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PubMed2005

[The first genetically supported case of chronic benign pemphigus (Hailey-Hailey disease in Hungary].

Hailey-Hailey disease, or chronic benign pemphigus (MIM# 169600), is a genodermatosis arising in adult age with recurrent vesicles and erosions primarily in the flexural areas. It is an autosomal dominant skin disorder characterized by abnormal keratinocyte adhesion in the suprabasal layers of the epidermis. ATP2C1, encoding the human secretory pathway Ca(2+)-ATPase (hSPCA1), was recently identified as the defective gene in Hailey-Hailey disease. More than 82 different ATP2C1 mutations have been described up to date. In this study, a case of Hailey-Hailey disease is presented where a nucleotide change (1402C > T) in the decoding region of ATP2C1 resulted in a premature stop mutation (R468X). This defect has been reported earlier in a patient of European descent. A brief molecular genetic review of the disorder is also given.

Aged↗
PubMed1992

The tRNA species for redundant genetic codons NNU and NNC. A thought on the absence of phenylalanine tRNA with AAA anticodon in Escherichia coli.

The redundant genetic codons NNU and NNC (where N is A, T, G, or C) specify the same amino acid and are decoded by their cognate tRNAs, which contain either a guanosine or a modified base in the wobble position of the anticodons. Since tRNAs with an adenosine in the wobble position of the anticodon, which are complementary to the NNU codons, are not found naturally, we have generated a tRNA(Phe) with AAA anticodon and examined how an adenosine in the wobble position would affect its biological function in Escherichia coli. We found that the tRNA(Phe) with GAA anticodon (wild-type) repressed the expression of the pheA gene via tRNA(Phe)-mediated attenuation of transcription, whereas the tRNA(Phe) with AAA anticodon did not influence the expression of the pheA gene. Furthermore, elevated levels of tRNA(Phe)(AAA) did not support the growth of an E. coli strain carrying a temperature-sensitive mutation in the pheS gene at 42 degrees C. Since the presence of a multicopy plasmid carrying the gene that encodes tRNA(Phe)(GAA), a substrate for phenylalanyl tRNA synthetase, enables the E. coli strain carrying the pheS(Ts) mutation to grow at 42 degrees C, the above observation suggests that unlike tRNA(Phe)(GAA), tRNA(Phe)(AAA) is not a good substrate for phenylalanyl-tRNA synthetase. Therefore, we postulate that the presence of adenosine at the wobble position of anticodons was specifically eliminated and the tRNAs with guanosine or a modified base in the wobble position were selected to decode both NNU and NNC codons in E. coli.

Anticodon↗
PubMed2006

Characterization of a Methanosarcina acetivorans mutant unable to translate UAG as pyrrolysine.

The methyltransferases initiating methanogenesis from trimethylamine, dimethylamine and monomethylamine possess a novel residue, pyrrolysine. Pyrrolysine is the 22nd amino acid, because it is encoded by a single amber (UAG) codon in methylamine methyltransferase transcripts. A dedicated tRNA(CUA) for pyrrolysine, tRNA(Pyl), is charged by a pyrrolysyl-tRNA synthetase with pyrrolysine. As the first step towards the genetic analysis of UAG translation as pyrrolysine, a 761 base-pair genomic segment in Methanosarcina acetivorans containing the pylT gene (encoding tRNA(Pyl)) was deleted and replaced by a puromycin resistance cassette. The DeltappylT mutant lacks detectable tRNA(Pyl), but grows as wild-type on methanol or acetate. Unlike wild-type, the DeltappylT strain cannot grow on any methylamine, nor use monomethylamine as sole nitrogen source. Wild-type cells, but not DeltappylT, have monomethylamine methyltransferase activity during growth on methanol. Immunoblot analysis indicated monomethylamine methyltransferase was absent in DeltappylT. The phenotype of DeltappylT reveals the deficiency in methylamine metabolism expected of a Methanosarcina species unable to decode UAG codons as pyrrolysine, but also that loss of pylT does not compromise growth on other substrates. These results indicate that in-depth genetic analysis of UAG translation as pyrrolysine is feasible, as deletion of pylT is conditionally lethal depending on growth substrate.

Amino Acyl-tRNA Synthetases↗
PubMed1999

Production scheduling and rescheduling with genetic algorithms.

