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PubMed1998

Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls.

Germ-line mutations in DNA mismatch-repair genes impart a markedly elevated cancer risk, often presenting as autosomal dominant hereditary nonpolyposis colorectal cancer (HNPCC). However, there are no pathognomonic features of HNPCC, not all gene carriers have a family history of the disease, and families fulfilling the Amsterdam criteria are relatively uncommon. Genetic testing of probands with early-onset colorectal cancer, irrespective of family history, is one approach that would allow predictive genetic testing of at-risk relatives. We cloned and sequenced hMSH2 and hMLH1 introns, to optimize genomic sequencing. We then systematically analyzed the entire hMSH2 and hMLH1 genes, by genomic sequencing and in vitro synthesized-protein-truncation assay (IVSP), in 50 colorectal cancer patients <30 years of age at diagnosis. To determine polymorphic variants, 26 anonymous donors also were sequenced. All subjects analyzed had at least 1 of 37 different polymorphic or pathogenic variants. IVSP complemented genomic sequencing, by detection of mutations not identified by genomic analysis. Fourteen cancer patients (28%) had pathogenic mutations, and a number of other variants also may have had a pathogenic significance that remains to be elucidated. Tumor replication-error status was useful in targeting sequencing efforts for this cohort of young patients: sensitivity was 86%, specificity 73%, and positive and negative predictive values 63% and 90%, respectively. These data indicate that an appreciable proportion of young colon cancer probands carry a germ-line mutation in a DNA mismatch-repair gene.

Adaptor Proteins, Signal Transducing↗
PubMed2006

VMD: a community annotation database for oomycetes and microbial genomes.

The VBI Microbial Database (VMD) is a database system designed to host a range of microbial genome sequences. At present, the database contains genome sequence and annotation data of two plant pathogens Phytophthora sojae and Phytophthora ramorum. With the completion of the draft genome sequences of these pathogens in collaboration with the DOE Joint Genome Institute (JGI), we have created this resource to make the sequences publicly available. The genome sequences (95 MB for P.sojae and 65 MB for P.ramorum) were annotated with approximately 19,000 and approximately 16,000 gene models, respectively. We used two different statistical methods to validate these gene models, Fickett's and a log-likelihood method. Functional annotation of the gene models is based on results from BlastX and InterProScan screens. From the InterProScan results, we could assign putative functions to 17,694 genes in P.sojae and 14,700 genes in P.ramorum. We created an easy-to-use genome browser to view the genome sequence data, which opens to detailed annotation pages for each gene model. A community annotation interface is available for registered community members to add or edit annotations. There are approximately 1600 gene models for P.sojae and approximately 700 models for P.ramorum that have already been manually curated. A toolkit is provided as an additional resource for users to perform a variety of sequence analysis jobs. The database is publicly available at http://phytophthora.vbi.vt.edu/.

Databases, Nucleic Acid↗
PubMed2001

The genome of the natural genetic engineer Agrobacterium tumefaciens C58.

The 5.67-megabase genome of the plant pathogen Agrobacterium tumefaciens C58 consists of a circular chromosome, a linear chromosome, and two plasmids. Extensive orthology and nucleotide colinearity between the genomes of A. tumefaciens and the plant symbiont Sinorhizobium meliloti suggest a recent evolutionary divergence. Their similarities include metabolic, transport, and regulatory systems that promote survival in the highly competitive rhizosphere; differences are apparent in their genome structure and virulence gene complement. Availability of the A. tumefaciens sequence will facilitate investigations into the molecular basis of pathogenesis and the evolutionary divergence of pathogenic and symbiotic lifestyles.

Agrobacterium tumefaciens↗
PubMed2005

Repetitive extragenic palindromic sequences in the Pseudomonas syringae pv. tomato DC3000 genome: extragenic signals for genome reannotation.

