Macromolecular changes during the life-span of the mosquito.
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Aging↗
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[Age-related changes of informational macromolecules (author's transl)].
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Aging↗
DNA sequence changes and speciation.
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Animals↗
Evolution of the mitochondrial protein synthetic machinery.
Comparative analysis of the components of the mitochondrial translational apparatus reveals a remarkable variability. For example the mitochondrial ribosomal rRNAs, display a three-fold difference in size in different organisms as a result of insertions or deletions, which affect specific areas of the rRNA molecule. This suggests that such areas are either not essential for mitoribosome function or that they can be replaced by proteins. Also mitochondrial tRNAs and mitoribosomal proteins are much less conserved than their cytoplasmic counterparts. Not only do the mitochondrial translational molecules vary in properties, also the location of the genes from which they are derived is not the same in all cases: mitochondrial tRNA genes which usually are found in the mtDNA, may have a nuclear location in protozoa and, conversely, only in fungi one finds a mitoribosomal protein gene in the organellar genome. The high rate of change of the components of the mitochondrial protein synthesizing machinery is accompanied by a number of unique features of the translation process: (i) the mitochondrial genetic code differs substantially from the standard code in a species-specific manner; (ii) special codon-anticodon recognition rules are followed; (iii) unusual mechanisms of translational initiation may exist. These observations suggest that the evolutionary pressures that have shaped the present day mitochondrial translational apparatus have been different in different organisms and also distinct from those acting on the cytoplasmic machinery. In spite of the interspecies variability, however, many features of the mitochondrial and bacterial protein synthetic apparatus show a clear resemblance, providing support for the hypothesis of a prokaryotic endosymbiont ancestry of mitochondria.
Animals↗
Variants in neurotrophic factor genes and schizophrenic psychoses: no associations in a Spanish population.
Possible associations between schizophrenic psychoses, a ciliary neurotrophic factor (CNTF) null mutation and a neurotrophin in 3 (NT3) bi-allele polymorphism were investigated in a Spanish population. The sample consisted of 107 patients suffering from schizophrenic psychoses and 100 healthy volunteers. There was no statistical difference in the frequencies of the mutant CNTF allele in the index and control groups (0.125 vs. 0.121). The frequency of the rare NT3 allele (Glu) was very low and similar in both groups (0.005). Previous findings supporting the involvement of these genetic markers in the pathogenesis of schizophrenic psychoses were thus not confirmed. In light of neurodevelopmental hypotheses of schizophrenia, however, genes coding for neurotrophic factors remain interesting susceptibility loci in schizophrenia research. Subsequent studies should not focus exclusively on genetic alterations but also take into account secondary changes of the neurotrophic factor system at the mRNA and protein levels. Further, the current unsatisfying operationalized classification of the heterogeneous syndrome 'schizophrenia' remains a crucial problem that could be partially resolved by introducing more differentiated diagnoses defined on the basis of neurobiological criteria.
Ciliary Neurotrophic Factor↗
Prokaryotic genetic code.
The prokaryotic genetic code has been influenced by directional mutation pressure (GC/AT pressure) that has been exerted on the entire genome. This pressure affects the synonymous codon choice, the amino acid composition of proteins and tRNA anticodons. Unassigned codons would have been produced in bacteria with extremely high GC or AT genomes by deleting certain codons and the corresponding tRNAs. A high AT pressure together with genomic economization led to a change in assignment of the UGA codon, from stop to tryptophan, in Mycoplasma.
Anticodon↗
Anterior basement membrane corneal dystrophy and pseudo-unilateral lattice corneal dystrophy in a patient with recurrent corneal erosions.
PURPOSE: To report the utility of genetic testing in the diagnosis and management of patients with suspected corneal dystrophies. DESIGN: Case report. METHODS: A 58-year-old man with a history of recurrent corneal erosions was diagnosed with bilateral anterior basement membrane dystrophy and unilateral lattice corneal dystrophy. All 17 exons of the TGFBI gene were screened for mutations previously associated with lattice corneal dystrophy as well as novel coding region changes. RESULTS: No mutations were found in the 17 exons of the TGFBI gene. A nucleotide change in exon 6 (651C>G) did not result in a change in the encoded amino acid (Leu217Leu). CONCLUSIONS: In cases of suspected TGFBI corneal dystrophies, genetic testing is a useful tool to confirm the clinical diagnosis. In this case of suspected unilateral lattice corneal dystrophy, screening of the TGFBI gene ruled out the diagnosis, raising the possibility that the corneal changes were related to the coexistent anterior basement membrane dystrophy.