A general model for job shop scheduling is described which applies to static, dynamic and non-deterministic production environments. Next, a Genetic Algorithm is presented which solves the job shop scheduling problem. This algorithm is tested in a dynamic environment under different workload situations. Thereby, a highly efficient decoding procedure is proposed which strongly improves the quality of schedules. Finally, this technique is tested for scheduling and rescheduling in a non-deterministic environment. It is shown by experiment that conventional methods of production control are clearly outperformed at reasonable run-time costs.

Algorithms↗
PubMed1994

Polygenic trait analysis by neural network learning.

AI techniques have been applied to the domain of DNA sequence analysis in predicting or identifying certain specialized regions, in recognizing genes, and in understanding the evolutionary relationships between sequences. This paper focuses on a kind of genetic pattern recognition, namely, the problem of identifying the gene combinations (patterns) causally related to a given trait determined by multiple genes (a so-called polygenic trait). A novel approach is presented which combines neural-network and knowledge-based techniques. The neural network is trained to predict the trait and then the knowledge embedded in the network is decoded into symbolic patterns. This hybrid approach is evaluated in the domain of identifying genes of insulin dependent diabetes mellitus. The consistency between the results with this approach and those reported in genetic literature supports the viability of this approach.

Artificial Intelligence↗
PubMed2005

A sequence of 'factishes': the media-metaphorical knowledge dynamics structuring the German press coverage of the human genome.

This article deals with the cultural framing of the near sequencing of the human genome and its impact on the media coverage in Germany. It investigates in particular the way in which the weekly journal Die Zeit and the daily newspaper Frankfurter Rundschau reported this media event and its aftermath between June 2000 and June 2001. Both newspapers are quality papers that played an essential role in framing the human genome debate--alongside the Frankfurter Allgemeine Zeitung--which became the most prominent genomic forum. The decoding of the human genome prompted a huge controversy concerning the ethics of human engineering, research on stem cells and Preimplantation Genetic Diagnosis. The main aim of this article is to show how this controversy was structured by metaphor. The media coverage of the genome generated DNA-factishes--a neologism designating the ambivalence of something as fact (fait) and as a fetish (fetiche)--that mostly propagated images of a new DNA-scienticism or biological determinism. Mediated by cultural experiences, the human genome became a highly artificial and social construct of a 'NatureCulture'.

Biotechnology↗
PubMed2002

Genomics and cancer.

Genetic and environmental factors are responsible for the genomic lesions that cause cancer, a complex genetic disease associated with genomic instability. Studies aimed at deciphering the lesions in cancer have focused mainly on one or a few genes, despite the genomic scope of the disease. The recently decoded human DNA sequence is anticipated to foster understanding of human evolution and disease and the role of environment and heredity in the human condition. This review addresses the opportunities and challenges that the availability of the human genome sequence holds for cancer research.

Genetic Therapy↗
PubMed1998

Structure and dynamics of ribosomal RNA.

Over the past two years, progress in X-ray crystallography, NMR spectroscopy and electron microscopy has begun to reveal the complex structure of the RNA within the ribosome. The structures of ribosomal proteins L11 and S15, among others, show how RNA-protein interactions organize the conformation of the junctions between ribosomal RNA helices. Genetic and biochemical methods have also identified a three base-pair switch within the 16S rRNA that is linked to mRNA decoding.

Base Sequence↗
PubMed2006

Biosynthesis of wybutosine, a hyper-modified nucleoside in eukaryotic phenylalanine tRNA.

Wybutosine (yW) is a tricyclic nucleoside with a large side chain found at the 3'-position adjacent to the anticodon of eukaryotic phenylalanine tRNA. yW supports codon recognition by stabilizing codon-anticodon interactions during decoding on the ribosome. To identify genes responsible for yW synthesis from uncharacterized genes of Saccharomyces cerevisiae, we employed a systematic reverse genetic approach combined with mass spectrometry ('ribonucleome analysis'). Four genes YPL207w, YML005w, YGL050w and YOL141w (named TYW1, TYW2, TYW3 and TYW4, respectively) were essential for yW synthesis. Mass spectrometric analysis of each modification intermediate of yW revealed its sequential biosynthetic pathway. TYW1 is an iron-sulfur (Fe-S) cluster protein responsible for the tricyclic formation. Multistep enzymatic formation of yW from yW-187 could be reconstituted in vitro using recombinant TYW2, TYW3 and TYW4 with S-adenosylmethionine, suggesting that yW synthesis might proceed through sequential reactions in a complex formed by multiple components assembled with the precursor tRNA. This hypothesis is also supported by the fact that plant ortholog is a large fusion protein consisting of TYW2 and TYW3 with the C-terminal domain of TYW4.