Repetitive extragenic palindromic (REPs) sequences were first described in enterobacteriacea and later in Pseudomonas putida. We have detected a new variant (51 base pairs) of REP sequences that appears to be disseminated in more than 300 copies in the Pseudomonas syringae DC3000 genome. The finding of REP sequences in P. syringae confirms the broad presence of this type of repetitive sequence in bacteria. We analyzed the distribution of REP sequences and the structure of the clusters, and we show that palindromy is conserved. REP sequences appear to be allocated to the extragenic space, with a special preference for the intergenic spaces limited by convergent genes, while their presence is scarce between divergent genes. Using REP sequences as markers of extragenicity we re-annotated a set of genes of the P. syringae DC3000 genome demonstrating that REP sequences can be used for refinement of annotation of a genome. The similarity detected between virulence genes from evolutionarily distant pathogenic bacteria suggests the acquisition of clusters of virulence genes by horizontal gene transfer. We did not detect the presence of P. syringae REP elements in the principal pathogenicity gene clusters. This absence suggests that genome fragments lacking REP sequences could point to regions recently acquired from other organisms, and REP sequences might be new tracers for gaining insight into key aspects of bacterial genome evolution, especially when studying pathogenicity acquisition. In addition, as the P. syringae REP sequence is species-specific with respect to the sequenced genomes, it is an exceptional candidate for use as a fingerprint in precise genotyping and epidemiological studies.

Base Sequence↗
PubMed2006

The long hard road to a completed Candida albicans genome.

After almost a decade of work, the sequencing, assembly, and annotation of the genome of the fungal pathogen Candida albicans is finally close at hand. This review covers the early history of the C. albicans genome project, from the release of early assemblies that provided the impetus for an explosion in functional genomics research, to a community-based annotation and a preview of the work that was necessary for the production of a final genome assembly.

Base Sequence↗
PubMed2003

Evidence from comparative genomics for a complete sexual cycle in the 'asexual' pathogenic yeast Candida glabrata.

BACKGROUND: Candida glabrata is a pathogenic yeast of increasing medical concern. It has been regarded as asexual since it was first described in 1917, yet phylogenetic analyses have revealed that it is more closely related to sexual yeasts than other Candida species. We show here that the C. glabrata genome contains many genes apparently involved in sexual reproduction. RESULTS: By genome survey sequencing, we find that genes involved in mating and meiosis are as numerous in C. glabrata as in the sexual species Kluyveromyces delphensis, which is its closest known relative. C. glabrata has a putative mating-type (MAT) locus and a pheromone gene (MFALPHA2), as well as orthologs of at least 31 other Saccharomyces cerevisiae genes that have no known roles apart from mating or meiosis, including FUS3, IME1 and SMK1. CONCLUSIONS: We infer that C. glabrata is likely to have an undiscovered sexual stage in its life cycle, similar to that recently proposed for C. albicans. The two Candida species represent two distantly related yeast lineages that have independently become both pathogenic and 'asexual'. Parallel evolution in the two lineages as they adopted mammalian hosts resulted in separate but analogous switches from overtly sexual to cryptically sexual life cycles, possibly in response to defense by the host immune system.

Candida glabrata↗
PubMed2005

Recognizing the pseudogenes in bacterial genomes.

Pseudogenes are now known to be a regular feature of bacterial genomes and are found in particularly high numbers within the genomes of recently emerged bacterial pathogens. As most pseudogenes are recognized by sequence alignments, we use newly available genomic sequences to identify the pseudogenes in 11 genomes from 4 bacterial genera, each of which contains at least 1 human pathogen. The numbers of pseudogenes range from 27 in Staphylococcus aureus MW2 to 337 in Yersinia pestis CO92 (e.g. 1-8% of the annotated genes in the genome). Most pseudogenes are formed by small frameshifting indels, but because stop codons are A + T-rich, the two low-G + C Gram-positive taxa (Streptococcus and Staphylococcus) have relatively high fractions of pseudogenes generated by nonsense mutations when compared with more G + C-rich genomes. Over half of the pseudogenes are produced from genes whose original functions were annotated as 'hypothetical' or 'unknown'; however, several broadly distributed genes involved in nucleotide processing, repair or replication have become pseudogenes in one of the sequenced Vibrio vulnificus genomes. Although many of our comparisons involved closely related strains with broadly overlapping gene inventories, each genome contains a largely unique set of pseudogenes, suggesting that pseudogenes are formed and eliminated relatively rapidly from most bacterial genomes.

