[Incomplete virus particles as the result of mutations in the genome of the bacteriophage fr].
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Coliphages↗
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Results for “Genome mutation”
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Somatic mutations of the mitochondrial genome in human colorectal tumours.
Alterations of oxidative phosphorylation in tumour cells were originally believed to have a causative role in cancerous growth. More recently, mitochondria have again received attention with regards to neoplasia, largely because of their role in apoptosis and other aspects of tumour biology. The mitochondrial genome is particularly susceptible to mutations because of the high level of reactive oxygen species (ROS) generation in this organelle, coupled with a low level of DNA repair. However, no detailed analysis of mitochondrial DNA in human tumours has yet been reported. In this study, we analysed the complete mtDNA genome of ten human colorectal cancer cell lines by sequencing and found mutations in seven (70%). The majority of mutations were transitions at purines, consistent with an ROS-related derivation. The mutations were somatic, and those evaluated occurred in the primary tumour from which the cell line was derived. Most of the mutations were homoplasmic, indicating that the mutant genome was dominant at the intracellular and intercellular levels. We showed that mitochondria can rapidly become homogeneous in colorectal cancer cells using cell fusions. These findings provide the first examples of homoplasmic mutations in the mtDNA of tumour cells and have potential implications for the abnormal metabolic and apoptotic processes in cancer.
Base Sequence↗
[Identification of blue grained wheat and its irradiation-mutated offsprings by genomic in situ hybridization (GISH)].
Transferring useful chromosome(s), chromosomal fragment(s) or genes from related species into common wheat (Triticum aestivum L.) is an effective method for improving wheat cultivars, and DNA:DNA in situ hybridization has been proven to be an effective method for directly demonstrating alien chromosome number and distribution in plant. In this study, genomic in situ hybridization (GISH) was used to identify the chromosomal constitutions of the blue-grained wheat Blue-58 originated from distant hybridization between Triticum aestivum L. and Agropyron elongatum (Host) Beauv (2n = 10x = 70) and its irradiation-mutated offsprings. The results showed that, as previously reported, Blue-58 (2n = 42) was a substitution line in which a pair of 4D chromosomes of common wheat was substituted by a pair of 4E chromosomes from Agropyron elongatum. Mutation line LW004 might be a homozygous reciprocal translocation line in which two pair of chromosomes might be involved in the translocation event and it showed high efficiency in utilizing soil phosphorus in our field screening experiments. Mutation line LW43-3-4 was a blue monosomic line with 40 wheat chromosomes plus one 4E chromosome from Agropyron elongatum in its genome and its seeds showed light-blue color. Some other chromosome rearrangements and structure changes were also detected among the mutated offsprings through GISH, such as telomonosomic line (40 W + 1't4E) and a line with a chromosomal constitution of 39 W + 1'4E + 1't4E. Our results indicated very clearly that it was the chromosome derived from Agropyron elongatum carried gene(s) responsible for the blue pigmentation in wheat grains and it was also illustrated from our results that the combination of effective methods for generating mutations at chromosomal level and convenient detection of these mutations played pivotal roles in creating materials for chromosome engineering and in breeding by means of chromosome engineering.
In Situ Hybridization↗
[Analysis of mutations in the genome of cold-adapted strains of influenza A virus using extended modification of polymerase chain restriction method].
Cold-adapted influenza viruses A/Leningrad/13 4/17/5 7 (H2N2) (Len/17) and A/Leningrad/I 34/4 7/57 (H2N2) (Len/47) are used in Russia to prepare live reassortant cold-adapted influenza vaccines (LIV) for adults and children, respectively. Comparison between the nucleotide sequences of the Len/17 strain and the initial wild-type strain A/Leningrad/13 4/5 7 (H2N2) revealed ten nucleotide substitutions (eight of them encoding). Four additional substitutions (three encoding) were found in the genome of the Len/47 virus. Gene segment restriction site (PCR-restriction) analysis was used for identification of the genotype of reassortant influenza viruses. Conventional methods of PCR-restriction analysis detect only five encoding nucleotides substitutions in the internal genes of the Len/17 and seven substitutions in the internal genes of the Len/47 virus. An extended modification of the PCR-restriction method detect all encoding mutations in the internal genes of the Len/17 and Len/47 viruses (eight and eleven encoding substitutions, respectively). This method is advantageous for genome composition analysis of reassortant influenza vaccine strains and for investigating the genetic stability of LIV during replication in vaccines.
