Mechanism of suppression in Drosophila: a change in tyrosine transfer RNA.
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Amino Acids↗
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Estimation of evolutionary changes in certain homologous polypeptide chains.
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Amino Acid Sequence↗
Changes in nuclear and cytoplasmic RNA in regenerating mouse liver.
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Animals↗
Genetic alterations in gastric cancer cell lines and their original tissues.
To investigate the genetic changes that occur during establishment of gastric cancer cell lines, 4 gastric cancer cell lines and their original tumor tissues were examined for microsatellite instability (MSI), loss of heterozygosity (LOH), and p53 mutation. MSI status did not change during the establishment, though the cell lines gained frameshift mutation in some of the genes with polytract coding sequences. There was no difference in p53 mutation between the cell lines and the original tumors. The frequency of LOH was similar between the cell lines and each original tumor, in the range 30.8% to 85.7%. The difference in the LOH results between the cell lines and the original tumors was not greater than the difference between the different areas of the original tumors. The above results suggested that most of the genetic alterations, such as MSI, LOH, and p53 gene mutation, were sustained during the establishment of gastric cancer cell lines. Minor genetic differences between original tumor tissues and cancer cell lines could be explained as a tumor heterogeneity because separate areas of the original tumor tissues manifest similar variations.
Frameshift Mutation↗
Insecticide resistance genes confer a predation cost on mosquitoes, Culex pipiens.
Newly occurring adaptive genes, such as those providing insecticide resistance, display a fitness cost which is poorly understood. In order to detect subtle behavioural changes induced by the presence of resistance genes, we used natural predators and compared their differential predation on susceptible and resistant Culex pipiens mosquitoes, using strains with a similar genetic background. Resistance genes were either coding an overproduced detoxifying esterase (locus Ester), or an insensitive target (locus ace-1). Differential predation was measured between susceptible and resistant individuals, as well as among resistant mosquitoes. A backswimmer, a water measurer, a water boatman and a predaceous diving beetle were used as larval predators, and a pholcid spider as adult predator. Overall, the presence of a resistance gene increased the probability of predation: all resistance genes displayed predation costs relative to susceptible ones, at either the larval or adult stage, or both. Interestingly, predation preferences among the susceptible and the resistance genes were not ranked uniformly. Possible explanations for these results are given, and we suggest that predators, which are designed by natural selection to detect specific behavioural phenotypes, are useful tools to explore non-obvious differences between two classes of individuals, for example when they differ by the presence or absence of one recent gene, such as insecticide resistance genes.
Animals↗
Coincident inactivation of 14-3-3sigma and p16INK4a is an early event in vulval squamous neoplasia.
The structure and expression of 14-3-3 sigma(sigma) was analysed in squamous carcinomas (SCC) of the vulva and in the vulval pre-malignant lesion vulval intraepithelial neoplasia (VIN). Sequence analysis of the sigma coding region did not detect mutations in any case of SCC or VIN III and loss of heterozygosity (LOH) occurred in only 2 out of 27 informative cases. In contrast to the absence of genetic change, methylation-specific PCR (MSP) analysis revealed dense CpG methylation within the sigma gene in approximately 60% of cases of vulval SCC, but methylation was not detected in matched, normal epithelial tissue. Methylation was associated in all cases with reduced or absent expression of sigma mRNA. There was no correlation between sigma methylation and HPV or p53 status. Analysis of pre-malignant vulval intraepithelial neoplasia (VIN) revealed that sigma methylation was detectable early in neoplastic development. Co-incident methylation, accompanied by loss of expression, of sigma and p16INK4a was commonly detected in both SCC and VIN III, suggesting that epigenetic silencing of these two genes is an early and important event in vulval neoplasia.
14-3-3 Proteins↗
A mammalian mitochondrial RNA processing activity contains nucleus-encoded RNA.
Ribonuclease mitochondrial RNA processing, a site-specific endoribonuclease involved in primer RNA metabolism in mammalian mitochondria, requires an RNA component for its activity. On the basis of copurification and selective inactivation with complementary oligonucleotides, a 135-nucleotide RNA species, not encoded in the mitochondrial genome, is identified as the RNA moiety of the endoribonuclease. This finding implies transport of a nucleus-encoded RNA, essential for organelle DNA replication, to the mitochondrial matrix.
Animals↗
[New concepts in systemic chemotherapy].