Genome, Bacterial↗
PubMed2001

Conserved RNA secondary structures in Picornaviridae genomes.

The family Picornaviridae contains important pathogens including, for example, hepatitis A virus and foot-and-mouth disease virus. The genome of these viruses is a single messenger-active (+)-RNA of 7200-8500 nt. Besides coding for the viral proteins, it also contains functionally important RNA secondary structures, among them an internal ribosomal entry site (IRES) region towards the 5'-end. This contribution provides a comprehensive computational survey of the complete genomic RNAs and a detailed comparative analysis of the conserved structural elements in seven of the currently nine genera in the family PICORNAVIRIDAE: Compared with previous studies we find: (i) that only smaller sections of the IRES region than previously reported are conserved at single base-pair resolution and (ii) that there is a number of significant structural elements in the coding region. Furthermore, we identify potential cis-acting replication elements in four genera where this feature has not been reported so far.

5' Untranslated Regions↗
PubMed2003

Viral bioinformatics: computational views of host and pathogen.

Wherever cellular life occurs, viruses are also found. As a result, complex organism and cellular antiviral responses co-evolve with virally encoded countermeasures. Since viruses co-opt or interfere with specific cellular pathways during their replication, knowledge of viral genome sequences has helped fundamental understanding of host biology. During viral infection, shifts in the balance between host and viral biological processes result in acute or chronic viral disease pathology accompanied with either active viral replication, viral containment/persistence or viral clearance. Studying host-virus interactions at the level of single gene effects, however, fails to produce a global systems-level understanding. This should now be achievable in the context of complete host and pathogen genome sequences. New experimental methods and computational approaches are rapidly developing, allowing global views of dynamic viral and cellular molecular mechanisms. Systems level virology using DNA microarrays and specific viral data resources will reveal the detailed cellular context in which viruses replicate, highlighting common and distinct antiviral mechanisms, the effect of different host cell gene expression programs, and the response of cells to similar or diverse virus types. Ultimately, microbiology and immunology will tend towards a systems-level view of how host and pathogen interact.

Amino Acid Motifs↗
PubMed1993

Evaluating two methods for fingerprinting genomes of Actinobacillus actinomycetemcomitans.

The arbitrary primer polymerase chain reaction (AP-PCR) and Southern blot restriction fragment length polymorphism (RFLP) were used to genotype the periodontal pathogen A. actinomycetemcomitans. Total genomic DNA from 73 strains was extracted by conventional methods. Three random-sequence 10-base oligonucleotide primers were chosen for AP-PCR. The amplified DNA products were separated electrophoretically in a 1% agarose gel containing ethidium bromide and the banding patterns were compared among different strains. For RFLP analysis, DNA was digested with EcoRI, separated on a 0.8% agarose gel and transferred to a nylon membrane. The membrane was probed with a previously characterized 5.2 kilobases (kb) DNA fragment cloned from A. actinomycetemcomitans strain Y4. The probe was labeled with digoxigenin, and hybridized fragments were detected with anti-digoxigenin antibody. AP-PCR produced 4-10 DNA bands in the 0.5-5 kb regions and distinguished 9, 13 or 17 genotypes, depending on the specific primer used. Southern blot RFLP analysis revealed 12 hybridization patterns consisting of 1 or 2 DNA fragments (2-23 kb). The addition of the Southern blot analysis to the AP-PCR analysis gave rise to a total of 30 DNA profiles among the 73 A. actinomycetemcomitans study strains. The results indicate that both AP-PCR and Southern blot analysis are useful in clonal analysis of A. actinomycetemcomitans.

Aggregatibacter actinomycetemcomitans↗
PubMed2003

Genome-based detection methods of Macrobrachium rosenbergii nodavirus, a pathogen of the giant freshwater prawn, Macrobrachium rosenbergii dot-blot, in situ hybridization and RT-PCR.

