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At least 487 records · Page 27Linked to original sources
PubMed1997

Genome analysis of the fungal plant pathogen, Leptosphaeria maculans using pulsed field gel electrophoresis.

Pulsed field gel electrophoresis (PFGE), or electrophoretic karyotyping, separates chromosomal-sized pieces of DNA in agarose gels where the orientation of the electric field is periodically altered. This technique has revealed that many fungi have a high degree of chromosomal length polymorphisms. Often the only isolates with identical karyotypes are derived from a single clone, thus PFGE provides a 'genetic fingerprint' for them. The size range and number of chromosomes within isolates of a particular species are usually constant, hence PFGE can distinguish between morphologically similar fungi. This technique can also be used to follow inheritance of chromosomal length polymorphisms and shows that in some fungi novel-sized chromosomes are produced during meiosis. As well as resolving the nuclear (A-type) chromosomes, it can also resolve dispensable (B-type) chromosomes and cytoplasmic genomes including mitochondrial DNA and linear plasmids. The application of this technique to Australian isolates of Leptosphaeria maculans, which causes blackleg disease of canola (Brassica napus), is discussed.

Ascomycota↗
PubMed2006

Mitochondrial tRNA sequences as unusual replication origins: pathogenic implications for Homo sapiens.

The heavy strand of vertebrate mitochondrial genomes accumulates deaminations proportionally to the time it spends single-stranded during replication. A previous study showed that the strength of genome-wide deamination gradients originating from tRNA gene's locations increases with their capacities to form secondary structures resembling mitochondrial origins of light strand replication (OL), suggesting an alternative function for tRNA sequences. We hypothesize that this function is frequently pathogenic for those tRNA genes that normally do not form OL-like structures, because this could cause excess mutations in genome regions unadapted to tolerate them. In human mitochondrial genomes, pathogenic tRNA variants usually form less OL-like structures than non-pathogenic ones in cases where the normal non-pathogenic tRNA variant can function as OL, as evolutionary analyses reveal. For tRNAs lacking the putative OL-like functioning capacity, pathogenic variants form more OL-like secondary structures, particularly structures that might invoke bi-directional replication (true for 14 among 21 tRNA species, p<0.05, sign test; significantly at p<0.05 (1 tailed test) for 7 tRNA species), but not more unidirectional replication invoking structures. Accounting for the functional cloverleaf-like structure-forming capacities of tRNAs yields similar results. Rare, non-pathogenic tRNA mutants tend to form more OL-like structures than the common, non-pathogenic ones, suggesting weak directional selection also among non-pathogenic variants. The duration spent single stranded by a region of the heavy strand (D(ssH)) during replication, estimated by integrating over all regions that can function as OL in Homo sapiens mitochondrial genomes, increases with distance of that region from the Dloop. This suggests convergence of single-strandedness during replication and transcription, and explains conserved locations of tRNA species in mitochondrial genomes and bacterial operons. These locations minimize deamination costs only in anticodons and not in other tRNA regions, during replication and transcription. Therefore, putative functioning as OLs by tRNA sequences is normal at some locations and pathogenic at others.

Aging↗
PubMed1995

Mutational analysis of the murine AIDS-defective viral genome reveals a high reversion rate in vivo and a requirement for an intact Pr60gag protein for efficient induction of disease.

Pr60gag appears to be the only protein encoded by the murine AIDS (MAIDS)-defective virus. To study the role of Pr60gag or some other sequences of the viral genome in the pathogenicity of the virus, we have generated mutants of the defective viral genome. These mutant defective viruses, prepared as helper-free stocks, were inoculated into susceptible C57BL/6 mice. Mutant Du5H-A virus, which had a stop codon within gag MA(p15), did not induce target cell proliferation or MAIDS. Mutants Du5H-B and -C encoded truncated Pr60gag proteins containing, respectively, MA(p15)-p12 or MA(p15)-p12 and part of CA(p30). These mutants showed a very limited capacity to induce early cell expansion and were poorly pathogenic. Only recombinant (revertant) viruses were recovered from organs of diseased mice inoculated with these two mutants. Mutant Du5H-D was generated by deleting 1.4 kbp of the 3'-end sequences, outside the gag coding region. The levels of RNA and proteins made by this mutant were low. This mutant also reverting frequently but was nevertheless able to induce MAIDS at a low efficiency without reverting. Our results indicate that the Pr60gag protein is necessary and sufficient to induce MAIDS. These data also suggest that the Pr60gag protein needs to be relatively intact to be fully pathogenic. In addition, our study shows a very high reversion rate of some mutants and emphasizes the need to check for the presence of revertant (recombinant) viruses in diseased organs when working with mutants of the MAIDS-defective virus.

