Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair.Mutation, Missense: A mutation in which a codon is mutated to one directing the incorporation of a different amino acid. This substitution may result in an inactive or unstable product. (From A Dictionary of Genetics, King & Stansfield, 5th ed)Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Frameshift Mutation: A type of mutation in which a number of NUCLEOTIDES deleted from or inserted into a protein coding sequence is not divisible by three, thereby causing an alteration in the READING FRAMES of the entire coding sequence downstream of the mutation. These mutations may be induced by certain types of MUTAGENS or may occur spontaneously.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Germ-Line Mutation: Any detectable and heritable alteration in the lineage of germ cells. Mutations in these cells (i.e., "generative" cells ancestral to the gametes) are transmitted to progeny while those in somatic cells are not.Pedigree: The record of descent or ancestry, particularly of a particular condition or trait, indicating individual family members, their relationships, and their status with respect to the trait or condition.Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.DNA Mutational Analysis: Biochemical identification of mutational changes in a nucleotide sequence.Exons: The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA.Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships.Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more AMINO ACIDS in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish, enhance, or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties.Mutagenesis, Site-Directed: Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.Heterozygote: An individual having different alleles at one or more loci regarding a specific character.Mutation Rate: The number of mutations that occur in a specific sequence, GENE, or GENOME over a specified period of time such as years, CELL DIVISIONS, or generations.Alleles: Variant forms of the same gene, occupying the same locus on homologous CHROMOSOMES, and governing the variants in production of the same gene product.Polymorphism, Single-Stranded Conformational: Variation in a population's DNA sequence that is detected by determining alterations in the conformation of denatured DNA fragments. Denatured DNA fragments are allowed to renature under conditions that prevent the formation of double-stranded DNA and allow secondary structure to form in single stranded fragments. These fragments are then run through polyacrylamide gels to detect variations in the secondary structure that is manifested as an alteration in migration through the gels.Mutagenesis: Process of generating a genetic MUTATION. It may occur spontaneously or be induced by MUTAGENS.Sequence Analysis, DNA: A multistage process that includes cloning, physical mapping, subcloning, determination of the DNA SEQUENCE, and information analysis.Sequence Deletion: Deletion of sequences of nucleic acids from the genetic material of an individual.Homozygote: An individual in which both alleles at a given locus are identical.Protein Structure, Tertiary: The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.DNA Primers: Short sequences (generally about 10 base pairs) of DNA that are complementary to sequences of messenger RNA and allow reverse transcriptases to start copying the adjacent sequences of mRNA. Primers are used extensively in genetic and molecular biology techniques.Genotype: The genetic constitution of the individual, comprising the ALLELES present at each GENETIC LOCUS.Phenotype: The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (CODON, TERMINATOR). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, TRANSFER) complementary to all codons. These codons are referred to as unassigned codons (CODONS, NONSENSE).Models, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Codon, Nonsense: An amino acid-specifying codon that has been converted to a stop codon (CODON, TERMINATOR) by mutation. Its occurance is abnormal causing premature termination of protein translation and results in production of truncated and non-functional proteins. A nonsense mutation is one that converts an amino acid-specific codon to a stop codon.Escherichia coli: A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc.Sequence Homology, Amino Acid: The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.DNA-Binding Proteins: Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.Gene Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus.Cloning, Molecular: The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.Genes, Dominant: Genes that influence the PHENOTYPE both in the homozygous and the heterozygous state.DNA: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).Genes, Recessive: Genes that influence the PHENOTYPE only in the homozygous state.Sequence Alignment: The arrangement of two or more amino acid or base sequences from an organism or organisms in such a way as to align areas of the sequences sharing common properties. The degree of relatedness or homology between the sequences is predicted computationally or statistically based on weights assigned to the elements aligned between the sequences. This in turn can serve as a potential indicator of the genetic relatedness between the organisms.Suppression, Genetic: Mutation process that restores the wild-type PHENOTYPE in an organism possessing a mutationally altered GENOTYPE. The second "suppressor" mutation may be on a different gene, on the same gene but located at a distance from the site of the primary mutation, or in extrachromosomal genes (EXTRACHROMOSOMAL INHERITANCE).Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.Plasmids: Extrachromosomal, usually CIRCULAR DNA molecules that are self-replicating and transferable from one organism to another. They are found in a variety of bacterial, archaeal, fungal, algal, and plant species. They are used in GENETIC ENGINEERING as CLONING VECTORS.Chromosome Mapping: Any method used for determining the location of and relative distances between genes on a chromosome.Transfection: The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.Genes, p53: Tumor suppressor genes located on the short arm of human chromosome 17 and coding for the phosphoprotein p53.Genetic Testing: Detection of a MUTATION; GENOTYPE; KARYOTYPE; or specific ALLELES associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing.Genetic Complementation Test: A test used to determine whether or not complementation (compensation in the form of dominance) will occur in a cell with a given mutant phenotype when another mutant genome, encoding the same mutant phenotype, is introduced into that cell.DNA, Mitochondrial: Double-stranded DNA of MITOCHONDRIA. In eukaryotes, the mitochondrial GENOME is circular and codes for ribosomal RNAs, transfer RNAs, and about 10 proteins.Mutant Proteins: Proteins produced from GENES that have acquired MUTATIONS.Saccharomyces cerevisiae: A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement.Transcription, Genetic: The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.Bacterial Proteins: Proteins found in any species of bacterium.Promoter Regions, Genetic: DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes.Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Introns: Sequences of DNA in the genes that are located between the EXONS. They are transcribed along with the exons but are removed from the primary gene transcript by RNA SPLICING to leave mature RNA. Some introns code for separate genes.Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain).Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.Syndrome: A characteristic symptom complex.Ethylnitrosourea: A nitrosourea compound with alkylating, carcinogenic, and mutagenic properties.DNA, Neoplasm: DNA present in neoplastic tissue.RNA, Messenger: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.Genetic Variation: Genotypic differences observed among individuals in a population.Polymorphism, Genetic: The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level.Models, Genetic: Theoretical representations that simulate the behavior or activity of genetic processes or phenomena. They include the use of mathematical equations, computers, and other electronic equipment.Polymorphism, Restriction Fragment Length: Variation occurring within a species in the presence or length of DNA fragment generated by a specific endonuclease at a specific site in the genome. Such variations are generated by mutations that create or abolish recognition sites for these enzymes or change the length of the fragment.Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes.Genetic Linkage: The co-inheritance of two or more non-allelic GENES due to their being located more or less closely on the same CHROMOSOME.Kinetics: The rate dynamics in chemical or physical systems.Recombinant Fusion Proteins: Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes.Founder Effect: A phenomenon that is observed when a small subgroup of a larger POPULATION establishes itself as a separate and isolated entity. The subgroup's GENE POOL carries only a fraction of the genetic diversity of the parental population resulting in an increased frequency of certain diseases in the subgroup, especially those diseases known to be autosomal recessive.Heterozygote Detection: Identification of genetic carriers for a given trait.Mutagenesis, Insertional: Mutagenesis where the mutation is caused by the introduction of foreign DNA sequences into a gene or extragenic sequence. This may occur spontaneously in vivo or be experimentally induced in vivo or in vitro. Proviral DNA insertions into or adjacent to a cellular proto-oncogene can interrupt GENETIC TRANSLATION of the coding sequences or interfere with recognition of regulatory elements and cause unregulated expression of the proto-oncogene resulting in tumor formation.Genes: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.Recombination, Genetic: Production of new arrangements of DNA by various mechanisms such as assortment and segregation, CROSSING OVER; GENE CONVERSION; GENETIC TRANSFORMATION; GENETIC CONJUGATION; GENETIC TRANSDUCTION; or mixed infection of viruses.Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a CONSENSUS SEQUENCE. AMINO ACID MOTIFS are often composed of conserved sequences.COS Cells: CELL LINES derived from the CV-1 cell line by transformation with a replication origin defective mutant of SV40 VIRUS, which codes for wild type large T antigen (ANTIGENS, POLYOMAVIRUS TRANSFORMING). They are used for transfection and cloning. (The CV-1 cell line was derived from the kidney of an adult male African green monkey (CERCOPITHECUS AETHIOPS).)Genes, Lethal: Genes whose loss of function or gain of function MUTATION leads to the death of the carrier prior to maturity. They may be essential genes (GENES, ESSENTIAL) required for viability, or genes which cause a block of function of an essential gene at a time when the essential gene function is required for viability.Genetic Predisposition to Disease: A latent susceptibility to disease at the genetic level, which may be activated under certain conditions.Genes, Bacterial: The functional hereditary units of BACTERIA.Restriction Mapping: Use of restriction endonucleases to analyze and generate a physical map of genomes, genes, or other segments of DNA.Consanguinity: The magnitude of INBREEDING in humans.Signal Transduction: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.RNA Splicing: The ultimate exclusion of nonsense sequences or intervening sequences (introns) before the final RNA transcript is sent to the cytoplasm.Protein Structure, Secondary: The level of protein structure in which regular hydrogen-bond interactions within contiguous stretches of polypeptide chain give rise to alpha helices, beta strands (which align to form beta sheets) or other types of coils. This is the first folding level of protein conformation.Saccharomyces cerevisiae Proteins: Proteins obtained from the species SACCHAROMYCES CEREVISIAE. The function of specific proteins from this organism are the subject of intense scientific interest and have been used to derive basic understanding of the functioning similar proteins in higher eukaryotes.Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity.Proteins: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.Genes, Suppressor: Genes that have a suppressor allele or suppressor mutation (SUPPRESSION, GENETIC) which cancels the effect of a previous mutation, enabling the wild-type phenotype to be maintained or partially restored. For example, amber suppressors cancel the effect of an AMBER NONSENSE MUTATION.Family Health: The health status of the family as a unit including the impact of the health of one member of the family on the family as a unit and on individual family members; also, the impact of family organization or disorganization on the health status of its members.Gene Frequency: The proportion of one particular in the total of all ALLELES for one genetic locus in a breeding POPULATION.DNA, Complementary: Single-stranded complementary DNA synthesized from an RNA template by the action of RNA-dependent DNA polymerase. cDNA (i.e., complementary DNA, not circular DNA, not C-DNA) is used in a variety of molecular cloning experiments as well as serving as a specific hybridization probe.Proto-Oncogene Proteins B-raf: A raf kinase subclass found at high levels in neuronal tissue. The B-raf Kinases are MAP kinase kinase kinases that have specificity for MAP KINASE KINASE 1 and MAP KINASE KINASE 2.Temperature: The property of objects that determines the direction of heat flow when they are placed in direct thermal contact. The temperature is the energy of microscopic motions (vibrational and translational) of the particles of atoms.Genes, Fungal: The functional hereditary units of FUNGI.Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes.Exome: That part of the genome that corresponds to the complete complement of EXONS of an organism or cell.Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.Evolution, Molecular: The process of cumulative change at the level of DNA; RNA; and PROTEINS, over successive generations.Crosses, Genetic: Deliberate breeding of two different individuals that results in offspring that carry part of the genetic material of each parent. The parent organisms must be genetically compatible and may be from different varieties or closely related species.Cells, Cultured: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration.Mice, Mutant Strains: Mice bearing mutant genes which are phenotypically expressed in the animals.Chromosome Deletion: Actual loss of portion of a chromosome.Oligonucleotide Probes: Synthetic or natural oligonucleotides used in hybridization studies in order to identify and study specific nucleic acid fragments, e.g., DNA segments near or within a specific gene locus or gene. The probe hybridizes with a specific mRNA, if present. Conventional techniques used for testing for the hybridization product include dot blot assays, Southern blot assays, and DNA:RNA hybrid-specific antibody tests. Conventional labels for the probe include the radioisotope labels 32P and 125I and the chemical label biotin.Fungal Proteins: Proteins found in any species of fungus.Microsatellite Repeats: A variety of simple repeat sequences that are distributed throughout the GENOME. They are characterized by a short repeat unit of 2-8 basepairs that is repeated up to 100 times. They are also known as short tandem repeats (STRs).Genes, BRCA1: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human CHROMOSOME 17 at locus 17q21. Mutations of this gene are associated with the formation of HEREDITARY BREAST AND OVARIAN CANCER SYNDROME. It encodes a large nuclear protein that is a component of DNA repair pathways.Amino Acid Motifs: Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a CONSERVED SEQUENCE which can be represented by a CONSENSUS SEQUENCE.Cercopithecus aethiops: A species of CERCOPITHECUS containing three subspecies: C. tantalus, C. pygerythrus, and C. sabeus. They are found in the forests and savannah of Africa. The African green monkey (C. pygerythrus) is the natural host of SIMIAN IMMUNODEFICIENCY VIRUS and is used in AIDS research.RNA Splice Sites: Nucleotide sequences located at the ends of EXONS and recognized in pre-messenger RNA by SPLICEOSOMES. They are joined during the RNA SPLICING reaction, forming the junctions between exons.DNA, Bacterial: Deoxyribonucleic acid that makes up the genetic material of bacteria.Repressor Proteins: Proteins which maintain the transcriptional quiescence of specific GENES or OPERONS. Classical repressor proteins are DNA-binding proteins that are normally bound to the OPERATOR REGION of an operon, or the ENHANCER SEQUENCES of a gene until a signal occurs that causes their release.Blotting, Southern: A method (first developed by E.M. Southern) for detection of DNA that has been electrophoretically separated and immobilized by blotting on nitrocellulose or other type of paper or nylon membrane followed by hybridization with labeled NUCLEIC ACID PROBES.Gene Expression Regulation: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.INDEL Mutation: A mutation named with the blend of insertion and deletion. It refers to a length difference between two ALLELES where it is unknowable if the difference was originally caused by a SEQUENCE INSERTION or by a SEQUENCE DELETION. If the number of nucleotides in the insertion/deletion is not divisible by three, and it occurs in a protein coding region, it is also a FRAMESHIFT MUTATION.Tumor Suppressor Protein p53: Nuclear phosphoprotein encoded by the p53 gene (GENES, P53) whose normal function is to control CELL PROLIFERATION and APOPTOSIS. A mutant or absent p53 protein has been found in LEUKEMIA; OSTEOSARCOMA; LUNG CANCER; and COLORECTAL CANCER.Gene Expression: The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.Reverse Transcriptase Polymerase Chain Reaction: A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols.Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.HeLa Cells: The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for VIRUS CULTIVATION and antitumor drug screening assays.Escherichia coli Proteins: Proteins obtained from ESCHERICHIA COLI.Selection, Genetic: Differential and non-random reproduction of different genotypes, operating to alter the gene frequencies within a population.Eye ProteinsDrug Resistance, Microbial: The ability of microorganisms, especially bacteria, to resist or to become tolerant to chemotherapeutic agents, antimicrobial agents, or antibiotics. This resistance may be acquired through gene mutation or foreign DNA in transmissible plasmids (R FACTORS).Genes, ras: Family of retrovirus-associated DNA sequences (ras) originally isolated from Harvey (H-ras, Ha-ras, rasH) and Kirsten (K-ras, Ki-ras, rasK) murine sarcoma viruses. Ras genes are widely conserved among animal species and sequences corresponding to both H-ras and K-ras genes have been detected in human, avian, murine, and non-vertebrate genomes. The closely related N-ras gene has been detected in human neuroblastoma and sarcoma cell lines. All genes of the family have a similar exon-intron structure and each encodes a p21 protein.Drug Resistance, Viral: The ability of viruses to resist or to become tolerant to chemotherapeutic agents or antiviral agents. This resistance is acquired through gene mutation.Jews: An ethnic group with historical ties to the land of ISRAEL and the religion of JUDAISM.Sequence Homology, Nucleic Acid: The sequential correspondence of nucleotides in one nucleic acid molecule with those of another nucleic acid molecule. Sequence homology is an indication of the genetic relatedness of different organisms and gene function.Drosophila Proteins: Proteins that originate from insect species belonging to the genus DROSOPHILA. The proteins from the most intensely studied species of Drosophila, DROSOPHILA MELANOGASTER, are the subject of much interest in the area of MORPHOGENESIS and development.Nucleic Acid Conformation: The spatial arrangement of the atoms of a nucleic acid or polynucleotide that results in its characteristic 3-dimensional shape.Age of Onset: The age, developmental stage, or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual.Oligodeoxyribonucleotides: A group of deoxyribonucleotides (up to 12) in which the phosphate residues of each deoxyribonucleotide act as bridges in forming diester linkages between the deoxyribose moieties.Trans-Activators: Diffusible gene products that act on homologous or heterologous molecules of viral or cellular DNA to regulate the expression of proteins.DNA Repair: The reconstruction of a continuous two-stranded DNA molecule without mismatch from a molecule which contained damaged regions. The major repair mechanisms are excision repair, in which defective regions in one strand are excised and resynthesized using the complementary base pairing information in the intact strand; photoreactivation repair, in which the lethal and mutagenic effects of ultraviolet light are eliminated; and post-replication repair, in which the primary lesions are not repaired, but the gaps in one daughter duplex are filled in by incorporation of portions of the other (undamaged) daughter duplex. Excision repair and post-replication repair are sometimes referred to as "dark repair" because they do not require light.Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.Genetic Diseases, X-Linked: Genetic diseases that are linked to gene mutations on the X CHROMOSOME in humans (X CHROMOSOME, HUMAN) or the X CHROMOSOME in other species. Included here are animal models of human X-linked diseases.Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter.Retinitis Pigmentosa: Hereditary, progressive degeneration of the neuroepithelium of the retina characterized by night blindness and progressive contraction of the visual field.Mice, Transgenic: Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.RNA, Transfer, Leu: A transfer RNA which is specific for carrying leucine to sites on the ribosomes in preparation for protein synthesis.Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases IMMUNITY, and provides energy for muscle tissue, BRAIN, and the CENTRAL NERVOUS SYSTEM.Abnormalities, MultipleCell Transformation, Neoplastic: Cell changes manifested by escape from control mechanisms, increased growth potential, alterations in the cell surface, karyotypic abnormalities, morphological and biochemical deviations from the norm, and other attributes conferring the ability to invade, metastasize, and kill.Arginine: An essential amino acid that is physiologically active in the L-form.MELAS Syndrome: A mitochondrial disorder characterized by focal or generalized seizures, episodes of transient or persistent neurologic dysfunction resembling strokes, and ragged-red fibers on muscle biopsy. Affected individuals tend to be normal at birth through early childhood, then experience growth failure, episodic vomiting, and recurrent cerebral insults resulting in visual loss and hemiparesis. The cortical lesions tend to occur in the parietal and occipital lobes and are not associated with vascular occlusion. VASCULAR HEADACHE is frequently associated and the disorder tends to be familial. (From Joynt, Clinical Neurology, 1992, Ch56, p117)Virus Replication: The process of intracellular viral multiplication, consisting of the synthesis of PROTEINS; NUCLEIC ACIDS; and sometimes LIPIDS, and their assembly into a new infectious particle.Polymorphism, Single Nucleotide: A single nucleotide variation in a genetic sequence that occurs at appreciable frequency in the population.DNA Transposable Elements: Discrete segments of DNA which can excise and reintegrate to another site in the genome. Most are inactive, i.e., have not been found to exist outside the integrated state. DNA transposable elements include bacterial IS (insertion sequence) elements, Tn elements, the maize controlling elements Ac and Ds, Drosophila P, gypsy, and pogo elements, the human Tigger elements and the Tc and mariner elements which are found throughout the animal kingdom.Drosophila melanogaster: A species of fruit fly much used in genetics because of the large size of its chromosomes.Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer.ras Proteins: Small, monomeric GTP-binding proteins encoded by ras genes (GENES, RAS). The protooncogene-derived protein, PROTO-ONCOGENE PROTEIN P21(RAS), plays a role in normal cellular growth, differentiation and development. The oncogene-derived protein (ONCOGENE PROTEIN P21(RAS)) can play a role in aberrant cellular regulation during neoplastic cell transformation (CELL TRANSFORMATION, NEOPLASTIC). This enzyme was formerly listed as EC 3.6.1.47.DNA Gyrase: A bacterial DNA topoisomerase II that catalyzes ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands. Gyrase binds to DNA as a heterotetramer consisting of two A and two B subunits. In the presence of ATP, gyrase is able to convert the relaxed circular DNA duplex into a superhelix. In the absence of ATP, supercoiled DNA is relaxed by DNA gyrase.Gene Expression Regulation, Bacterial: Any of the processes by which cytoplasmic or intercellular factors influence the differential control of gene action in bacteria.Penetrance: The percent frequency with which a dominant or homozygous recessive gene or gene combination manifests itself in the phenotype of the carriers. (From Glossary of Genetics, 5th ed)Drug Resistance, Bacterial: The ability of bacteria to resist or to become tolerant to chemotherapeutic agents, antimicrobial agents, or antibiotics. This resistance may be acquired through gene mutation or foreign DNA in transmissible plasmids (R FACTORS).Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event.Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from GLYCINE or THREONINE. It is involved in the biosynthesis of PURINES; PYRIMIDINES; and other amino acids.Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.Mitochondrial Encephalomyopathies: A heterogenous group of disorders characterized by alterations of mitochondrial metabolism that result in muscle and nervous system dysfunction. These are often multisystemic and vary considerably in age at onset (usually in the first or second decade of life), distribution of affected muscles, severity, and course. (From Adams et al., Principles of Neurology, 6th ed, pp984-5)X Chromosome: The female sex chromosome, being the differential sex chromosome carried by half the male gametes and all female gametes in human and other male-heterogametic species.Genes, BRCA2: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human chromosome 13 at locus 13q12.3. Mutations in this gene predispose humans to breast and ovarian cancer. It encodes a large, nuclear protein that is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (from Genes Dev 2000;14(11):1400-6)CHO Cells: CELL LINE derived from the ovary of the Chinese hamster, Cricetulus griseus (CRICETULUS). The species is a favorite for cytogenetic studies because of its small chromosome number. The cell line has provided model systems for the study of genetic alterations in cultured mammalian cells.Models, Biological: Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.Loss of Heterozygosity: The loss of one allele at a specific locus, caused by a deletion mutation; or loss of a chromosome from a chromosome pair, resulting in abnormal HEMIZYGOSITY. It is detected when heterozygous markers for a locus appear monomorphic because one of the ALLELES was deleted.Tumor Cells, Cultured: Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.Codon, Terminator: Any codon that signals the termination of genetic translation (TRANSLATION, GENETIC). PEPTIDE TERMINATION FACTORS bind to the stop codon and trigger the hydrolysis of the aminoacyl bond connecting the completed polypeptide to the tRNA. Terminator codons do not specify amino acids.Eye Abnormalities: Congenital absence of or defects in structures of the eye; may also be hereditary.DNA, Viral: Deoxyribonucleic acid that makes up the genetic material of viruses.Ethyl Methanesulfonate: An antineoplastic agent with alkylating properties. It also acts as a mutagen by damaging DNA and is used experimentally for that effect.Protein Transport: The process of moving proteins from one cellular compartment (including extracellular) to another by various sorting and transport mechanisms such as gated transport, protein translocation, and vesicular transport.Mice, Inbred C57BLProtein Folding: Processes involved in the formation of TERTIARY PROTEIN STRUCTURE.Cysteine: A thiol-containing non-essential amino acid that is oxidized to form CYSTINE.Repetitive Sequences, Nucleic Acid: Sequences of DNA or RNA that occur in multiple copies. There are several types: INTERSPERSED REPETITIVE SEQUENCES are copies of transposable elements (DNA TRANSPOSABLE ELEMENTS or RETROELEMENTS) dispersed throughout the genome. TERMINAL REPEAT SEQUENCES flank both ends of another sequence, for example, the long terminal repeats (LTRs) on RETROVIRUSES. Variations may be direct repeats, those occurring in the same direction, or inverted repeats, those opposite to each other in direction. TANDEM REPEAT SEQUENCES are copies which lie adjacent to each other, direct or inverted (INVERTED REPEAT SEQUENCES).Drosophila: A genus of small, two-winged flies containing approximately 900 described species. These organisms are the most extensively studied of all genera from the standpoint of genetics and cytology.Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents.Cell Nucleus: Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)DNA, Fungal: Deoxyribonucleic acid that makes up the genetic material of fungi.Adenosine Triphosphatases: A group of enzymes which catalyze the hydrolysis of ATP. The hydrolysis reaction is usually coupled with another function such as transporting Ca(2+) across a membrane. These enzymes may be dependent on Ca(2+), Mg(2+), anions, H+, or DNA.HEK293 Cells: A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.Mitochondrial Diseases: Diseases caused by abnormal function of the MITOCHONDRIA. They may be caused by mutations, acquired or inherited, in mitochondrial DNA or in nuclear genes that code for mitochondrial components. They may also be the result of acquired mitochondria dysfunction due to adverse effects of drugs, infections, or other environmental causes.Viral Proteins: Proteins found in any species of virus.Operon: In bacteria, a group of metabolically related genes, with a common promoter, whose transcription into a single polycistronic MESSENGER RNA is under the control of an OPERATOR REGION.Genetic Heterogeneity: The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees. In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including ALZHEIMER DISEASE; CYSTIC FIBROSIS; LIPOPROTEIN LIPASE DEFICIENCY, FAMILIAL; and POLYCYSTIC KIDNEY DISEASES. (Rieger, et al., Glossary of Genetics: Classical and Molecular, 5th ed; Segen, Dictionary of Modern Medicine, 1992)Adaptor Proteins, Signal Transducing: A broad category of carrier proteins that play a role in SIGNAL TRANSDUCTION. They generally contain several modular domains, each of which having its own binding activity, and act by forming complexes with other intracellular-signaling molecules. Signal-transducing adaptor proteins lack enzyme activity, however their activity can be modulated by other signal-transducing enzymesCell Line, Tumor: A cell line derived from cultured tumor cells.Genes, Regulator: Genes which regulate or circumscribe the activity of other genes; specifically, genes which code for PROTEINS or RNAs which have GENE EXPRESSION REGULATION functions.Protein Stability: The ability of a protein to retain its structural conformation or its activity when subjected to physical or chemical manipulations.Phylogeny: The relationships of groups of organisms as reflected by their genetic makeup.Mitochondrial Myopathies: A group of muscle diseases associated with abnormal mitochondria function.Asian Continental Ancestry Group: Individuals whose ancestral origins are in the southeastern and eastern areas of the Asian continent.RNA: A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)Neoplasm Proteins: Proteins whose abnormal expression (gain or loss) are associated with the development, growth, or progression of NEOPLASMS. Some neoplasm proteins are tumor antigens (ANTIGENS, NEOPLASM), i.e. they induce an immune reaction to their tumor. Many neoplasm proteins have been characterized and are used as tumor markers (BIOMARKERS, TUMOR) when they are detectable in cells and body fluids as monitors for the presence or growth of tumors. Abnormal expression of ONCOGENE PROTEINS is involved in neoplastic transformation, whereas the loss of expression of TUMOR SUPPRESSOR PROTEINS is involved with the loss of growth control and progression of the neoplasm.Protein-Serine-Threonine Kinases: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors.RNA, Viral: Ribonucleic acid that makes up the genetic material of viruses.Charcot-Marie-Tooth Disease: A hereditary motor and sensory neuropathy transmitted most often as an autosomal dominant trait and characterized by progressive distal wasting and loss of reflexes in the muscles of the legs (and occasionally involving the arms). Onset is usually in the second to fourth decade of life. This condition has been divided into two subtypes, hereditary motor and sensory neuropathy (HMSN) types I and II. HMSN I is associated with abnormal nerve conduction velocities and nerve hypertrophy, features not seen in HMSN II. (Adams et al., Principles of Neurology, 6th ed, p1343)Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single ZYGOTE, as opposed to CHIMERISM in which the different cell populations are derived from more than one zygote.

Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation. (1/13935)

The aetiology of sporadic medullary thyroid carcinoma is unknown. About 50% harbour a somatic mutation at codon 918 of RET (M918T). To investigate whether other RET sequence variants may be associated with or predispose to the development of sporadic medullary thyroid carcinoma, we analysed genomic DNA from the germline and corresponding tumour from 50 patients to identify RET sequence variants. In one patient, tumour DNA showed a novel somatic 12 bp in-frame deletion in exon 15. More interestingly, we found that the rare polymorphism at codon 836 (c.2439C > T; S836S) occurred at a significantly higher frequency than that in control individuals without sporadic medullary thyroid carcinoma (Fisher's exact test, P = 0.03). Further, among the nine evaluable cases with germline c.2439C/T, eight also had the somatic M918T mutation in MTC DNA which was more frequent than in patients with the more common c.2439C/C (89% vs 40%, respectively; Fisher's exact test, P = 0.01). These findings suggest that the rare sequence variant at codon 836 may somehow play a role in the genesis of sporadic medullary thyroid carcinoma.  (+info)

Cooperative binding of heat shock factor to the yeast HSP82 promoter in vivo and in vitro. (2/13935)

Previous work has shown that heat shock factor (HSF) plays a central role in remodeling the chromatin structure of the yeast HSP82 promoter via constitutive interactions with its high-affinity binding site, heat shock element 1 (HSE1). The HSF-HSE1 interaction is also critical for stimulating both basal (noninduced) and induced transcription. By contrast, the function of the adjacent, inducibly occupied HSE2 and -3 is unknown. In this study, we examined the consequences of mutations in HSE1, HSE2, and HSE3 on HSF binding and transactivation. We provide evidence that in vivo, HSF binds to these three sites cooperatively. This cooperativity is seen both before and after heat shock, is required for full inducibility, and can be recapitulated in vitro on both linear and supercoiled templates. Quantitative in vitro footprinting reveals that occupancy of HSE2 and -3 by Saccharomyces cerevisiae HSF (ScHSF) is enhanced approximately 100-fold through cooperative interactions with the HSF-HSE1 complex. HSE1 point mutants, whose basal transcription is virtually abolished, are functionally compensated by cooperative interactions with HSE2 and -3 following heat shock, resulting in robust inducibility. Using a competition binding assay, we show that the affinity of recombinant HSF for the full-length HSP82 promoter is reduced nearly an order of magnitude by a single-point mutation within HSE1, paralleling the effect of these mutations on noninduced transcript levels. We propose that the remodeled chromatin phenotype previously shown for HSE1 point mutants (and lost in HSE1 deletion mutants) stems from the retention of productive, cooperative interactions between HSF and its target binding sites.  (+info)

The alphaE-catenin gene (CTNNA1) acts as an invasion-suppressor gene in human colon cancer cells. (3/13935)

The acquisition of invasiveness is a crucial step in the malignant progression of cancer. In cancers of the colon and of other organs the E-cadherin/catenin complex, which is implicated in homotypic cell-cell adhesion as well as in signal transduction, serves as a powerful inhibitor of invasion. We show here that one allele of the alphaE-catenin (CTNNA1) gene is mutated in the human colon cancer cell family HCT-8, which is identical to HCT-15, DLD-1 and HRT-18. Genetic instability, due to mutations in the HMSH6 (also called GTBP) mismatch repair gene, results in the spontaneous occurrence of invasive variants, all carrying either a mutation or exon skipping in the second alphaE-catenin allele. The alphaE-catenin gene is therefore, an invasion-suppressor gene in accordance with the two-hit model of Knudsen for tumour-suppressor genes.  (+info)

