Canadas Michael Smith Genome science Center

Vancouver, Canada

Canadas Michael Smith Genome science Center

Vancouver, Canada
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Gardy J.L.,British Columbia Center for Disease Control | Gardy J.L.,University of British Columbia | Johnston J.C.,British Columbia Center for Disease Control | Ho Sui S.J.,British Columbia Center for Disease Control | And 22 more authors.
New England Journal of Medicine | Year: 2011

Background: An outbreak of tuberculosis occurred over a 3-year period in a medium-size community in British Columbia, Canada. The results of mycobacterial interspersed repetitive unit-variable-number tandem-repeat (MIRU-VNTR) genotyping suggested the outbreak was clonal. Traditional contact tracing did not identify a source. We used whole-genome sequencing and social-network analysis in an effort to describe the outbreak dynamics at a higher resolution. Methods: We sequenced the complete genomes of 32 Mycobacterium tuberculosis outbreak isolates and 4 historical isolates (from the same region but sampled before the outbreak) with matching genotypes, using short-read sequencing. Epidemiologic and genomic data were overlaid on a social network constructed by means of interviews with patients to determine the origins and transmission dynamics of the outbreak. Results: Whole-genome data revealed two genetically distinct lineages of M. tuberculosis with identical MIRU-VNTR genotypes, suggesting two concomitant outbreaks. Integration of social-network and phylogenetic analyses revealed several transmission events, including those involving "superspreaders." Both lineages descended from a common ancestor and had been detected in the community before the outbreak, suggesting a social, rather than genetic, trigger. Further epidemiologic investigation revealed that the onset of the outbreak coincided with a recorded increase in crack cocaine use in the community. Conclusions: Through integration of large-scale bacterial whole-genome sequencing and social-network analysis, we show that a socioenvironmental factor - most likely increased crack cocaine use - triggered the simultaneous expansion of two extant lineages of M. tuberculosis that was sustained by key members of a high-risk social network. Genotyping and contact tracing alone did not capture the true dynamics of the outbreak. (Funded by Genome British Columbia and others.) Copyright © 2011 Massachusetts Medical Society.


Hasan M.R.,Texas College | Hasan M.R.,Canadas Michael Smith Genome science Center | Rahman M.,Texas College | Rahman M.,University of British Columbia | And 3 more authors.
Journal of Biological Chemistry | Year: 2010

Glucose 6-phosphate (G6P) is a metabolic intermediate with many possible cellular fates. In mycobacteria, G6P is a substrate for an enzyme, F 420-dependent glucose-6-phosphate dehydrogenase (Fgd), found in few bacterial genera. Intracellular G6P levels in six Mycobacterium sp. were remarkably higher (∼17-130-fold) than Escherichia coli and Bacillus megaterium. The high G6P level in Mycobacterium smegmatis may result from 10-25-fold higher activity of the gluconeogenic enzyme fructose-1,6- bisphosphatase when grown on glucose, glycerol, or acetate compared with B. megaterium and E. coli. In M. smegmatis this coincided with up-regulation of the first gluconeogenic enzyme, phosphoenolpyruvate carboxykinase, when acetate was the carbon source, suggesting a cellular program for maintaining high G6P levels. G6P was depleted in cells under oxidative stress induced by redox cycling agents plumbagin and menadione, whereas an fgd mutant of M. smegmatis used G6P less well under such conditions. The fgd mutant was more sensitive to these agents and, in contrast to wild type, was defective in its ability to reduce extracellular plumbagin and menadione. These data suggest that intracellular G6P in mycobacteria serves as a source of reducing power and, with the mycobacteria-specific Fgd-F420 system, plays a protective role against oxidative stress. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Chaudhuri R.R.,University of Cambridge | Chaudhuri R.R.,University of Liverpool | Morgan E.,Institute for Animal Health | Peters S.E.,University of Cambridge | And 20 more authors.
PLoS Genetics | Year: 2013