Basement Membrane↗
Ribozyme-catalyzed tRNA aminoacylation.
The RNA world hypothesis implies that coded protein synthesis evolved from a set of ribozyme catalyzed acyl-transfer reactions, including those of aminoacyl-tRNA synthetase ribozymes. We report here that a bifunctional ribozyme generated by directed in vitro evolution can specifically recognize an activated glutaminyl ester and aminoacylate a targeted tRNA, via a covalent aminoacyl-ribozyme intermediate. The ribozyme consists of two distinct catalytic domains; one domain recognizes the glutamine substrate and self-aminoacylates its own 5'-hydroxyl group, and the other recognizes the tRNA and transfers the aminoacyl group to the 3'-end. The interaction of these domains results in a unique pseudoknotted structure, and the ribozyme requires a change in conformation to perform the sequential aminoacylation reactions. Our result supports the idea that aminoacyl-tRNA synthetase ribozymes could have played a key role in the evolution of the genetic code and RNA-directed translation.
Acylation↗
PTPN11 mutations are not responsible for the Cardiofaciocutaneous (CFC) syndrome.
Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomalies/mental retardation syndrome characterized by congenital heart defects, characteristic facial appearance, short stature, ectodermal abnormalities and mental retardation. It was described in 1986, and to date is of unknown genetic etiology. All reported cases are sporadic, born to non-consanguineous parents and have apparently normal chromosomes. Noonan and Costello syndromes remain its main differential diagnosis. The recent finding of PTPN11 missense mutations in 45-50% of the Noonan patients studied with penetrance of almost 100% and the fact that in animals mutations of this gene cause defects of semilunar valvulogenesis, made PTPN11 mutation screening in CFC patients a matter of interest. We sequenced the entire coding region of the PTPN11 gene in ten well-characterised CFC patients and found no base changes. We also studied PTPN11 cDNA in our patients and demonstrated that there are no interstitial deletions either. The genetic cause of CFC syndrome remains unknown, and PTPN11 can be reasonably excluded as a candidate gene for the CFC syndrome, which we regard as molecular evidence that CFC and Noonan syndromes are distinct genetic entities.
Abnormalities, Multiple↗
Eosinophilic peroxidase deficiency: Identification of a point mutation (D648N) and prediction of structural changes.
ABSTRACT Hereditary eosinophil peroxidase (EPO; EC 1.11.1.7) deficiency is a rare abnormality without clinical symptoms characterized by decreased or absent peroxidase activity and decreased volume of the granule matrix in eosinophils. Nearly 100 cases have been reported, but a specific mutation has been reported in only one case. We report the genetic analysis of an EPO-deficient subject and his family. The case was found by automated blood analyzer. Sequencing of the entire coding region of the EPO gene disclosed a novel mutation, a 2060 G-A transition (g. 2060G>A) causing an amino acid change from aspartic acid to asparagine (D648N). Both the son and daughter of the propositus inherited the G-A transition, and in vitro expression experiments suggest this transition is responsible for the deficiency. We then analyzed the location of the affected amino acid within this molecule using a structural model of EPO based on myeloperoxidase (MPO). Asn648 is on the inside of the molecule; changing D to N would cause loss of the electrostatic interaction with Arg146 which is crucial for disulfide bonds of the light chain in the N terminus.
Amino Acid Substitution↗
Genetic rearrangements in the pathogenicity locus of Clostridium difficile strain 8864--implications for transcription, expression and enzymatic activity of toxins A and B.