Correlation between the status of the p53 gene and survival in patients with stage I non-small cell lung carcinoma. (4/13935)

The association of p53 abnormalities with the prognosis of patients with non-small cell lung carcinoma (NSCLC) has been extensively investigated to date, however, this association is still controversial. Therefore, we investigated the prognostic significance of p53 mutations through exons 2 to 11 and p53 protein expression in 103 cases of stage I NSCLC. p53 mutations were detected in 49 of 103 (48%) tumors. Two separate mutations were detected in four tumors giving a total of 53 unique mutations in 49 tumors. Ten (19%) of mutations occurred outside exons 5-8. Positive immunohistochemical staining of p53 protein was detected in 41 of 103 (40%) tumors. The concordance rate between mutations and protein overexpression was only 69%. p53 mutations, but not expression, were significantly associated with a shortened survival of patients (P<0.001). Furthermore, we investigated the correlation between the types of p53 mutations and prognosis. p53 missense mutations rather than null mutations were associated with poor prognosis (P < 0.001 in missense mutations and P=0.243 in null mutations). These results indicated that p53 mutations, in particular missense mutations, rather than p53 expression could be a useful molecular marker for the prognosis of patients with surgically resected stage I NSCLC.  (+info)

p73 at chromosome 1p36.3 is lost in advanced stage neuroblastoma but its mutation is infrequent. (5/13935)

p73, a novel p53 family member, is a recently identified candidate neuroblastoma (NBL) suppressor gene mapped at chromosome 1p36.33 and was found to inhibit growth and induce apoptosis in cell lines. To test the hypothesis that p73 is a NBL suppressor gene, we analysed the p73 gene in primary human NBLs. Loss of heterozygosity (LOH) for p73 was observed in 19% (28/151) of informative cases which included 92 mass-screening (MS) tumors. The high frequency of p73 LOH was significantly associated with sporadic NBLs (9% vs 34%, P<0.001), N-myc amplification (10% vs 71%, P<0.001), and advanced stage (14% vs 28%, P<0.05). Both p73alpha and p73beta transcripts were detectable in only 46 of 134 (34%) NBLs at low levels by RT-PCR methods, while they were easily detectable in most breast cancers and colorectal cancers under the same conditions. They found no correlation between p73 LOH and its expression levels (P>0.1). We found two mutations out of 140 NBLs, one somatic and one germline, which result in amino acid substitutions in the C-terminal region of p73 which may affect transactivation functions, though, in the same tumor samples, no mutation of the p53 gene was observed as reported previously. These results suggest that allelic loss of the p73 gene may be a later event in NBL tumorigenesis. However, p73 is infrequently mutated in primary NBLs and may hardly function as a tumor suppressor in a classic Knudson's manner.  (+info)

RNA binding by the novel helical domain of the influenza virus NS1 protein requires its dimer structure and a small number of specific basic amino acids. (6/13935)

The RNA-binding/dimerization domain of the NS1 protein of influenza A virus (73 amino acids in length) exhibits a novel dimeric six-helical fold. It is not known how this domain binds to its specific RNA targets, one of which is double-stranded RNA. To elucidate the mode of RNA binding, we introduced single alanine replacements into the NS1 RNA-binding domain at specific positions in the three-dimensional structure. Our results indicate that the dimer structure is essential for RNA binding, because any alanine replacement that causes disruption of the dimer also leads to the loss of RNA-binding activity. Surprisingly, the arginine side chain at position 38, which is in the second helix of each monomer, is the only amino-acid side chain that is absolutely required only for RNA binding and not for dimerization, indicating that this side chain probably interacts directly with the RNA target. This interaction is primarily electrostatic, because replacement of this arginine with lysine had no effect on RNA binding. A second basic amino acid, the lysine at position 41, which is also in helix 2, makes a strong contribution to the affinity of binding. We conclude that helix 2 and helix 2', which are antiparallel and next to each other in the dimer conformation, constitute the interaction face between the NS1 RNA-binding domain and its RNA targets, and that the arginine side chain at position 38 and possibly the lysine side chain at position 41 in each of these antiparallel helices contact the phosphate backbone of the RNA target.  (+info)

A concise promoter region of the heart fatty acid-binding protein gene dictates tissue-appropriate expression. (7/13935)

The heart fatty acid-binding protein (HFABP) is a member of a family of binding proteins with distinct tissue distributions and diverse roles in fatty acid metabolism, trafficking, and signaling. Other members of this family have been shown to possess concise promoter regions that direct appropriate tissue-specific expression. The basis for the specific expression of the HFABP has not been previously evaluated, and the mechanisms governing expression of metabolic genes in the heart are not completely understood. We used transient and permanent transfections in ventricular myocytes, skeletal myocytes, and nonmyocytic cells to map regulatory elements in the HFABP promoter, and audited results in transgenic mice. Appropriate tissue-specific expression in cell culture and in transgenic mice was dictated by 1.2 kb of the 5'-flanking sequence of FABP3, the HFABP gene. Comparison of orthologous murine and human genomic sequences demonstrated multiple regions of near-identity within this promoter region, including a CArG-like element close to the TATA box. Binding and transactivation studies demonstrated that this element can function as an atypical myocyte enhancer-binding factor 2 site. Interactions with adjacent sites are likely to be necessary for fully appropriate, tissue-specific, developmental and metabolic regulation.  (+info)

The DNA binding activity of Translin is mediated by a basic region in the ring-shaped structure conserved in evolution. (8/13935)

DNA binding proteins, for the most part, function as dimers or tetramers which recognize their target sequences. Here we show that Translin, a novel single-stranded DNA end binding protein, forms a ring-shaped structure conserved throughout evolution and that this structure is responsible for its DNA binding activity. Point mutations at Leu184 and Leu191 in the leucine zipper motif of human Translin resulted in loss of the multimeric structure and abrogation of DNA binding. Point mutations at R86, H88, H90 to T86, N88, N90 in one of the basic regions, however, completely inhibited the DNA binding activity without affecting the multimeric structure. These results support the view that the DNA binding domain of Translin is formed in the ring-shaped structure in combination with its basic region (amino acids 86-97) polypeptides.  (+info)

