences
Nicholas J Croucher, Georgios S Vernikos, Julian Parkhill, Stephen D Bentley
BMC Genomics , 2011, DOI: 10.1186/1471-2164-12-120
Abstract: Analysis of the genome of S. pneumoniae ATCC 700669 revealed the presence of a third repeat family, which we have named SPRITE. All three repeats are present at a reduced density in the genome of the closely related species S. mitis. However, they are almost entirely absent from all other streptococci, although a set of elements related to the pneumococcal BOX repeat was identified in the zoonotic pathogen S. suis. In conjunction with information regarding their distribution within the pneumococcal chromosome, this suggests that it is unlikely that these repeats are specialised sequences performing a particular role for the host, but rather that they constitute parasitic elements. However, comparing insertion sites between pneumococcal sequences indicates that they appear to transpose at a much lower rate than IS elements. Some large BOX elements in S. pneumoniae were found to encode open reading frames on both strands of the genome, whilst another was found to form a composite RNA structure with two T box riboswitches. In multiple cases, such BOX elements were demonstrated as being expressed using directional RNA-seq and RT-PCR.BOX, RUP and SPRITE repeats appear to have proliferated extensively throughout the pneumococcal chromosome during the species' past, but novel insertions are currently occurring at a relatively slow rate. Through their extensive secondary structures, they seem likely to affect the expression of genes with which they are co-transcribed. Software for annotation of these repeats is freely available from ftp://ftp.sanger.ac.uk/pub/pathogens/strep_repeats/ webcite.Small interspersed repeats, spatially separated genomic regions of similar sequence typically < 200 bp in length, are frequently found in bacterial chromosomes [1]. These can be classified as either 'simple', when consisting of a single repeated unit, or 'composite', when comprised of a combination of different subsequences arranged in particular patterns [2]. For example, a number of e
Re-annotation and re-analysis of the Campylobacter jejuni NCTC11168 genome sequence
Ozan Gundogdu, Stephen D Bentley, Matt T Holden, Julian Parkhill, Nick Dorrell, Brendan W Wren
BMC Genomics , 2007, DOI: 10.1186/1471-2164-8-162
Abstract: Re-annotation was carried out using sequence database searches such as FASTA, along with programs such as TMHMM for additional support. The re-annotation also utilises sequence data from additional Campylobacter strains and species not available during the original annotation. Re-annotation was accompanied by a full literature search that was incorporated into the updated EMBL file [EMBL: AL111168]. The C. jejuni NCTC11168 re-annotation reduced the total number of coding sequences from 1654 to 1643, of which 90.0% have additional information regarding the identification of new motifs and/or relevant literature. Re-annotation has led to 18.2% of coding sequence product functions being revised.Major updates were made to genes involved in the biosynthesis of important surface structures such as lipooligosaccharide, capsule and both O- and N-linked glycosylation. This re-annotation will be a key resource for Campylobacter research and will also provide a prototype for the re-annotation and re-interpretation of other bacterial genomes.Campylobacter jejuni is the leading bacterial cause of human gastroenteritis in the developed world [1]. C. jejuni infection has also been associated with post-infection sequelae including septicaemia and neuropathies such as Guillain-Barré Syndrome (GBS) [2]. Infection has largely been linked with the consumption of contaminated poultry or meat products. Given the socioeconomic importance of this pathogen, it is surprising that the ecology, the epidemiology and, in particular, the pathogenesis are still so poorly understood [3]. The lack of information on this problematic pathogen was one of the main driving forces for the original C. jejuni NCTC11168 genome project published in 2000 [4], and equally is why a re-annotation and re-analysis of the genome is required.Since the publication of the C. jejuni NCTC11168 genome sequence in 2000, there has been a spectacular increase in research on this important human pathogen. One result of this h
Evolutionary diversification of an ancient gene family (rhs) through C-terminal displacement
Andrew P Jackson, Gavin H Thomas, Julian Parkhill, Nicholas R Thomson
BMC Genomics , 2009, DOI: 10.1186/1471-2164-10-584