Adaptation, Physiological↗
Dependence of the UV sensitivity of phage T4 on the localization of conditionally lethal (amber) mutations in the genome.
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Chromosome Mapping↗
Mutations in the genomic deoxyribonucleic acid for SLC3A1 in patients with cystinuria.
Cystinuria is an inherited transport disorder characterized by defective renal resorption of cystine and other dibasic amino acids. We have studied the occurrence of mutations in the SLC3A1 gene, which codes for a dibasic amino acid transporter-like protein, in 33 unrelated cystinurics. We found mutations in 34 of the 66 chromosomes studied. There were 14 different mutations in our study population, 8 of which had not been previously described. Of these new mutations, 4 were missense mutations: G1934C, C1259G, T1607G, and G1373A. The other 4 mutations consisted of a single base insertion mutation (2022 ins T), a single base deletion mutation (163 del C), a 23-base deletion mutation (del 782A-804A), and a complex mutation that consisted of a 36-base deletion (del C431-3 to T463) and a duplication insertion of 468 T to 474 A after nucleotide 474.
Adolescent↗
Unscheduled polyploidy synergizes with oncogenic mutations to enhance genome instability and tumorigenesis.
Polyploid Giant Cancer Cells (PGCCs) occur across multiple cancer types and are associated with therapy resistance, genome instability, disease progression, and metastasis. PGCCs can grow through endocycles, a variant cell cycle of alternating Growth (G) and DNA Synthesis (S) phases without cell division. Unlike programmed endocycles that occur during normal tissue development, PGCCs switch from mitotic cycles to unscheduled endocycles in response to stress. PGCCs can subsequently return to error-prone divisions which generate aneuploid daughter cells that contribute to disease progression. However, the regulation of PGCC cell cycles and contributions to cancer are still being defined. Filling this knowledge gap will lead to the development of improved cancer therapies. In this study, we used a molecular-genetic system in the model organism Drosophila melanogaster to examine how oncogenes interact with unscheduled endocycles in vivo. We found that several oncogenes promote bypass of an endocycle arrest, resulting in increased polyploid cell size and DNA content. The extent of this increased growth was dependent on the type of oncogenic mutation. When these polyploid cells returned to division, RasG12V promoted continued divisions of polyploid daughter cells with elevated genome instability. RasG12V expression during transient endocycles and subsequent divisions also induced expression of a matrix metalloprotease and a Wnt pathway ligand. Importantly, RasG12V with transient endocycles enhanced the growth of large, neoplastic tumors. These findings indicate that oncogenic mutations can synergize with transient, unscheduled endocycles to promote tumorigenesis with important broader implications for cancer prognosis and therapies.
Animals↗
Molecular approach in cancer epidemiology: early detection of carcinogen-induced mutations in a whole genome (Review).
Chronic exposure of organisms to endo- or exogenous genotoxic products results in the accumulation of mutations in the genome and eventually to the development of cancers. Early detection of these mutations would allow the identification of at risk individuals who present a high load of mutations either because of an occupational or environmental exposure, or because of less efficient DNA repair processes. However, highly specific and sensitive assays are required to allow the detection of point mutations in a whole genome. We review a long-term study on the mutagenesis induced in E.coli by an aromatic amide, the N-2-acetylaminofluorene. A major contribution of this work was to reveal the presence of specific mutation hot spot sequences. Taking advantage of this observation, we designed a specific, sensitive and semi-quantitative in vitro assay allowing the detection of carcinogen induced mutations. This assay has been validated in vivo and demonstrate the sensitivity of the technique in early detection of mutations and its usefullness in molecular epidemiology, early diagnostic and prognosis.
2-Acetylaminofluorene↗
Mapping temperature-sensitive mutations at a genome scale to engineer growth switches in Escherichia coli.
Temperature-sensitive (TS) mutants are a unique tool to perturb and engineer cellular systems. Here, we constructed a CRISPR library with 15,120 Escherichia coli mutants, each with a single amino acid change in one of 346 essential proteins. 1,269 of these mutants showed temperature-sensitive growth in a time-resolved competition assay. We reconstructed 94 TS mutants and measured their metabolism under growth arrest at 42°C using metabolomics. Metabolome changes were strong and mutant-specific, showing that metabolism of nongrowing E. coli is perturbation-dependent. For example, 24 TS mutants of metabolic enzymes overproduced the direct substrate metabolite due to a bottleneck in their associated pathway. A strain with TS homoserine kinase (ThrBF267D ) produced homoserine for 24 h, and production was tunable by temperature. Finally, we used a TS subunit of DNA polymerase III (DnaXL289Q ) to decouple growth from arginine overproduction in engineered E. coli. These results provide a strategy to identify TS mutants en masse and demonstrate their large potential to produce bacterial metabolites with nongrowing cells.