Chickens, pigs, and cattle are key reservoirs of Salmonella enterica, a foodborne pathogen of worldwide importance. Though a decade has elapsed since publication of the first Salmonella genome, thousands of genes remain of hypothetical or unknown function, and the basis of colonization of reservoir hosts is ill-defined. Moreover, previous surveys of the role of Salmonella genes in vivo have focused on systemic virulence in murine typhoid models, and the genetic basis of intestinal persistence and thus zoonotic transmission have received little study. We therefore screened pools of random insertion mutants of S. enterica serovar Typhimurium in chickens, pigs, and cattle by transposon-directed insertion-site sequencing (TraDIS). The identity and relative fitness in each host of 7,702 mutants was simultaneously assigned by massively parallel sequencing of transposon-flanking regions. Phenotypes were assigned to 2,715 different genes, providing a phenotype-genotype map of unprecedented resolution. The data are self-consistent in that multiple independent mutations in a given gene or pathway were observed to exert a similar fitness cost. Phenotypes were further validated by screening defined null mutants in chickens. Our data indicate that a core set of genes is required for infection of all three host species, and smaller sets of genes may mediate persistence in specific hosts. By assigning roles to thousands of Salmonella genes in key reservoir hosts, our data facilitate systems approaches to understand pathogenesis and the rational design of novel cross-protective vaccines and inhibitors. Moreover, by simultaneously assigning the genotype and phenotype of over 90% of mutants screened in complex pools, our data establish TraDIS as a powerful tool to apply rich functional annotation to microbial genomes with minimal animal use. © 2013 Chaudhuri et al.


Mandakova T.,Masaryk University | Joly S.,University of Quebec at Montréal | Krzywinski M.,Canadas Michael Smith Genome science Center | Mummenhoff K.,University of Osnabrück | Lysaka M.A.,Masaryk University
Plant Cell | Year: 2010

Mesopolyploid whole-genome duplication (WGD) was revealed in the ancestry of Australian Brassicaceae species with diploid-like chromosome numbers (n = 4 to 6). Multicolor comparative chromosome painting was used to reconstruct complete cytogenetic maps of the cryptic ancient polyploids. Cytogenetic analysis showed that the karyotype of the Australian Camelineae species descended from the eight ancestral chromosomes (n = 8) through allopolyploid WGD followed by the extensive reduction of chromosome number. Nuclear and maternal gene phylogenies corroborated the hybrid origin of the mesotetraploid ancestor and suggest that the hybridization event occurred ̃ 6 to 9 million years ago. The four, five, and six fusion chromosome pairs of the analyzed close relatives of Arabidopsis thaliana represent complex mosaics of duplicated ancestral genomic blocks reshuffled by numerous chromosome rearrangements. Unequal reciprocal translocations with or without preceeding pericentric inversions and purported end-to-end chromosome fusions accompanied by inactivation and/or loss of centromeres are hypothesized to be the main pathways for the observed chromosome number reduction. Our results underline the significance of multiple rounds of WGD in the angiosperm genome evolution and demonstrate that chromosome number per se is not a reliable indicator of ploidy level. © American Society of Plant Biologists.


Chikhi R.,Pennsylvania State University | Limasset A.,Ecole Normale Superieure de Cachan | Jackman S.,Canadas Michael Smith Genome science Center | Simpson J.T.,Ontario Cancer Institute | Medvedev P.,Pennsylvania State University
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2014

The de Bruijn graph plays an important role in bioinformatics, especially in the context of de novo assembly. However, the representation of the de Bruijn graph in memory is a computational bottleneck for many assemblers. Recent papers proposed a navigational data structure approach in order to improve memory usage. We prove several theoretical space lower bounds to show the limitations of these types of approaches. We further design and implement a general data structure (dbgfm) and demonstrate its use on a human whole-genome dataset, achieving space usage of 1.5 GB and a 46% improvement over previous approaches. As part of dbgfm, we develop the notion of frequency-based minimizers and show how it can be used to enumerate all maximal simple paths of the de Bruijn graph using only 43 MB of memory. Finally, we demonstrate that our approach can be integrated into an existing assembler by modifying the ABySS software to use dbgfm. © 2014 Springer International Publishing Switzerland.