The pathogenicity locus (PaLoc) of Clostridium difficile isolate 8864 was investigated to locate genetic rearrangements that would explain the exceptional pathogenicity of this particular isolate. Two major changes were defined: an insertion of 1.1 kb between the two genes tcdA and tcdE, coding for the enterotoxin and an accessory protein of unknown function, respectively, and a deletion of 5.9 kb encompassing the 3' ends of tcdA and tcdC. Transcription of the tcdA-E genes is severely affected by both rearrangements, explaining the demonstrated complete lack of TcdA polypeptide. We present a model of coordinate, growth-related transcription of the tcdA-E genes that confirms our previous findings in strain 10463. Recombinant TcdA-8864 had UDP-glucose-glucosyltransferase activity, proving that the N-terminal 698 amino acids of the polypeptide represent the catalytic domain. However, this truncated TcdA molecule lacks a ligand and translocation domain. To assess the catalytic domain of TcdB-8864, the sequence of the 5' end of its gene was determined. TcdB-8864 shows high homology to TcdB-1470 but lower homology to TcdB-10463 within this domain. This fits well with the altered glucosylation specificity of TcdB-8864 (Rac1, Rap2 and Ra1). Having defined the variations of transcription, expression and enzymatic activity of toxins A and B, implications for the pathogenic potential of strain 8864 are discussed.
Amino Acid Sequence↗
Properties of gray and binary representations.
Representations are formalized as encodings that map the search space to the vertex set of a graph. We define the notion of bit equivalent encodings and show that for such encodings the corresponding Walsh coefficients are also conserved. We focus on Gray codes as particular types of encoding and present a review of properties related to the use of Gray codes. Gray codes are widely used in conjunction with genetic algorithms and bit-climbing algorithms for parameter optimization problems. We present new convergence proofs for a special class of unimodal functions; the proofs show that a steepest ascent bit climber using any reflected Gray code representation reaches the global optimum in a number of steps that is linear with respect to the encoding size. There are in fact many different Gray codes. Shifting is defined as a mechanism for dynamically switching from one Gray code representation to another in order to escape local optima. Theoretical results that substantially improve our understanding of the Gray codes and the shifting mechanism are presented. New proofs also shed light on the number of unique Gray code neighborhoods accessible via shifting and on how neighborhood structure changes during shifting. We show that shifting can improve the performance of both a local search algorithm as well as one of the best genetic algorithms currently available.
Algorithms↗
Identification of a mutation in the MP19 gene, Lim2, in the cataractous mouse mutant To3.
PURPOSE: Lim2, the gene encoding the second most abundant lens specific integral membrane protein, MP19, has recently been proposed as an ideal candidate gene for the cataractous mouse mutant, To3. The aim of this study was to screen the Lim2 gene in the To3 mutant for a genetic lesion that was correlated and consistent with the mutant phenotype. METHODS: Genomic DNA was isolated from both normal mouse parental strains as well as the heterozygous and homozygous To3 cataract mutant. PCR was used to generate overlapping fragments of the entire Lim2 gene from these DNAs. The coding regions, including splice junctions and the translational termination site, of these fragments were then sequenced. RESULTS: A single G -> T transversion was identified within the first coding exon of the Lim2 gene in the To3 mutant DNA. This DNA change results in the nonconservative substitution of a valine for the normally encoded glycine at amino acid 15 of the MP19 polypeptide. CONCLUSIONS: The identified genetic lesion in the Lim2 gene of the cataractous mouse mutant, To3, confirms Lim2 as an ideal candidate gene. Future transgenic experiments should provide proof or disproof of a causative relationship between the identified mutation and the cataractous phenotype. These studies indicate that MP19 may play an important role in both normal lens development and cataractogenesis, and warrants more intense investigation of its role within the ocular lens.
Amino Acid Sequence↗
Probability of exclusion in paternity testing: time to reassess.
The average exclusion probability is a measure of efficiency in paternity testing; it refers to the a priori ability of a battery of tests to detect paternity inconsistencies. This parameter measures the capacity of the system to detect a false accusation of paternity. Traditionally, this average exclusion probability has been estimated as the probability of excluding a man who is not the father by an inconsistency in at least one of the studied loci. We suggest that this criterion should be corrected, as currently the presumed father is excluded when at least three genetic inconsistencies are found with the child being tested, not just one. This change of criterion has occurred because of the use of microsatellite loci, whose mutation rates are much greater than those of the coding genes used previously in paternity studies. We propose the use of the average probability of exclusion for at least three loci (not only one), as an honest measure of the combined probability of exclusion of several loci, and we propose an algebraic expression to calculate it.
False Positive Reactions↗
Identification of the host determinant of two prolate-headed phages infecting Lactococcus lactis.