The availability of sufficient amounts of cytokines for clinical use has opened new opportunities in the systemic treatment of malignant diseases. The two haematopoetic growth factors G-CSF and GM-CSF, used either alone or in combination with separation and retransfusion of peripheral haematopoetic progenitor cells, have allowed dose escalations of cytostatic agents for which myelosuppression is a dose-limiting toxicity. This has implications especially for the treatment of relapsed and very advanced testicular carcinomas. High-dose chemotherapy followed by autologous blood progenitor cells and haematopoetic growth factors seems to produce significantly better therapeutic results than standard-dosed chemotherapy in these situations. The immunomodulating agents IL2 and IL4 are currently undergoing clinical trials and seem to have direct cytotoxic activities, especially in renal cancer. A new, potentially promising therapeutic modality is becoming available with the ability to transfer genetic material directly into either tumour or immunomodulatory effector cells (gene therapy). The insertion of certain genes coding for the production of cytokines or surface molecules can produce systemic antitumour reactions when these genetically altered cells are reimplanted into the host. All these subjects are currently subjects of detailed investigation and may change the therapeutic options for the treatment of advanced urological malignancies.
Adjuvants, Immunologic↗
A novel germ-line mutation in the noncoding region of the p53 gene in a Li-Fraumeni family.
We identified a novel germ-line p53 mutation in the noncoding, nonsplicing regions of a Li-Fraumeni family. Patients belonging to this family included pediatric medulloblastoma and rhabdomyosarcoma patients and a breast carcinoma patient. Three positions in the p53 gene were analyzed for loss of heterozygosity (LOH). One of the three loci retained heterozygosity, whereas the other two exhibited LOH. Sequence analysis of the third locus identified a change of 5'-CCGGGTGA-3' to 5'-CCAGGTTGGA-3', 63 bp downstream of exon 6. The mutation was identified in the germ line of the two pediatric patients and in each of the related parents. We excluded any additional mutation in the entire coding region of the p53 gene, including splice-site intronic sequences. Strong positive nuclear staining of the p53 protein was detected in both normal and tumor paraffin-embedded tissues. Eighty-five normal persons were negative for this alteration, which thus supports it as a mutation. These results may indicate that genetic changes within the noncoding region of the p53 gene may serve as an alternative mechanism of activating this gene. Mutations in the noncoding region of this gene should be further studied.
Adolescent↗
Complete sequence of a cloned cDNA encoding rabbit secreted mu-chain of VHa2 allotype: comparisons with VHa1 and membrane mu sequences.
The complete sequence of a cDNA clone (pmu3) encoding a secreted IgM heavy chain from a rabbit of VHa2 allotype has been determined. Comparison of the nucleic acid and amino acid sequences with a comparable mouse mu-chain shows unusually high homologies of the sequences of the fourth domains and secretory portions of the molecules (80 to 90% vs 56 to 73% for the other domains). This high degree of homology is also seen with the sequences of the fourth domain and secreted terminus of human mu-chain. The DNA sequence of a second cDNA clone encoding the membrane form of rabbit IgM is approximately 90% homologous with the mouse and human coding sequences for the membrane terminus, and there is 98 and 97% amino acid sequence homology. We found an unusually long (156 base pair) 5' untranslated region in clone pmu3 and discovered that 105 bases at the 5' end were complementary to the terminal portion of the CH4 domain of our mu sequence. Southern blotting analyses and the finding of a 13 base pair segment in rabbit genomic V region DNA that is homologous to the complementary strand of a segment of the CH4 of rabbit mu strongly suggests that this extended sequence resulted from a reverse transcriptase "hooking error". We have also obtained and sequenced another cDNA clone from a VHa1 cDNA library. Comparison of the V region of clone pmu3 from VHa2 with the 117 available positions of a1 DNA sequence shows 25 differences, nine of which are in allotype-associated codons. There is also a two-codon deletion in the VHa1 compared to VHa2 in the third framework region that may contribute to allotypic differences. Development of VHa allotype-specific probes, now in progress, is complicated by the fact that most of the allotype-associated amino acids of a1, a2, and a3 can be derived from each other by single base changes.
Amino Acid Sequence↗
Rewiring of the yeast transcriptional network through the evolution of motif usage.
Recent experiments revealed large-scale differences in the transcription programs of related species, yet little is known about the genetic basis underlying the evolution of gene expression and its contribution to phenotypic diversity. Here we describe a large-scale modulation of the yeast transcription program that is connected to the emergence of the capacity for rapid anaerobic growth. Genes coding for mitochondrial and cytoplasmic ribosomal proteins display a strongly correlated expression pattern in Candida albicans, but this correlation is lost in the fermentative yeast Saccharomyces cerevisiae. We provide evidence that this change in gene expression is connected to the loss of a specific cis-regulatory element from dozens of genes following the apparent whole-genome duplication event. Our results shed new light on the genetic mechanisms underlying the large-scale evolution of transcriptional networks.
Aerobiosis↗
Molecular cloning and analysis of functional envelope genes from human immunodeficiency virus type 1 sequence subtypes A through G. The WHO and NIAID Networks for HIV Isolation and Characterization.