Animals↗
PubMed2005

Comparative genomics of Dictyostelium discoideum and Entamoeba histolytica.

Amoebozoa represent one of the earliest branches from the last common ancestor of all eukaryotes and contain some of the most dangerous human pathogens. Two amoebozoan genomes -- from the model organism Dictyostelium discoideum and the human pathogen Entamoeba histolytica -- have been published this year. Owing to their high A+T content, both genomes were difficult to sequence. In addition to nine amoebozoan expressed sequence tag projects, efforts are underway for comparative sequencing of four additional Entamoeba species. The completed genome sequences of D. discoideum and E. histolytica revealed unusual telomere structures, a high percentage of repetitive elements and a remarkably high gene content that is close to the one of Drosophila melanogaster. Finally, both organisms are brilliant examples of the influence of the lifestyle of an organism on its genome.

Adaptation, Biological↗
PubMed2026

Genome-wide Association Studies of the Pathogenic Sphingosine-1-Phosphate Gene in Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease that can lead to malignancies over time. Sphingosine-1-phosphate (S1P) receptor signaling affects lymphocyte trafficking and vascular integrity, influencing intestinal inflammation. This study aimed to identify S1P-related key genes in UC. METHODS: Differentially expressed genes (DEGs) between the UC and control groups were analyzed in the GSE87473 (training) dataset. Genes overlapping between the DEGs and S1P-related genes were considered candidate genes. These genes were incorporated into machine learning algorithms and subjected to expression analysis to identify key genes. Gene functions were determined through a gene&#x2013;gene interaction network, enrichment analysis, and immune cell infiltration analysis. In addition, transcription factor&#x2013;mRNA and mRNA&#x2013;miRNA&#x2013;lncRNA networks were constructed. Finally, reverse transcription&#x2013;quantitative polymerase chain reaction (RT-qPCR) was performed to evaluate the expression of key candidate genes in UC and control tissues. RESULTS: This study identified two key genes (SPHK2 and SPNS2) associated with UC. Notably, SPHK2 expression was lower and SPNS2 expression was higher in the UC group in both training and validation datasets and in clinical UC tissues (RT-qPCR). The area under the curve values of SPHK2 and SPNS2 exceeded 0.7 in both datasets, indicating that the genes had good diagnostic efficacy for UC. Consistently, the nomogram showed that the two genes had promising diagnostic value in UC. SPHK2 and SPNS2 were found to be localized to the plasma membrane. The correlations of the two genes with different immune cells showed significantly opposite trends. In particular, SPHK2 had the strongest positive correlation with M2 macrophages (r = 0.6) and the strongest negative correlation with neutrophils. Moreover, mRNA&#x2013;miRNA&#x2013;lncRNA and transcription factor&#x2013; mRNA networks of the key genes were constructed. CONCLUSION: This study suggests that SPHK2 and SPNS2 are key genes associated with UC, highlighting their potential as effective diagnostic biomarkers.

Humans↗
PubMed2004

Genome and proteome analysis of Chlamydia.

It has been difficult to study the molecular biology of the obligate intracellular bacterium Chlamydia due to lack of genetic transformation systems. Therefore, genome sequencing has greatly expanded the information concerning the biology of these pathogens. Comparing the genomes of seven sequenced Chlamydia genomes has provided information of the common gene content and gene variation. In addition, the genome sequences have enabled global investigation of both transcript and protein content during the developmental cycle of chlamydiae. During this cycle Chlamydia alternates between an infectious extracellular form and an intracellular dividing form surrounded by a phagosome membrane termed the chlamydial inclusion. Proteins secreted from the chlamydial inclusion into the host cell may interact with host cell proteins and modify the host cell's response to infection. However, identification of such proteins has been difficult because the host cell cytoplasm of Chlamydia infected cells cannot be purified. This problem has been circumvented by comparative proteomics.