A gene responsible for host determination was identified in two prolate-headed bacteriophages of the c2 species infecting strains of Lactococcus lactis. The identification of the host determinant gene was based on low DNA sequence homology in a specific open reading frame (ORF) between prolate-headed phages with different host ranges. When a host carrying this ORF from one phage on a plasmid was infected with another phage, we obtained phages with an altered host range at a frequency of 10(-6) to 10(-7). Sequencing of phage DNA originating from 10 independent single plaques confirmed that a genetic recombination had taken place at different positions between the ORF on the plasmid and the infecting phage. The adsorption of the recombinant phages to their bacterial hosts had also changed to match the phage origin of the ORF. Consequently, it is concluded that this ORF codes for the host range determinant.
Amino Acid Sequence↗
[Hypertrophic cardiomyopathy].
Hypertrophic cardiomyopathy is a heterogeneous, progressive disease with a variable age of debut. Hypertrophic cardiomyopathy is characterized by myocardial hypertrophy with a bizarre fibre disarray. Angina pectoris, dyspnoea and syncope are the most frequent symptoms. Hypertrophic cardiomyopathy is an important cause of sudden death, especially in children and young adults. The aetiology is genetic in more than 60% of the cases, with an autosomal dominant mode of inheritance. More than 50 different mutations involving six genes have so far been associated with the development of hypertrophic cardiomyopathy. These mutations are located to genes coding for several of the proteins in the cardiac sarcomere. The protein changes seem to compromise contractility as well as sarcomere assembly, thereby secondarily causing compensatory hypertrophy. The management of hypertrophic cardiomyopathy has been markedly improved within the last few years. This emphasizes the importance of determining prognostic markers in each patient. A specific genetic diagnosis may prove to be of major importance.
Adult↗
Engineering of the aspartate family biosynthetic pathway in barley (Hordeum vulgare L.) by transformation with heterologous genes encoding feed-back-insensitive aspartate kinase and dihydrodipicolinate synthase.
In prokaryotes and plants the synthesis of the essential amino acids lysine and threonine is predominantly regulated by feed-back inhibition of aspartate kinase (AK) and dihydrodipicolinate synthase (DHPS). In order to modify the flux through the aspartate family pathway in barley and enhance the accumulation of the corresponding amino acids, we have generated transgenic barley plants that constitutively express mutant Escherichia coli genes encoding lysine feed-back insensitive forms of AK and DHPS. As a result, leaves of primary transformants (T0) exhibited a 14-fold increase of free lysine and an 8-fold increase in free methionine. In mature seeds of the DHPS transgenics, there was a 2-fold increase in free lysine, arginine and asparagine and a 50% reduction in free proline, while no changes were observed in the seeds of the two AK transgenic lines analysed. When compared to that of control seeds, no differences were observed in the composition of total amino acids. The introduced genes were inherited in the T1 generation where enzymic activities revealed a 2.3-fold increase of AK activity and a 4.0-9.5-fold increase for DHPS. T1 seeds of DHPS transformants showed the same changes in free amino acids as observed in T0 seeds. It is concluded that the aspartate family pathway may be genetically engineered by the introduction of genes coding for feed-back-insensitive enzymes, preferentially giving elevated levels of lysine and methionine.
Amino Acids↗
Identification of a novel gene NCRMS on chromosome 12q21 with differential expression between rhabdomyosarcoma subtypes.
Rhabdomyosarcoma (RMS) is a malignant soft tissue tumor showing varying degrees of skeletal muscle differentiation. Two major histologic subtypes exist, alveolar and embryonal, each with associated molecular genetic changes. We have used Representational Difference Analysis (RDA) to compare gene expression between the two RMS subtypes and have identified the novel gene NCRMS (non-coding RNA in RMS) that has increased expression in the alveolar subtype relative to the embryonal subtype. Multiple alternatively spliced forms of NCRMS were identified through library screening, RACE, and comparison to human expressed sequence tags (ESTs). Northern blot analysis indicated the transcript size to be 1.25 kb in alveolar RMS. There was no sequence homology to any of the known genes in GenBank, but extensive homology to ESTs from various species. Comparison to human genomic sequences identified at least 11 exons mapping to chromosomal region 12q21. Differential expression of NCRMS was noted between various tumor types. Since NCRMS RNA possesses limited potential for protein coding, yet with conserved sequences between different species, it is likely that NCRMS is a functional non-coding RNA. Known genes in its proximity include myogenic regulators Myf5 and Myf6, growth factor Igf1, and another potential differentially expressed gene (ATP2B1) in RMS isolated by RDA.
Alanine Racemase↗