Present knowledge of human immunodeficiency virus type 1 (HIV-1) envelope immunobiology has been derived almost exclusively from analyses of subtype B viruses, yet such viruses represent only a minority of strains currently spreading worldwide. To generate a more representative panel of genetically diverse envelope genes, we PCR amplified, cloned, and sequenced complete gp160 coding regions of 35 primary (peripheral blood mononuclear cell-propagated) HIV-1 isolates collected at major epicenters of the current AIDS pandemic. Analysis of their deduced amino acid sequences revealed several important differences from prototypic subtype B strains, including changes in the number and distribution of cysteine residues, substantial length differences in hypervariable regions, and premature truncations in the gp41 domain. Moreover, transiently expressed glycoprotein precursor molecules varied considerably in both size and carbohydrate content. Phylogenetic analyses of full-length env sequences indicated that the panel included members of all major sequence subtypes of HIV-1 group M (clades A to G), as well as an intersubtype recombinant (F/B) from an infected individual in Brazil. In addition, all subtype E and three subtype G viruses initially classified on the basis of partial env sequences were found to cluster in subtype A in the 3' half of their gp41 coding region, suggesting that they are also recombinant. The biological activity of PCR-derived env genes was examined in a single-round virus infectivity assay. This analysis identified 20 clones, including 1 from each subtype (or recombinant), which expressed fully functional envelope glycoproteins. One of these, derived from a patient with rapid CD4 cell decline, contained an amino acid substitution in a highly conserved endocytosis signal (Y721C), as mediated virus entry with very poor efficiency, although they did not contain sequence changes predicted to alter protein function. These results indicate that the env genes of primary HIV-1 isolates collected worldwide can vary considerably in their genetic, phylogenetic, and biological properties. The panel of env constructs described here should prove valuable for future structure-function studies of naturally occurring envelope glycoproteins as well as AIDS vaccine development efforts targeted against a broader spectrum of viruses.
Amino Acid Sequence↗
From insects to human hosts: Identification of major genomic differences between entomopathogenic strains of Photorhabdus and the emerging human pathogen Photorhabdus asymbiotica.
Pathogenic bacteria of the genus Photorhabdus are naturally found in symbiotic association with soil entomopathogenic nematodes, and are of increasing economic interest in view of their potential for the development of novel biopesticides. This bipartite natural system is currently used for the biological control of crop pests in several countries. However, an increasing number of Photorhabdus strains have recently been isolated from human clinical specimens in both the United States and Australia, associated with locally invasive soft tissue infections and disseminated bacteraemia. In view of their growing use in biological control, which increases the potential rate of exposure of humans to these pathogens, we decided to undertake a comparative study of the genomic differences between insect and human pathogenic strains of Photorhabdus, in an attempt to understand the genetic mechanisms involved in the apparent change of host specificity, presumably responsible for their recently acquired capacity to infect humans. The data presented here demonstrates that major genomic differences exist between strains of Photorhabdus exhibiting virulence against insects or humans. Several individual genes, coding for virulence factors, were isolated and shown to be specific to the Photorhabdus asymbiotica human pathogens. One of these genes, sopB, encoding a host cell invasion factor translocated via the type III secretion system, has been cloned and the comparison of its genomic context in different pathogens strongly indicates that horizontal gene transfer is implicated in the acquisition of these virulence factors specific to the human pathogens. The precise role of this and other virulence factors identified here in the pathogenicity of P. asymbiotica towards humans is currently under investigation.
Animals↗
The isolation and sequence of missense and nonsense mutations in the cloned bacteriophage P22 tailspike protein gene.
Twenty-seven new mutations in the structural gene for the Salmonella typhimurium bacteriophage P22 tailspike protein have been isolated, mapped using a powerful plasmid-based genetic system and their DNA sequence changes determined. The mutations were generated by hydroxylamine treatment of the cloned gene on a plasmid expression vector. Assaying the activity of the tailspike protein produced from this plasmid and screening for plasmid mutants were accomplished by the in situ complementation of P22 capsids imbedded in soft agar to produce infectious phage. Deletion mutations in the cloned gene have been constructed by a two step procedure involving oligonucleotide linker insertion and in vitro deletion by restriction endonuclease digestion. The deletions, whose physical endpoints were determined by DNA sequencing, define 12 genetic and physical intervals into which the new mutations were mapped by marker rescue experiments. These deletions were transferred to phage P22 by recombination and used to map mutations carried on plasmids. Following mapping, the nucleotide change for each of the mutations was determined by DNA sequencing. The majority were absolute missense mutations although both amber and ochre nonsense mutations were also identified in the protein coding portion of the gene. The suppression pattern of the nonsense mutations was determined on several nonsense suppressors. Four of the mutations cause severely depressed levels of tailspike protein expression from both the cloned gene on the plasmid expression vector and from P22 phage carrying these mutations. These mutations were identified as nucleotide changes in what is probably the P22 late operon transcription terminator which immediately follows the tailspike protein coding sequence.