Amino Acid Sequence↗
PubMed2006

Ribonucleome analysis identified enzyme genes responsible for wybutosine synthesis.

Wybutosine (yW) is a hyper modified guanosine with a tricyclic base found at the 3'-position adjacent to the anticodon of eukaryotic phenylalanine tRNA. yW supports reading frame maintenance by stabilizing codon-anticodon interactions during decoding on the ribosome. To identify genes responsible for yW synthesis from uncharacterized genes of Saccharomyces cerevisiae, we employed a systematic reverse genetic approach combined with mass spectrometry ('ribonucleome analysis'). We found four new genes YPL207w, YML005w, YOL141w and YGL050w (named TYW1, TYW2, TYW3 and TYW4, respectively) to be responsible for wybutosine (yW) synthesis. Mass spectrometric analysis of each modification intermediate of yW revealed its sequential biosynthetic pathway. Multi-step enzymatic formation of yW was partially reconstituted in vitro using recombinant proteins. The results suggested that yW synthesis might proceed through sequential reactions in a complex formed by multiple protein components assembled with the precursor tRNA.

Gene Deletion↗
PubMed2004

A combined linkage-physical map of the human genome.

We have constructed de novo a high-resolution genetic map that includes the largest set, to our knowledge, of polymorphic markers (N=14,759) for which genotype data are publicly available; that combines genotype data from both the Centre d'Etude du Polymorphisme Humain (CEPH) and deCODE pedigrees; that incorporates single-nucleotide polymorphisms; and that also incorporates sequence-based positional information. The position of all markers on our map is corroborated by both genomic sequence and recombination-based data. This specific combination of features maximizes marker inclusion, coverage, and resolution, making this map uniquely suitable as a comprehensive resource for determining genetic map information (order and distances) for any large set of polymorphic markers.

Chromosome Mapping↗
PubMed2006

Using expanded genetic alphabets to simplify high-throughput genetic testing.

DNA is the only chemistry that allows for molecular recognition on demand. Unlike any other molecular recognition chemistry, DNA enables the simple design and rapid synthesis of molecule sets that will recognize each other and self-assemble into nanostructures. In molecular diagnostics, DNA is used to capture complementary sequences in order to decode complex mixes. Expanding DNA chemistry to include additional base pairs enables a more precise manipulation of nanostructures constructed with DNA. MultiCode technology is that type of expanded DNA chemistry. The technology exploits DNA hydrogen bonding patterns that differ from natural DNA, thereby enabling a simple means of transcending problems that are otherwise unsolvable. Made up of additional base pairs (not simply single bases), MultiCode technology is used today to decode sequences in an orthogonal manner to natural DNA. This review will discuss MultiCode technology and specifically focus on how the technology can be used to build molecular testing platforms.

CpG Islands↗
PubMed2003

X-ray crystal structures of the WT and a hyper-accurate ribosome from Escherichia coli.

Protein biosynthesis on the ribosome requires accurate reading of the genetic code in mRNA. Two conformational rearrangements in the small ribosomal subunit, a closing of the head and body around the incoming tRNA and an RNA helical switch near the mRNA decoding site, have been proposed to select for complementary base-pairing between mRNA codons and tRNA anticodons. We determined x-ray crystal structures of the WT and a hyper-accurate variant of the Escherichia coli ribosome at resolutions of 10 and 9 A, respectively, revealing that formation of the intact 70S ribosome from its two subunits closes the conformation of the head of the small subunit independent of mRNA decoding. Moreover, no change in the conformation of the switch helix is observed in two steps of tRNA discrimination. These 70S ribosome structures indicate that mRNA decoding is coupled primarily to movement of the small subunit body, consistent with previous proposals, whereas closing of the head and the helical switch may function in other steps of protein synthesis.

Base Sequence↗
PubMed2003

Genetic and signaling pathway alterations in glioblastoma: relevance to novel targeted therapies.