Bacterial Physiological Phenomena↗
PubMed2026

A brief history of gene therapy for ornithine transcarbamylase deficiency.

Gene therapy encompasses the use of nucleic acids, including DNA and RNA, as therapeutic agents. This broad category includes approaches that permanently modify the genome to correct pathogenic variants, as well as strategies that restore gene expression without altering genomic DNA. In ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder, the goal of somatic gene therapy is to restore hepatic expression of functional OTC enzyme and thereby reestablish urea cycle activity. Both viral and non-viral delivery platforms have been investigated in preclinical models and clinical studies to achieve therapeutic OTC expression. Despite contemporary medical therapy, individuals with OTC deficiency (OTCD) remain at risk for recurrent hyperammonemia which may result in neurocognitive impairment and reduced quality of life. Novel therapy that restores liver OTC expression and lessens chronic disease burden is highly desired. In this manuscript, we summarize the history of gene therapy development for OTC deficiency, spanning early preclinical investigations to contemporary clinical trials. Although a definitive cure through gene therapy has not yet been achieved, substantial progress has been made toward the development of safe and effective liver-directed nucleic acid therapeutics for this disorder.

Adeno-associated virus vector↗
PubMed1998

Global dinucleotide signatures and analysis of genomic heterogeneity.

Early biochemical experiments measuring nearest neighbor frequencies established that the set of dinucleotide relative abundance values (dinucleotide biases) is a remarkably stable property of the DNA of an organism. Analyses of currently available genomic sequence data have extended these earlier results, showing that the dinucleotide biases evaluated for successive 50 kb segments of a genome are significantly more similar to each other than to those of sequences from more distant organisms. From this perspective, the set of dinucleotide biases constitutes a 'genomic signature' that can discriminate sequences from different organisms. The dinucleotide biases appear to reflect species-specific properties of DNA stacking energies, modification, replication, and repair mechanisms. The genomic signature is useful for detecting pathogenicity islands in bacterial genomes.

Bacteria↗
PubMed2005

Characterization of an infectious cDNA copy of the genome of a naturally occurring, avirulent coxsackievirus B3 clinical isolate.

Group B coxsackieviruses (CVB) cause numerous diseases, including myocarditis, pancreatitis, aseptic meningitis and possibly type 1 diabetes. To date, infectious cDNA copies of CVB type 3 (CVB3) genomes have all been derived from pathogenic virus strains. An infectious cDNA copy of the well-characterized, non-pathogenic CVB3 strain GA genome was cloned in order to facilitate mapping of the CVB genes that influence expression of a virulence phenotype. Comparison of the sequence of the parental CVB3/GA population, derived by direct RT-PCR-mediated sequence analysis, to that of the infectious CVB3/GA progeny genome demonstrated that an authentic copy was cloned; numerous differences were observed in coding and non-coding sequences relative to other CVB3 strains. Progeny CVB3/GA replicated similarly to the parental strain in three different cell cultures and was avirulent when inoculated into mice, causing neither pancreatitis nor myocarditis. Inoculation of mice with CVB3/GA protected mice completely against myocarditis and pancreatitis induced by cardiovirulent CVB3 challenge. The secondary structure predicted for the CVB3/GA domain II, a region within the 5' non-translated region that is implicated as a key site affecting the expression of a cardiovirulent phenotype, differs from those predicted for cardiovirulent and pancreovirulent CVB3 strains. This is the first report characterizing a cloned CVB3 genome from an avirulent strain.

5' Untranslated Regions↗
PubMed1997

Plant viral synergism: the potyviral genome encodes a broad-range pathogenicity enhancer that transactivates replication of heterologous viruses.