Abstract: Rhs genes are ubiquitous and comprise six structurally distinct lineages within the Enterobacteriaceae. There is considerable intergenomic variation in rhs repertoire; for instance, in Salmonella enterica, rhs are restricted to mobile elements, while in Escherichia coli one rhs lineage has diversified through transposition as older lineages have been deleted. Overall, comparative genomics reveals frequent, independent gene gains and losses, as well as occasional lateral gene transfer, in different genera. Furthermore, we demonstrate that Rhs 'core' domains and variable C-termini are evolutionarily decoupled, and propose that rhs diversity is driven by homologous recombination with circular intermediates. Existing C-termini are displaced by laterally acquired alternatives, creating long arrays of dissociated 'tips' that characterize the appearance of rhs loci.Rhs repertoires are highly dynamic among Enterobacterial genomes, due to repeated gene gains and losses. In contrast, the primary structures of Rhs genes are evolutionarily conserved, indicating that rhs sequence diversity is driven, not by rapid mutation, but by the relatively slow evolution of novel core/tip combinations. Hence, we predict that a large pool of dissociated rhs C-terminal tips exists episomally and these are potentially transmitted across taxonomic boundaries.Enterobacterial genomes are far from stable entities undergoing a constant process of gene acquisition and loss [1]. Genome flux can have a profound effect on the particular organism and in many instances is associated with adaptation to different niches and may eventually come to define different isolates, pathotypes or even species [2]. Genome flux can occur by Lateral Gene Transfer (LGT) though processes such as natural transformation, bacteriophage mediated transduction and conjugation [3-6]. In addition, the expansion of different gene families through gene duplication can introduce functional variation into a population, especially wh
Patent Human Infections with the Whipworm, Trichuris trichiura, Are Not Associated with Alterations in the Faecal Microbiota
Philip Cooper, Alan W. Walker, Jorge Reyes, Martha Chico, Susannah J. Salter, Maritza Vaca, Julian Parkhill
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076573
Abstract: Background The soil-transmitted helminth (STH), Trichuris trichiura colonises the human large intestine where it may modify inflammatory responses, an effect possibly mediated through alterations in the intestinal microbiota. We hypothesised that patent T. trichiura infections would be associated with altered faecal microbiota and that anthelmintic treatment would induce a microbiota resembling more closely that observed in uninfected individuals. Materials and Methods School children in Ecuador were screened for STH infections and allocated to 3 groups: uninfected, T. trichiura only, and mixed infections with T. trichiura and Ascaris lumbricoides. A sample of uninfected children and those with T. trichiura infections only were given anthelmintic treatment. Bacterial community profiles in faecal samples were studied by 454 pyrosequencing of 16 S rRNA genes. Results Microbiota analyses of faeces were done for 97 children: 30 were uninfected, 17 were infected with T. trichiura, and 50 with T. trichiura and A. lumbricoides. Post-treatment samples were analyzed for 14 children initially infected with T. trichiura alone and for 21 uninfected children. Treatment resulted in 100% cure of STH infections. Comparisons of the microbiota at different taxonomic levels showed no statistically significant differences in composition between uninfected children and those with T. trichiura infections. We observed a decreased proportional abundance of a few bacterial genera from the Clostridia class of Firmicutes and a reduced bacterial diversity among children with mixed infections compared to the other two groups, indicating a possible specific effect of A. lumbricoides infection. Anthelmintic treatment of children with T. trichiura did not alter faecal microbiota composition. Discussion Our data indicate that patent human infections with T. trichiura may have no effect on faecal microbiota but that A. lumbricoides colonisation might be associated with a disturbed microbiota. Our results also catalogue the microbiota of rural Ecuadorians and indicate differences with individuals from more urban industrialised societies.
A Novel Linear Plasmid Mediates Flagellar Variation in Salmonella Typhi
Stephen Baker ,Jonathan Hardy,Kenneth E Sanderson,Michael Quail,Ian Goodhead,Robert A Kingsley,Julian Parkhill,Bruce Stocker ?,Gordon Dougan
PLOS Pathogens , 2007, DOI: 10.1371/journal.ppat.0030059
Abstract: Unlike the majority of Salmonella enterica serovars, Salmonella Typhi (S. Typhi), the etiological agent of human typhoid, is monophasic. S. Typhi normally harbours only the phase 1 flagellin gene (fliC), which encodes the H:d antigen. However, some S. Typhi strains found in Indonesia express an additional flagellin antigen termed H:z66. Molecular analysis of H:z66+ S. Typhi revealed that the H:z66 flagellin structural gene (fljBz66) is encoded on a linear plasmid that we have named pBSSB1. The DNA sequence of pBSSB1 was determined to be just over 27 kbp, and was predicted to encode 33 coding sequences. To our knowledge, pBSSB1 is the first non-bacteriophage–related linear plasmid to be described in the Enterobacteriaceae.
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