Escherichia coli↗
Human-specific nonsense mutations identified by genome sequence comparisons.
The comparative study of the human and chimpanzee genomes may shed light on the genetic ingredients for the evolution of the unique traits of humans. Here, we present a simple procedure to identify human-specific nonsense mutations that might have arisen since the human-chimpanzee divergence. The procedure involves collecting orthologous sequences in which a stop codon of the human sequence is aligned to a non-stop codon in the chimpanzee sequence and verifying that the latter is ancestral by finding homologs in other species without a stop codon. Using this procedure, we identify nine genes (CML2, FLJ14640, MT1L, NPPA, PDE3B, SERPINA13, TAP2, UIP1, and ZNF277) that would produce human-specific truncated proteins resulting in a loss or modification of the function. The premature terminations of CML2, MT1L, and SERPINA13 genes appear to abolish the original function of the encoded protein because the mutation removes a major part of the known active site in each case. The other six mutated genes are either known or presumed to produce functionally modified proteins. The mutations of five genes (CML2, FLJ14640, MT1L, NPPA, TAP2) are known or predicted to be polymorphic in humans. In these cases, the stop codon alleles are more prevalent than the ancestral allele, suggesting that the mutant alleles are approaching fixation since their emergence during the human evolution. The findings support the notion that functional modification or inactivation of genes by nonsense mutation is a part of the process of adaptive evolution and acquisition of species-specific features.
Animals↗
Restriction map and location of mutations on the genome of bacteriophage Hp1c1 of Haemophilus influenzae Rd.
A physical map of the 32.4-kb chromosome of the Haemophilus influenzae bacteriophage Hp1c1 has been constructed, using the cleavage sites of eight restriction endonucleases. Two temperature-sensitive mutations have also been localized on the phage chromosome. The phage DNA exhibited an affinity for the specific DNA receptor of Haemophilus transformation approx. 1.5-fold higher than that obtained with bulk chromosomal DNA of H. influenzae.
Bacteriophages↗
Deletion mutations of the genome segments of wound tumor virus.
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Animals↗
Genomic structure and mutation screening of the E2F4 gene in human tumors.
E2F4, a member of the E2F family of transcription factors, is abundant in non-proliferating and differentiated cells where it plays an important role in the suppression of proliferation-associated genes. The E2F4 gene spans 6 kb and has 10 exons. It contains a serine (CAG) repeat tract in exon 7, which is unstable in gastrointestinal tumors. To further investigate a possible role of this gene in tumorigenesis we performed mutational analysis and expression studies in different tumors. Primary human tumor tissue of the stomach, colon, breast and lung (28), metastatic tumors of the colon (3) and small cell lung tumor cell lines (18) were screened for somatic mutations in the coding region of E2F4. No mutation was found. Microsatellite instability of the CAG repeat, however, was documented in primary stomach and colon tumors. Northern blot analysis revealed upregulated E2F4 transcript levels in tumor cell lines. Our data suggest that a direct involvement of E2F4 in tumorigenesis is unlikely, although increased E2F4 expression may be associated with human cancer.
Base Sequence↗
Structural organization, complete genomic sequences and mutational analyses of the Fukuyama-type congenital muscular dystrophy gene, fukutin.
Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive severe muscular dystrophy in combination with cerebral cortical dysplasia. Previously, we identified the gene responsible for FCMD, termed fukutin, through positional cloning. In this study, we have sequenced 131892 bp of genomic DNA in the region of the fukutin gene on chromosome 9q31 and obtained its complete genomic structure. The fukutin genomic sequence spans approximately 100 kb and is organized into 10 exons (41-6067 bp) and nine introns (1841-21460 bp). Using these sequence data, we have identified three novel fukutin mutations in FCMD patients. We have also located a putative TATA box in the flanking 5' region and identified numerous alternatively spliced fukutin mRNA transcripts. Analysis of expressed sequence tag clusters within the region revealed two novel genes upstream of the fukutin gene. These data provide fundamental information to support detailed genetic and functional analyses of the fukutin gene.