Synergistic viral diseases of higher plants are caused by the interaction of two independent viruses in the same host and are characterized by dramatic increases in symptoms and in accumulation of one of the coinfecting viruses. In potato virus X (PVX)/potyviral synergism, increased pathogenicity and accumulation of PVX are mediated by the expression of potyviral 5' proximal sequences encoding P1, the helper component proteinase (HC-Pro), and a fraction of P3. Here, we report that the same potyviral sequence (termed P1/HC-Pro) enhances the pathogenicity and accumulation of two other heterologous viruses: cucumber mosaic virus and tobacco mosaic virus. In the case of PVX-potyviral synergism, we show that the expression of the HC-Pro gene product, but not the RNA sequence itself, is sufficient to induce the increase in PVX pathogenicity and that both P1 and P3 coding sequences are dispensable for this aspect of the synergistic interaction. In protoplasts, expression of the potyviral P1/HC-Pro region prolongs the accumulation of PVX (-) strand RNA and transactivates expression of a reporter gene from a PVX subgenomic promoter. Unlike the synergistic enhancement of PVX pathogenicity, which requires only expression of HC-Pro, the enhancement of PVX (-) strand RNA accumulation in protoplasts is significantly greater when the entire P1/HC-Pro sequence is expressed. These results indicate that the potyviral P1/HC-Pro region affects a step in disease development that is common to a broad range of virus infections and suggest a mechanism involving transactivation of viral replication.

Cucumovirus↗
PubMed1989

Molecular epidemiology and restriction site mapping of adenovirus type 3 genome types.

One hundred thirty-eight strains of adenovirus type 3 isolated from patients in the United States, West Germany, and other regions between 1961 and 1984 were analyzed with six restriction endonucleases; 18 genome types were found. BglII was the most discriminative enzyme. Mapping of altered restriction sites was also performed for all six enzymes. The genome types D1 (like the prototype) and D3 prevailed among 45 and 47 strains, respectively. All genome types could be divided into two groups related to D1 or D3. Several clusters of infections by strains with the same genome type were observed. Only hints of differences were found in the pathogenicities of individual genome types. D1 strains were present in the United States and in Europe; group D3 prevailed almost exclusively in the United States.

Adenoviridae Infections↗
PubMed1993

Host species-specific repetitive DNA sequence in the genome of Magnaporthe grisea, the rice blast fungus.

We cloned a repetitive sequence to show RFLPs in the genome of Magnaporthe grisea, a fungal pathogen responsible for rice blast. As the sequence was 0.8 kb in length and dispersed in the genome, it was named MGSR1 (for Magnaporthe grisea short repeat 1). MGSR1 was conserved highly in the genome of rice pathogens, but poorly in the genome of pathogens of grasses other than rice. And the RFLPs, displayed with the sequence, could distinguish between clonal lineages in rice-pathogenic isolates. The nucleotide sequence showed the presence of an internal promoter of RNA polymerase III, a 3'-poly(T), and an 8-bp direct repeat in it.

Ascomycota↗
PubMed2007

Black holes, antivirulence genes, and gene inactivation in the evolution of bacterial pathogens.

The evolution of bacterial pathogens from nonpathogenic ancestors is marked principally by the acquisition of virulence gene clusters on plasmids and pathogenicity islands via horizontal gene transfer. The flip side of this evolutionary force is the equally important adaptation of the newly minted pathogen to its new host niche. Pathoadaptive mutations take the form of modification of gene expression such that the pathogen is better fit to survive within the new niche. This mini-review describes the concept of pathoadaptation by loss of gene function. In this process, genes that are no longer compatible with the novel lifestyle of the pathogen are selectively inactivated either by point mutation, insertion, or deletion. These genes are called 'antivirulence genes'. Selective pressure sometimes leads to the deletion of large regions of the genome that contain antivirulence genes generating 'black holes' in the pathogen genome. Inactivation of antivirulence genes leads to a pathogen that is highly adapted to its host niche. Identification of antivirulence genes for a particular pathogen can lead to a better understanding of how it became a pathogen and the types of genetic traits that need to be silenced in order for the pathogen to colonize its new host niche successfully.