  • When a mutation is fixed, it is automatically passed on to every succeeding generation with probability 1.0 (unless there is a ``back mutation'' that changes the locus back to its original form, but this is a very rare event). (ornl.gov)
  • According to the constitutive activity hypothesis for G-protein coupling receptors, we inferred that point mutations might possibly exsit in the third intracellular loop of alpha 1B- and/or alpha 1D-adrenergic receptor (AR), the main subtypes of alpha 1-AR mediating phosphatidylinositol hydrolysis in SHR aortae. (mysciencework.com)
  • A point mutation can either be in a specific location of the DNA or it can give rise to the change in a specific position of a critical viral protein. (peoplesdispatch.org)
  • A change of a single base in the DNA or a single amino acid of a protein - the hallmark of point mutation - can bring in huge change in terms of physiology, infectivity and severity of a microorganism, and for that matter, in any organism. (peoplesdispatch.org)
  • that is, both alleles are mutant, but in spite of previous reports it remains debatable irrespective of whether a heterozygous mutation can cause or improve the danger of PD .In , Hedrich et al. (idhinhibitor.com)
  • A single point mutation, G442R, resulted in a mutant displaying an a(1~2) regioselectivity. (ac.ke)
  • Most scientists who study brain conditions such as Parkinson's naturally focus on the brain, but new research from the Van Andel Research Institute in Michigan shows that the obvious starting point is not the only way to go. (parkinsonsnewstoday.com)
  • In the study "Enrichment of risk SNPs in regulatory regions implicate diverse tissues in Parkinson's disease etiology," published in the journal Scientific Report s, scientists now say that collections of small DNA mutations, linked to the risk of Parkinson's, can be found in liver, fat, immune, and developmental cells. (parkinsonsnewstoday.com)
  • It can be a useful tool for other research groups, and could be especially important for recruitment of patients with GBA mutations to clinical trials, because this method, unlike other methods, will be able to identify all forms of GBA mutations. (michaeljfox.org)
  • When a mutation enters the population, it occurs in only one individual and is plotted as a point somewhere on the x axis. (ornl.gov)
  • If by chance the mutation continues to spread in each successive generation, it may reach a point when it occurs in every individual, i.e. it becomes fixed. (ornl.gov)
  • Lundin, Erik;Tang, Po-Cheng;Guy, Lionel;Näsvall, Joakim;Andersson, Dan I 2018-03-01 00:00:00 Abstract The distribution of fitness effects of mutations is a factor of fundamental importance in evolutionary biology. (deepdyve.com)
  • Using the MMRF CoMMpass (NCT0145429) study (IA13), we determined the frequency of nonsynonymous coding mutations in the BCL2 family. (bloodjournal.org)
  • Voets, together with his colleague Joris Vriens (KU Leuven) and their team at the Laboratory for Ion Channel Research, could show that both mutations affect TRPM3 channel gating. (vib.be)
  • Comparisons with other Drosophila mutant phenotypes suggests potential CAM targets that may mediate these developmental and behavioral effects, and analysis of the CAM crystal structure suggests the structural consequences of the individual mutations. (genetics.org)
  • This study indicates that mutations in obligate symbionts can have major consequences for host fitness and geographic distributions. (pubmedcentralcanada.ca)
  • Since the functional consequences of the mutations remained elusive, we set out to understand how disturbances of this particular ion channel can cause intellectual disability and epileptic seizures. (vib.be)
  • We here investigated, in vitro and in silico, the biophysical consequences of clinically-observed Wilson disease mutations, G85V in MBD1 and G591D in MBD6, incorporated in domain 4. (diva-portal.org)
  • Two studies highlighted the higher potency of repotrectinib as compared to other proxy investigational and the currently approved ROS1 and TRK tyrosine kinase inhibitors (TKIs), Xalkori and Vitrakvi, against fusion ROS1s, wildtype TRK, and many resistance mutations, including solvent front, gatekeeper, and compound mutations. (businesswire.com)
  • Specifically, Dr. Russell described the QuantStudio™ 3D rare mutation analysis solution's subset of 38 wet lab-validated TaqMan ® SNP Genotyping Assays for use in detecting and quantifying rare somatic mutations, e.g. (thermofisher.com)
  • Understanding the specific mutations that trigger signals in cell receptors to stimulate cell growth will help us identify biomarkers for specific subtypes of neuroblastoma," said study co-leader Mark A. Lemmon, PhD, professor and chair of Biochemistry and Biophysics at Penn. (oncologynurseadvisor.com)
  • Furthermore, specific mutations that occur as a result of a recombination between the gene and the pseudogene are often missed by the traditional genetic methods. (michaeljfox.org)
  • Whereas the individual effects of both mutations differ, both can be considered as strong gain-of-function mutants, with increased activity, both under basal conditions and when stimulated," says Voets. (vib.be)
  • This study was aimed at analyzing the functional relevance of these two ABCB4 mutations: MDR3 expression and lipid content in the culture supernatant were evaluated in cell lines stably transfected with the ABCB4 wild-type clone and corresponding mutants. (uniprot.org)
  • Moreover, antibodies reactive with antigenic region F (aa 235 to 242) of VP7 might also be involved since cross-reactivity to serotype G3 was decreased in double mutants carrying an additional mutation, which creates a potential glycosylation site at position 238. (asm.org)
  • We determined the distribution of fitness effects of 510 mutants that each carried between 1 and 10 mutations (synonymous and nonsynonymous) in the hisA gene, encoding an essential enzyme in the l-histidine biosynthesis pathway of Salmonella enterica. (deepdyve.com)
  • For the full set of mutants, the distribution was bimodal with many apparently neutral mutations and many lethal mutations. (deepdyve.com)
  • For a subset of 81 single, nonsynonymous mutants most mutations appeared neutral at high expression levels, whereas at low expression levels only a few mutations were neutral. (deepdyve.com)
  • Three different class I LamB missense mutants (mutations at sites 247, 245, and 148) were used to select 11 independent, new, one-step host range mutants (lambda h phages). (pasteur.fr)
  • and (iv) no single sequence-based predictor could confidently predict the fitness effects of mutations in HisA, but a combination of multiple predictors could predict the effect with a SD of 0.04 resulting in 80% of the mutations predicted within 12% of their observed selection coefficients. (deepdyve.com)
  • Whatever your ethnicity or your race, if you have a high-risk profile -- that is, early breast cancer -- it predicts the likelihood of genetic mutations across all ethnicities and races," said Dr. Jeffrey N. Weitzel, director of the department of clinical cancer genetics at the City of Hope Comprehensive Cancer Center, in Duarte, Calif. (bio-medicine.org)