Alternative Splicing↗
The human mammary-derived growth inhibitor (MDGI) gene: genomic structure and mutation analysis in human breast tumors.
The mammary-derived growth inhibitor (MDGI) gene is a candidate tumor suppressor gene for human breast cancer. It has been shown to reduce the tumorigenicity of breast cancer cell lines in nude mice, and loss of expression of this gene has been shown in primary breast tumors. Furthermore, the human MDGI gene has been mapped to human chromosome 1p32-p35, a common region of deletion in sporadic breast tumors. We have determined the genomic structure of the human MDGI gene from a cosmid clone mapping to chromosome 1p32-p35 and have more finely mapped the MDGI gene relative to chromosome 1p microsatellite markers. The gene covers approximately 8 kb of genomic DNA and is divided into four exons. In an attempt to identify possible inactivating mutations in the MDGI gene in human breast cancer, we have sequenced all four exons and their surrounding splice junctions in 30 sporadic breast tumors. Ten of these tumors showed loss of heterozygosity (LOH) in the 1p32-p35 region, with 5 tumors showing LOH in the subregion containing the MDGI gene. No mutations were found in this analysis. A polymorphism was identified in exon 2 in the constitutional DNA of 1/30 cases in this study, which resulted in the conversion of a lysine to an arginine residue at codon 53. This variant was present in the constitutional DNA of a further 3/26 women with sporadic breast cancer and 2/90 control individuals (P = 0.20). Despite experimental evidence that MDGI has tumor suppressor activity, our data suggest that mutations in the coding region are uncommon in human breast tumorigenesis.
Base Sequence↗
Proceedings: Mitotic anomalies as the source of mutation of the genome: polyploidization cycles--segregation in mammalian cell population.
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Aneuploidy↗
The human ROX gene: genomic structure and mutation analysis in human breast tumors.
We have recently isolated a human gene, ROX, encoding a new member of the basic helix-loop-helix leucine zipper protein family. ROX is capable of heterodimerizing with Max and acts as a transcriptional repressor in an E-box-driven reporter gene system, while it was found to activate transcription in HeLa cells. ROX expression levels vary during the cell cycle, being down-regulated in proliferating cells. These biological properties of ROX suggest a possible involvement of this gene in cell proliferation and differentiation. The ROX gene maps to chromosome 17p13.3, a region frequently deleted in human malignancies. Here we report the genomic structure of the human ROX gene, which is composed of six exons and spans a genomic region of less than 40 kb. In an attempt to identify possible inactivating mutations in the ROX gene in human breast cancer, we performed a single-strand conformation polymorphism analysis of its coding region in 16 sporadic breast carcinomas showing loss of heterozygosity in the 17p13.3 region. No mutations were found in this analysis. Five nucleotide polymorphisms were identified in the ROX gene, three of which caused an amino acid substitution. These nucleotide changes were present in the peripheral blood DNAs of both the patients and the control individuals. In vitro translated assays did not show a significant decrease in the ability of the ROX mutant proteins to bind DNA or to repress transcription of a driven reporter gene in HEK293 cells. Despite experimental evidence that ROX might act as a tumor suppressor gene, our data suggest that mutations in the coding region of ROX are uncommon in human breast tumorigenesis.
Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
Point mutations of mitochondrial genome in Parkinson's disease.
Oxidative stress and subsequent energy crisis have been proposed as the cause of nigral neuronal cell death in Parkinson's disease. We have reported defects in the mitochondrial respiratory chain and increased amount of deleted mitochondrial genome in the nigrostriatal system of patients with Parkinson's disease. Deletion in mitochondrial DNA could be ascribed to somatically acquired premature aging leading to cell death. To elucidate the contribution of maternally transmitted point mutations in mitochondrial DNA to the premature DNA damages, we employed a direct sequencing system and analyzed the total nucleotide sequences of mitochondrial DNA in the brains of five patients with idiopathic Parkinson's disease. There were no predominant point mutations among the patients in contrast to some neuromuscular diseases. However, each patient had several point mutations that would result in a significant change in the gene products. Some of these mutations may be involved either in the increased production of oxygen radicals from the mitochondrial respiratory chain or in the increased susceptibility of the respiratory chain components to oxidative damage. We propose that some of these mutations can be regarded as one of the risk factors accelerating degeneration of nigrostriatal pathway in Parkinson's disease.
Base Sequence↗