The availability of specific and rapid detection methods is essential for monitoring the health status of farmed species, particularly in viral diseases as in this case early diagnosis is a critical factor in containing disease outbreaks. Three complementary genome-based methods were developed for the detection of Macrobrachium rosenbergii nodavirus (MrNV), i.e. dot-blot hybridization, in situ hybridization and reverse transcriptase-polymerase chain reaction (RT-PCR). Detection limits were established for dot-blot hybridization and RT-PCR and are c. 7 fg and 8 pg of viral RNA, respectively. In situ hybridization indicated that infection was confined to the striated muscle tissue. As a result of its sensitivity, RT-PCR can be used for in-depth investigations to examine the extent of the viral infection and establish the onset of infection in hatcheries. The application of RT-PCR on samples collected from prawn farms in China showed the possible use of this method in routine health monitoring.

Animals↗
PubMed2000

Chromosome structure and sequence organization between pathogenic and non-pathogenic Leishmania spp.

We have used a chromosome fragmentation strategy based on systematic genomic insertions of the rare cutting yeast I-SceI endonuclease to assess structure and sequence organization of homologous chromosomes between evolutionary divergent pathogenic and non-pathogenic Leishmania species. This method was combined to physical mapping and hybridization studies using a number of specific chromosomal markers as probes. Our studies have concentrated on two different chromosomes of Leishmania major (L. major), L. donovani and L. infantum and of the non-pathogenic species L. tarentolae. Specific chromosome fragmentation events at the level of multiple I-SccI genomic integrations indicated that very similar distances separated internal genomic sequences between homologous chromosomes and that distances from chromosome ends were more variable. The order and orientation of genes along the homologous chromosomes were also conserved between species. With only few exceptions, genome organization between pathogenic and non-pathogenic Leishmania species was found to be highly conserved. Genomic comparison of pathogenic and non-pathogenic species may be useful for depicting regions involved in species-specific related pathologies.

Animals↗
PubMed2004

Fatty acid synthesis in Xylella fastidiosa: correlations between genome studies, 13C NMR data, and molecular models.

Xylella fastidiosa was the first plant pathogen to have its complete genome sequence elucidated. Routine database analyses suggested that two enzymes essential for fatty acid synthesis were missing, one of these is the holo-acyl-carrier-protein synthase. However, here we demonstrate, using (13)C NMR spectroscopy, that X. fastidiosa is indeed able to synthesize fatty acids from acetate via an apparently conventional metabolic pathway. We further identify a gene product HetI, an alternative phosphopantetheinyl transferase, which we propose to fill the missing link. Homology modeling of HetI shows conservation of the Coenzyme A binding site suggesting it to be an active enzyme and reveals several interesting structural features when compared with the surfactin synthase-activating enzyme, on which the model was built. These include a simplified topology due to N- and C-terminal deletions and the observation of a novel serine ladder.

Acetates↗
PubMed2004

Pathogenomics of mobile genetic elements of toxigenic bacteria.

The growing knowledge of genetic diversity and whole genome organization in bacteria shows that pathogenicity islands (PAIs) represent a subtype of a more general genetic element, termed genomic island (GEI), which is widespread among pathogenic and non-pathogenic microbes. These findings mirror the importance of horizontal gene transfer, genome reduction and recombination events as fundamental mechanisms involved in evolution of bacterial variants. GEIs are part of the flexible gene pool and carry selfish genes, but also determinants which may be beneficial under certain conditions thus increasing bacterial fitness and consequently their survival or transmission. In this review, we focus on the role of mobile genetic elements that may also contain toxin-encoding genes for genome variability and evolution of bacteria.

Bacterial Toxins↗
PubMed2005

ibeA, a virulence factor of avian pathogenic Escherichia coli.

The presence of ibeA, a gene encoding a known virulence factor of Escherichia coli strains responsible for neonatal meningitis in humans, was investigated in the genome of 213 avian pathogenic E. coli (APEC) strains and 55 non-pathogenic E. coli strains of avian origin. Fifty-three strains were found to be ibeA(+), all of which belonged to the APEC group. The ibeA gene is therefore positively linked to the pathogenicity of strains (P<0.0001). Analysis of the serogroup of strains revealed a positive association of ibeA with serogroups O18, O88 and O2. On the contrary, only 1/59 O78 strains are ibeA(+), indicating a negative association of ibeA with this serogroup (P<0.0001). The role of ibeA in the virulence of the APEC strain BEN 2908 was investigated by constructing an ibeA mutant. Challenge assays on 3-week-old chickens showed a reduced virulence for the ibeA mutant. Furthermore, the APEC strain BEN 2908 was able to invade brain microvascular epithelial cells, this invasion being significantly reduced upon inactivation of ibeA. Altogether, these results suggest a role of ibeA in the pathogenicity of some APEC strains and confirm the close relationship between APEC and other human extraintestinal pathogenic E. coli isolates.