Amino Acid Sequence↗
CARD4/NOD1 is not involved in inflammatory bowel disease.
BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex genetic disorders. CARD15/NOD2, a member of the Ced4 superfamily which includes Apaf-1 and CARD4/NOD1, has recently been associated with genetic predisposition to CD but additional genetic factors remain to be identified. Because CARD4/NOD1 shares many structural and functional similarities with CARD15, we tested its putative role in IBD. PATIENTS AND METHODS: The 11 exons of CARD4 were screened for the presence of variants in 63 unrelated IBD patients. The only non-private genetic variation encoding for a substitution in the peptidic chain was genotyped in 381 IBD families (235 CD, 58 UC, 81 mixed, and seven indeterminate colitis families) using a polymerase chain reaction-restriction fragment length polymorphism procedure. Genotyping data were analysed by the transmission disequilibrium test. RESULTS: Five of nine sequence variations identified in the coding sequence of the gene encoded for non-conservative changes (E266K, D372N, R705Q, T787M, and T787K). Four were present in only one family. The remaining variant (E266K), which exhibited an allele frequency of 0.28, was not associated with CD, UC, or IBD. Furthermore, IBD patients carrying sequence variations in their CARD4 gene had a similar phenotype to those with a normal sequence. CONCLUSION: Our results suggest that CARD4 does not play a major role in genetic susceptibility to IBD.
Adaptor Proteins, Signal Transducing↗
The natural selection of the chemical elements.
Evolution is treated here in a novel way. DNA or any other code is considered to be conservative and therefore, once life began, it would prevent change. Change was imposed upon the DNA code as a stress resulting in vulnerability to "advantageous" DNA damage and mutation. In this respect it is the stress, the changing environment, that opened up a possibility of evolution once an early life form had optimised itself in primitive circumstances. Here I examine the initial slow-coming-to-terms with the environment of primitive life, and then its evolution as the environment forced the DNA into novel development by introducing chemical elements in new forms. The situation today is no different. Environmental change is hostile to present day life and will lead to further evolution.
Biological Evolution↗
DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin-1 gene: two novel mutations.
Many different mutations that cause Alzheimer's disease (AD) have been found in the presenilin-1 gene (PSEN1) and are associated with the most aggressive forms of the disease. With the aim of screening for PSEN1 genetic variations, we developed a method based on denaturing gradient gel electrophoresis (DGGE) that allows the mutational analysis of all the coding exons and the proximal promoter of PSEN1 using only four DGGE gels. The analysis by this methodology of a sample of 58 early-onset AD (EOAD) patients nonselected for family history resulted in finding four genetic variants within the PSEN1 coding region, two of which are novel mutations (M233L and A409T), whereas the other two have been reported previously (L282R and E318G). We also found a novel mutation within the PSEN1 proximal promoter (-280 C-->G) that, interestingly, provokes significant changes in the transcriptional activity of the gene in cell lines of neuronal and astrocytic, but not hepatic origin. These data strongly suggest that the region around -280 of PSEN1 promoter contains a regulatory element that controls its transcription specifically in neural cells.
Adult↗
Screening of the 3' two-thirds of the coding area of the apo B gene in Finnish hypercholesterolemic patients report of six new genetic variants.
Hypercholesterolemia clustering in families not explained by either low density lipoprotein (LDL)-receptor mutations producing familial hypercholesterolemia (FH), or the apolipoprotein B (apo B) Arg3500-->Gln mutation with familial defective apo B (FDB), is common in the Finnish population. In search of previously unknown apo B mutations, we screened exons 26 to 29 of the apo B gene in 68 Finnish severely hypercholesterolemic (> or = 8 mmol/l) non-FH, non-FDB patients, using a single-strand conformation polymorphism analysis based screening method. Four rare and two polymorphic previously unreported DNA variations were detected. The rare variants were a three-nucleotide deletion, with the deletion of Asp2186, an A11961-->G change leading to a Thr3918-->Ala change, a T12922-->G change causing a Val4238-->Ala substitution, and a neutral T12935-->C change leading to a new RsaI cutting site. The polymorphic G12937-->C and G13569-->A changes leading to Arg4243-->Thr and Ala4454-->Thr substitutions, respectively, had minor allele frequencies of 0.03 and 0.02. None of these variants seemed to explain the hyperlipidemia in these patients. A major Finnish mutation causing severe hypercholesterolemia is unlikely to exist in the 3' two-thirds of the coding area of the apo B gene.
Apolipoproteins B↗