Haridas S.,University of British Columbia | Wang Y.,University of British Columbia | Lim L.,University of British Columbia | Massoumi Alamouti S.,University of British Columbia | And 6 more authors.
BMC Genomics | Year: 2013

Background: Ophiostoma piceae is a wood-staining fungus that grows in the sapwood of conifer logs and lumber. We sequenced its genome and analyzed its transcriptomes under a range of growth conditions. A comparison with the genome and transcriptomes of the mountain pine beetle-associated pathogen Grosmannia clavigera highlights differences between a pathogen that colonizes and kills living pine trees and a saprophyte that colonizes wood and the inner bark of dead trees.Results: We assembled a 33 Mbp genome in 45 scaffolds, and predicted approximately 8,884 genes. The genome size and gene content were similar to those of other ascomycetes. Despite having similar ecological niches, O. piceae and G. clavigera showed no large-scale synteny. We identified O. piceae genes involved in the biosynthesis of melanin, which causes wood discoloration and reduces the commercial value of wood products. We also identified genes and pathways involved in growth on simple carbon sources and in sapwood, O. piceae's natural substrate. Like the pathogen, the saprophyte is able to tolerate terpenes, which are a major class of pine tree defense compounds; unlike the pathogen, it cannot utilize monoterpenes as a carbon source.Conclusions: This work makes available the second annotated genome of a softwood ophiostomatoid fungus, and suggests that O. piceae's tolerance to terpenes may be due in part to these chemicals being removed from the cells by an ABC transporter that is highly induced by terpenes. The data generated will provide the research community with resources for work on host-vector-fungus interactions for wood-inhabiting, beetle-associated saprophytes and pathogens. © 2013 Haridas et al.; licensee BioMed Central Ltd.


Butterfield Y.S.,Canadas Michael Smith Genome science Center | Kreitzman M.,Canadas Michael Smith Genome science Center | Thiessen N.,Canadas Michael Smith Genome science Center | Corbett R.D.,Canadas Michael Smith Genome science Center | And 5 more authors.
PLoS ONE | Year: 2014

JAGuaR is an alignment protocol for RNA-seq reads that uses an extended reference to increase alignment sensitivity. It uses BWA to align reads to the genome and reference transcript models (including annotated exon-exon junctions) specifically allowing for the possibility of a single read spanning multiple exons. Reads aligned to the transcript models are then re-mapped on to genomic coordinates, transforming alignments that span multiple exons into large-gapped alignments on the genome. While JAGuaR does not detect novel junctions, we demonstrate how JAGuaR generates fast and accurate transcriptome alignments, which allows for both sensitive and specific SNV calling. © 2014 Butterfield et al.


Firme M.R.,Canadas Michael Smith Genome science Center | Marra M.A.,Canadas Michael Smith Genome science Center
Current Neurology and Neuroscience Reports | Year: 2014

Pediatric brain tumors are a leading cause of cancer-related death in children. In recent years, the application of next-generation sequencing and other high-throughput technologies to analysis of pediatric brain tumors has generated an abundance of molecular information. This has provided an unprecedented understanding of their biology and is refining tumor classification into clinically relevant subgroups. In this review, we provide an overview of our evolving molecular knowledge of the commonest pediatric brain tumors, pilocytic astrocytomas, ependymomas, medulloblastomas, and pediatric glioblastomas, as well as the biological and potential clinical implications of this new knowledge. Studies aimed at investigating intratumoral heterogeneity are also discussed. © 2014 Springer Science+Business Media.


Altman N.,Pennsylvania State University | Krzywinski M.,Canadas Michael Smith Genome science Center
Nature Methods | Year: 2015

The statistician knows...that in nature there never was a normal distribution, there never was a straight line, yet with normal and linear assumptions, known to be false, he can often derive results which match, to a useful approximation, those found in the real world. © 2015 Nature America, Inc.


Krzywinski M.,Canadas Michael Smith Genome science Center
Molecular Cell | Year: 2016

Rapid and inexpensive single-cell sequencing is driving new visualizations of cancer instability and evolution. Krzywinski discusses how to present clone evolution plots in order to visualize temporal, phylogenetic, and spatial aspects of a tumor in a single static image. © 2016 Elsevier Inc.

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