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PubMed2003

From genes to genomes: universal scale-invariant properties of microbial chromosome organisation.

The availability of complete genome sequences for a large variety of organisms is a major advance in understanding genome structure and function. One attribute of genome structure is chromosome organisation in terms of gene localisation and orientation. For example, bacterial operons, i.e. clusters of co-oriented genes that form transcription units, enable functionally related genes to be expressed simultaneously. The description of genome organisation was pioneered with the study of the distribution of genes of the Escherichia coli partial genetic map before the full genome sequence was known. Deploying powerful techniques from circular statistics and signal processing, we revisit the issue of gene localisation and orientation using 89 complete microbial chromosomes from the eubacterial and archaeal domains. We demonstrate that there is no characteristic size pertinent to the description of chromosome structure, e.g. there does not exist any single length appropriate to describe gene clustering. Our results show that, for all 89 chromosomes, gene positions and gene orientations share a common form of scale-invariant correlations known as "long-range correlations" that we can reveal for distances from the gene length, up to the chromosome size. This observation indicates that genes tend to assemble and to co-orient over any scale of observation greater than a few kilobases. This unexpected property of chromosome structure can be portrayed as an operon-like organisation at all scales and implies that a complete scale range extending over more than three orders of magnitudes of chromosome segment lengths is necessary to properly describe prokaryotic genome organisation. We propose that this pattern results from the effects of the superhelical context on gene expression coupled with the structure and dynamics of the nucleoid, possibly accommodating the diverse gene expression profiles needed during the different stages of cellular life.

Archaea↗
PubMedDate not supplied

Frontiers in genomics: insights into protist evolutionary biology, University of Iowa, May 19-21, 2004.

Protists constitute the bulk of eukaryotic diversity yet their genomes remain relatively unexplored. To address this issue, a workshop entitled, "Frontiers in Genomics: Insights into Protist Evolutionary Biology", was convened at the University of Iowa on June 19-21, 2004. The specific aims of the workshop were to define the role of genomics in the eukaryotic tree of life, to identify challenges in characterizing protist (i.e. microbial eukaryote) genomes, and in proposing specific solutions to these challenges. The findings of the workshop are presented here and in a white paper that provide a set of guidelines for organizing the protist community and for planning and executing a protist genome project.

Animals↗
PubMed1999

Chemotyping of yeast mutants using robotics.

By now, the EUROFAN programme for the functional analysis of genes from the yeast genome has attained its cruising speed. Indeed, several hundreds of yeast mutants with no phenotype as tested by growth on standard media and no significant sequence similarity to proteins of known function are available through the efforts of various laboratories. Based on the methodology initiated during the pilot project on yeast chromosome III (Yeast 13, 1547-1562, 1997) we adapted it to High Throughput Screening (HTS), using robotics. The first 100 different gene deletions from EUROSCARF, constructed in an FY1679 strain background, were run against a collection of about 300 inhibitors. Many of these inhibitors have not been reported until now to interfere in vivo with growth of Saccharomyces cerevisiae. In the present paper we provide a list of novel growth conditions and a compilation of 49 yeast deletants (from chromosomes II, IV, VII, X, XIV, XV) corresponding to 58% of the analysed genes, with at least one clear and stringent phenotype. The majority of these deletants are sensitive to one or two compounds (monotropic phenotype) while a distinct subclass of deletants displays a hyper-pleiotropic phenotype with sensitivities to a dozen or more compounds. Therefore, chemotyping of unknown genes with a large spectrum of drugs opens new vistas for a more in-depth functional analysis and a more precise definition of molecular targets.

Antifungal Agents↗
PubMed2002

Extrusion of penem antibiotics by multicomponent efflux systems MexAB-OprM, MexCD-OprJ, and MexXY-OprM of Pseudomonas aeruginosa.

The high intrinsic penem resistance of Pseudomonas aeruginosa is due to the interplay among the outer membrane barrier, the active efflux system MexAB-OprM, and AmpC beta-lactamase. We studied the roles of two other efflux systems, MexCD-OprJ and MexXY-OprM, in penem resistance by overexpressing each system in an AmpC- and MexAB-OprM-deficient background and found that MexAB-OprM is the most important among the three efflux systems for extrusion of penems from the cell interior.

Bacterial Outer Membrane Proteins↗
PubMed2003

Protein microarray technology for unraveling the antibody specificity repertoire against microbial proteomes.

The genomes of microorganisms responsible for diseases of worldwide medical importance have been sequenced or will be available in the near future. Combinatorial cloning technologies for producing large numbers of proteins have been developed and high-throughput assays such as protein microarrays have been clinically validated for detecting the presence of antibodies directed against microbial antigens in human serum. These scientific and technical achievements offer the opportunity to investigate the natural immune response against the whole proteome of a variety of microorganisms. A powerful combination of genomic information, molecular tools and immunological assays are potentially available to identify the antigens that, either alone or in combination, function as targets of protective immunity, or could be used as markers for serodiagnosis.