Animals↗
PubMed2005

Molecular analyses of disease pathogenesis: application of bovine microarrays.

The molecular analysis of disease pathogenesis in cattle has been limited by the lack of availability of tools to analyze both host and pathogen responses. These limitations are disappearing with the advent of methodologies such as microarrays that facilitate rapid characterization of global gene expression at the level of individual cells and tissues. The present review focuses on the use of microarray technologies to investigate the functional pathogenomics of infectious disease in cattle. We discuss a number of unique issues that must be addressed when designing both in vitro and in vivo model systems to analyze host responses to a specific pathogen. Furthermore, comparative functional genomic strategies are discussed that can be used to address questions regarding host responses that are either common to a variety of pathogens or unique to individual pathogens. These strategies can also be applied to investigations of cell signaling pathways and the analyses of innate immune responses. Microarray analyses of both host and pathogen responses hold substantial promise for the generation of databases that can be used in the future to address a wide variety of questions. A critical component limiting these comparative analyses will be the quality of the databases and the complete functional annotation of the bovine genome. These limitations are discussed with an indication of future developments that will accelerate the validation of data generated when completing a molecular characterization of disease pathogenesis in cattle.

Animals↗
PubMed1987

Determination of the nucleotide sequence flanking the deletion (0.762 to 0.789 map units) in the genome of an intraperitoneally avirulent HSV-1 strain HFEM.

Herpes simplex virus type 1 (HSV-1) strain HFEM which harbours a deletion of 4.1 kbp in its genome (0.762 to 0.789 map units, HpaI DNA fragment P of HSV-1), is apathogenic for mice and tree shrews by the intraperitoneal application route. The exact position of this deletion was determined by DNA sequence analysis. This analysis was performed using the recombinant plasmid pU18HSHF-XmI-B which harbours the flanking genome regions (0.752 to 0.762 and 0.789 to 0.7895 map units) of the deletion in the genome of HSV-1 HFEM, and the recombinant plasmids pU18HSF-XmI-B, pU18HSF-AS, and pHSF-BB-BsH-D, harbouring particular regions of the genome of the virulent HSV-1 strain F at the coordinates 0.752 to 0.761, 0.786 to 0.790, and 0.762 to 0.771, respectively. The comparison of the DNA sequence of this region with the DNA sequences of the corresponding genome regions of the pathogenic HSV-1 strain F and HSV-1 strain 17 showed that the 5' end of the deletion in the genome of HSV-1 HFEM starts at the nucleotide position 3774 of the BamHI DNA fragment B from HSV-1/17. This position is 71 bp upstream of the UL/RL junction of the HSV-1 genome. The 3' terminus of the deletion ends at the nucleotide position 7226 of the BamHI DNA fragment B from HSV-1/17. The position is within the incomplete ninth repetitive box (ACTCC-CACGCACCCCC) and is located 36 bp upstream of the 3' end of the IE 110 mRNA.

Animals↗
PubMed2003

Why do mammalian mitochondria possess a mismatch repair activity?

All nucleated mammalian cells contain mitochondrial DNA, a small (approximately 15-17 kb) circular genome found in the matrix. This molecule is present in multiple copies, with numbers routinely exceeding 1000 per cell. Many pathogenic mutations of this genome have been reported, with the vast majority being highly recessive. A mismatch repair activity has been recently described in mitochondria that shows no strand bias for correcting point mutations. What could be the physiological function of such an activity? Mammalian mtDNA is remarkable in being a patchwork of many short repeat sequences. With reference to several recent publications, we hypothesise that the function of this activity is to preserve the mitochondrial genome by repairing short loop out sequences that would otherwise be lost as mitochondrial DNA polymerase gamma replicates the mitochondrial genome.

Animals↗