Glioblastomas multiforme (GBM) is the most common malignant primary brain tumor in adults. GBM patients have a dismal prognosis, with a median survival of less than 1 year. During the past decade, significant advances have been made in our understanding of the molecular pathogenesis of these tumors. Specific genetic defects have been identified that appear to be important for the development, as well as maintenance of the malignant characteristics that are associated with GBM. Some of these genetic aberrations appear to have prognostic significance. However, even more exciting in this era of molecularly targeted therapy are the clues these gene alterations provide for identifying signaling mechanisms responsible for carcinogenesis, and for identifying potential therapeutic targets. Cancer drug therapy is currently undergoing a major transition with an attempt to move from the use of cytotoxic drugs towards the use of tumor mechanism-based drugs. Advances such as the decoding of the human genome, combinatorial chemistry, and gene expression profiling have led to an increase in the rate at which new drugs are being developed. In this review, we will describe the most common genetic and signaling pathway alterations that have relevance to new drug development for the treatment of GBM.

Animals↗
PubMed2006

Deciphering the pig genome to understand gamete production.

The field of livestock genomics has made considerable advances in the past decade. In the area of pig reproduction, a number of genome scans have identified several genomic regions associated with variation in reproductive measures ranging from ovulation rate, litter size and testis size. Additionally, several candidate genes have been associated with variation in litter size. These studies primarily focused on developing genetic markers to facilitate selection decisions. To date, their results have made minor contributions to commercial pig performance and our knowledge on the inheritance of complex phenotypes. With the availability of additional resources for pig, as well as from human and mouse studies, future studies should be directed to identifying genetic variation that affects biological processes. To reach this goal, teams of diversely trained scientists need to be formed that include geneticists, physiologists, molecular biologists and bioinformaticists. A diversified team of scientists equipped with all of the available research tools (genomic sequence data, expression arrays, knowledge of gene product functions, etc.) and appropriate swine populations should be able to decode the genome's hidden secrets on how it controls reproductive processes.

Animals↗
PubMed1993

Evaluation of a three-exposure mouse bone marrow micronucleus protocol: results with 49 chemicals.

Forty-nine chemicals were tested in a mouse bone marrow micronucleus test that employed three daily exposures by intraperitoneal injection. Bone marrow samples were obtained 24 hr following the final exposure. Twenty-five rodent carcinogens and 24 noncarcinogens were selected randomly from the 44 carcinogens and 29 noncarcinogens used by Tennant et al. (Science 236:933-941, 1987) to evaluate the performance of four in vitro genetic toxicity tests. As in that study of in vitro tests, the micronucleus tests were conducted with coded chemicals and test results (positive or negative) were determined prior to decoding. This study was conducted as part of an effort to assess the ability of the micronucleus test to discriminate between rodent carcinogens and noncarcinogens and to determine its potential role, in combination with other short-term tests, in identifying genotoxic chemicals that present a carcinogenic hazard. Nine chemicals were judged to be positive in the micronucleus test. This relatively low number of positive results, along with published and unpublished results from rodent micronucleus and chromosome aberration assays on several of these 49 chemicals, contributed to the conclusion that a single micronucleus test protocol is not adequate to detect all chemicals capable of inducing chromosomal damage in the bone marrow. However, a combination of two relatively simple assays such as the Salmonella and micronucleus tests can provide important information on the genetic toxicity of test chemicals and may provide guidance on the need for and the nature and extent of future toxicity studies.

Animals↗
PubMed1995

A deviation from the universal genetic code in Candida maltosa and consequences for heterologous expression of cytochromes P450 52A4 and 52A5 in Saccharomyces cerevisiae.

We demonstrate that serine instead of leucine is specified by the CUG codon in the yeast Candida maltosa. Evidence for this deviation from the universal genetic code was obtained by means of in vitro translation experiments. Depending on the cell-free system used, either serine, in the C. maltosa system, or leucine, in the control with the conventional wheat germ system, was found to be incorporated into the translation products of artificial CUG-containing mRNAs. Moreover, we were able to transfer the non-universal decoding of CUG to the wheat germ system by adding a tRNA fraction isolated from C. maltosa. This finding indicates the presence in C. maltosa of an unusual serine tRNA that recognizes CUG. As a consequence of the altered genetic code, expression in Saccharomyces cerevisiae of C. maltosa cytochrome P450 genes required an exchange of their CTG triplets by TCT encoding serine in order to produce the authentic proteins. In contrast, heterologous expression of the original C. maltosa genes resulted in the formation of still active but unstable enzymes probably subject to selective proteolysis in the host cells.

Base Sequence↗