Animals↗
PubMed2001

Escherichia coli ykfE ORFan gene encodes a potent inhibitor of C-type lysozyme.

The complete nucleotide sequences of over 37 microbial and three eukaryote genomes are already publicly available, and more sequencing is in progress. Despite this accumulation of data, newly sequenced microbial genomes continue to reveal up to 50% of functionally uncharacterized "anonymous" genes. A majority of these anonymous proteins have homologues in other organisms, whereas the rest exhibit no clear similarity to any other sequence in the data bases. This set of unique, apparently species-specific, sequences are referred to as ORFans. The biochemical and structural analysis of ORFan gene products is of both evolutionary and functional interest. Here we report the cloning and expression of Escherichia coli ORFan ykfE gene and the functional characterization of the encoded protein. Under physiological conditions, the protein is a homodimer with a strong affinity for C-type lysozyme, as revealed by co-purification and co-crystallization. Activity measurements and fluorescence studies demonstrated that the YkfE gene product is a potent C-type lysozyme inhibitor (K(i) approximately 1 nm). To denote this newly assigned function, ykfE has now been registered under the new gene name Ivy (inhibitor of vertebrate lysozyme) at the E. coli genetic stock center.

Amino Acid Sequence↗
PubMed2006

16S rRNA gene-based analysis of microbial community by whole-genome amplification and minigel-single-strand conformation polymorphism technique.

We have developed an analytical technique for the 16S rRNA gene that comprises whole-genome amplification and the polymerase chain reaction (PCR)-minigel-single-strand conformation polymorphism technique (WGA-SSCP). Under optimal conditions, SSCP bands could be detected when genomic DNA from bacteria of interest comprised 0.5% or more of the specimen. This method will be effective for the identification of nonculturable bacteria in a microbial community.

DNA, Bacterial↗
PubMed1999

SVMPA, a mutant of sindbis virus resistant to mycophenolic acid and ribavirin, shows an increased sensitivity to chick interferon.

SVMPA is a mutant of Sindbis virus, selected for its ability to replicate in mycophenolic acid (MPA)-treated mosquito cells. SVMPA has another phenotype: although able to replicate normally in primary cultures of chick embryo fibroblasts (CEF), its replication is restricted in secondary cultures prepared from aged primary CEF cultures. The mutations responsible for these phenotypes mapped to the region of the viral genome that codes for nsP1. We report here that SVMPA has yet another phenotype. Relative to our standard Sindbis virus (SVSTD) from which it was derived, SVMPA shows an increased sensitivity to chick interferon, both crude interferon prepared from virus-infected cells and recombinant interferon. Characterization of viral mutants obtained after site-directed mutagenesis indicated that the same mutations responsible for the host restriction of SVMPA in secondary cultures of CEF were also responsible for its increased sensitivity to chick interferon.

Animals↗
PubMed2000

Use of genomics and combinatorial chemistry in the development of new antimycobacterial drugs.

With the completion of the genome of Mycobacterium tuberculosis comes the promise of a new generation of potent drugs to combat the emerging epidemic of multiply drug-resistant isolates. Translating this genomic information into realistic assays, valid targets, and preclinical drug candidates represents the next great hope in tuberculosis control. We propose a paradigm for exploiting the genome to inform the development of novel antituberculars, utilizing the techniques of differential gene expression as monitored by DNA microarrays coupled with the emerging discipline of combinatorial chemistry. A comparison of currently used antituberculars with the properties of other pharmaceuticals suggests that such compounds will have a defined range of physiochemical properties. In general, we can expect the next generation of antituberculars to be small, relatively hydrophilic molecules that bind tightly to specific cellular targets. Many current antimycobacterials require some form of cellular activation (e.g. the activation of isoniazid by a catalase-peroxidase). Activation corresponds to the oxidative, reductive, or hydrolytic unmasking of reactive groups, which occurs with many current antimycobacterial prodrugs. Understanding the mechanisms involved in activation of current antimycobacterial therapeutics also may facilitate the development of alternative activation strategies or of analogs that require no such processes.

Animals↗
PubMed2002

HIV resistance testing: an update.

In recent years, resistance testing has become an important tool in optimizing the combination therapy for treating HIV infected individuals. The identification of resistance mutations has allowed physicians to select the antiviral agents with maximum therapeutic benefic and minimum toxic side effects. The current therapeutic agents approved by the Food and Drug Administration (FDA), their mechanisms of actions, and the mutations of the HIV viral genome that lead to resistance to antiviral agents are discussed. In addition, methods of resistance testing, both genotypic and phenotypic, are evaluated with consideration of their inherent advantages and disadvantages.

Drug Resistance, Microbial↗