Adaptation, Biological↗
PubMed2026

Genomic and ecological systems-thinking framework for pathogenic Leptospira in Puerto Rico.

INTRODUCTION: Leptospirosis is a complex zoonotic disease requiring high-resolution surveillance. A systems-thinking framework was used to connect genomic and ecological data and map the geographic and host-based structuring of co-circulating pathogenic Leptospira lineages in Puerto Rico. METHODS: Forty-four core genomes of L. interrogans, L. borgpetersenii, and L. kirschneri from human, domestic, and wildlife hosts were analyzed. Spatiotemporal and landscape metadata were integrated using root-to-tip regression, isolation-by-distance profiling and calibrated single-nucleotide polymorphism (SNP) thresholds (&#x2264;1, &#x2264;5, and &#x2264;10 SNPs) to define transmission clusters. RESULTS: Leptospira species exhibited distinct ecological pathways partitioned by geography, explaining 56% of genomic variance for L. interrogans and 91% for L. borgpetersenii (PERMANOVA). L. interrogans displayed high landscape connectivity across multiple hosts, forming localized networks (&#x2264;1 to &#x2264;10 SNPs) that capture active spillovers (human-to-rat linkages at &#x2264;1 SNP) and resolved into rodent host-specific lineages (R2 =&#x202f;0.34). Conversely, L. borgpetersenii showed spatial and temporal genomic homogeneity and a lack of host-associated structure within an unpartitioned transmission pool dominated by Mus musculus. As a result, fixed genomic thresholds yielded disparate outcomes: L. interrogans resolved into 4 to 5 discrete, expanding clusters, whereas L. borgpetersenii grouped into a single uniform population at the &#x2264;10-SNP threshold. CONCLUSION: Co-circulating pathogenic leptospires occupy distinct ecological niches shaped by varying host restriction and environmental persistence. Fixed genomic thresholds lack universal applicability; effective genomic epidemiological surveillance must employ species-specific threshold calibration to accurately map transmission pathways.

Puerto Rico↗
PubMed2005

Aspergillus fumigatus: saprophyte or pathogen?

Large-scale genome comparisons have shown that no gene sets are shared exclusively by both Aspergillus fumigatus and any other human pathogen sequenced to date, such as Candida or Cryptococcus species. By contrast, and in agreement with the environmental occurrence of this fungus in decaying vegetation, the enzymatic machinery required by a fungus to colonize plant substrates has been found in the A. fumigatus genome. In addition, the proteome of this fungus contains numerous efflux pumps, including >100 major facilitators that help the fungus to resist either natural aggressive molecules present in the environment or antifungal drugs in humans. Environment sensing, counteracting reactive oxidants, and retrieving essential nutriments from the environment are general metabolic traits that are associated with the growth of the saprotrophic mold A. fumigatus in an unfriendly environment such as its human host.

Aspergillosis↗
PubMed2005

Citrobacter rodentium of mice and man.

The major classes of enteric bacteria harbour a conserved core genomic structure, common to both commensal and pathogenic strains, that is most likely optimized to a life style involving colonization of the host intestine and transmission via the environment. In pathogenic bacteria this core genome framework is decorated with novel genetic islands that are often associated with adaptive phenotypes such as virulence. This classical genome organization is well illustrated by a group of extracellular enteric pathogens, which includes enteropathogenic Escherichia coli (EPEC), enterohaemorrhagic E. coli (EHEC) and Citrobacter rodentium, all of which use attaching and effacing (A/E) lesion formation as a major mechanism of tissue targeting and infection. Both EHEC and EPEC are poorly pathogenic in mice but infect humans and domestic animals. In contrast, C. rodentium is a natural mouse pathogen that is related to E. coli, hence providing an excellent in vivo model for A/E lesion forming pathogens. C. rodentium also provides a model of infections that are mainly restricted to the lumen of the intestine. The mechanism's by which the immune system deals with such infections has become a topic of great interest in recent years. Here we review the literature of C. rodentium from its emergence in the mid-1960s to the most contemporary reports of colonization, pathogenesis, transmission and immunity.

Adhesins, Bacterial↗