  • Mayo Clinic researchers are using precision genomics to search for undiscovered, inheritable genetic mutations that cause accelerated aging. (laboratoryequipment.com)
  • Not to destroy, but to zero in on genetic mutations that may be linked with short telomere and other inherited bone marrow failure syndromes, providing unique insights into their disease biology. (laboratoryequipment.com)
  • Certain genetic mutations are known to be associated with short telomeres. (laboratoryequipment.com)
  • 2015). Fitness landscapes are vast and have as many dimensions as there are possible mutations in a system (de Visser and Krug 2014). (deepdyve.com)
  • However, from a synthetic biology point of view, such a boosted-stress resistance gene represents a useful BioBrick (or building block) for the design of more physiologically robust probiotics or, indeed, plants that are more resistant to cold arid conditions. (science20.com)
  • Ouabain-resistance test detecting mutations in the Na + /K + ATPase was used to investigate the effect of BCR/ABL kinase-mediated inhibition of MMR on mutagenesis. (aacrjournals.org)
  • overall, point mutations in the kinase domain of BCR/ABL have been detected in 50% to 90% of patients with acquired resistance to imatinib, including ∼23% of the imatinib-naive patients ( 3 ). (aacrjournals.org)
  • High-level Cip r (MIC ≥ 64 μg/ml) due to point mutations in the quinolone resistance-determining region was unique to a distinct hospital-adapted genetic complex in E. faecium , previously designated CC17. (asm.org)
  • Acquisition of mutations in parC and gyrA , leading to high-level Cip r , is, in addition to ampicillin resistance and the presence of a putative pathogenicity island, another cumulative step in hospital adaptation of CC17. (asm.org)
  • In the present study, we report a Thai female with a de novo mutation in thyroid hormone receptor-beta (TRbeta) gene causing resistance to thyroid hormone (RTH). (eurekamag.com)
  • Background - Point mutations in the BCR-ABL kinase domain are associated with resistance to TKI therapy. (linkos.cz)
  • Assessing in how many CML patients with failure and warning mutations can be identified, especially now that more sensitive NGS-based mutation screening methods are available, would advance our knowledge of the biology of TKI resistance as well as contribute useful data to revise the ELN recommendations as to when and how BCR-ABL mutation analysis should be performed. (linkos.cz)
  • The counter-selection system takes advantage of the fact that mutations within rpsL leading to streptomycin resistance are recessive in a merodiploid strain. (biomedcentral.com)
  • LamB missense mutations yielding resistance to lambda group in two classes. (pasteur.fr)
  • This mutation impaired Tat responsiveness of the LTR in transient transfection assays, and the measured defect was complemented in cells that had been treated with tetradecanoyl phorbol acetate or tumor necrosis factor type alpha (TNF-alpha). (pnas.org)
  • In the ongoing TRIDENT-1 clinical trial repotrectinib was active against the solvent front mutation ETV6-TRKC G623E in an entrectinib-resistant patient with a salivary gland tumor (-82%, confirmed partial response, RECIST v1.1). (businesswire.com)
  • In the second tumor, 6139B-PRO, both alleles of the L26 gene have point mutations, and each encodes a different tumor-specific CD4 + T cell-recognized antigen. (rupress.org)
  • In some instances, a somatic mutation encoding a tumor-specific antigen is believed to contribute to the development of cancer ( 4 )( 6 )( 7 )( 8 ). (rupress.org)
  • On the other hand, it is also known that the p53 tumor suppressor gene plays an important role in restriction of abnormal cell proliferation and that loss of this safeguard function induced by its mutation may be a key factor in carcinogenesis. (aacrjournals.org)
  • An international group of researchers led by those at Baylor College of Medicine has analyzed the 42 mutations in FOXF1 in DNA from infants with the disorder and in a report that appears in the journal Human Mutation recommends that genetic testing be considered in infants with persistent pulmonary arterial hypertension with no known cause. (bcm.edu)
  • The researchers have identified a single point mutation (out of a total of 3 million or so nucleotides that constitute the entire listerial genome), which dramatically improves the growth of the pathogen in the refrigerator. (science20.com)
  • WEDNESDAY, Dec. 26 (HealthDay News) -- The gene mutation BRCA1, which is known to increase the risk of breast cancer, is prevalent among Hispanics and young black women with breast cancer, researchers report. (bio-medicine.org)
  • The mutation is known to heighten the risk for Ashkenazi Jews, so the new ethnic findings are something of a surprise, the California researchers noted. (bio-medicine.org)
  • The researchers found that Ashkenazi women with breast cancer had the highest rate of the BRCA1 mutation, at 8.3 percent. (bio-medicine.org)
  • The researchers speculate that Sephardic Jews, who settled in Spain, could have shared the mutation with Ashkenazi Jews, who settled in central and Eastern Europe. (bio-medicine.org)
  • Researchers have now elucidated how both independent mutations affect the channel's function: by making it overly active and highly sensitive to stimulation. (vib.be)
  • Researchers are now able to detect low-frequency mutations by combining TaqMan™ fluorogenic 5' nuclease chemistry with dPCR methodology using the QuantStudio™ 3D Digital PCR System . (thermofisher.com)
  • Researchers analyzed pretreatment GIST samples for mutations from 377 patients in the trial. (cancernetwork.com)
  • The researchers also investigated which ALK mutations were more sensitive to crizotinib in cell cultures. (oncologynurseadvisor.com)
  • Boston, MA - Researchers say they have discovered a gene mutation that slows the metabolism of sugar in the gut, giving people who have the mutation a distinct advantage over those who do not. (mindzilla.com)
  • The researchers say their finding could provide the basis for drug therapies that could mimic the workings of this gene mutation, offering a potential benefit for the millions of people who suffer with diabetes, heart disease, and obesity. (mindzilla.com)
  • In the study, the researchers analyzed the relationship between SGLT-1 mutations and cardiometabolic disease using genetic data obtained from 8,478 participants in the Atherosclerosis Risk In Communities (ARIC) study. (mindzilla.com)
  • The researchers found that about 6 percent of the subjects carried a mutation in SGLT-1 that causes limited impairment of glucose absorption. (mindzilla.com)
  • One of these mutations produces a striking pupal lethal phenotype involving failure of head eversion. (genetics.org)
  • BCR/ABL-positive cells surviving the treatment with MNNG displayed ∼15-fold higher mutation frequency than parental counterparts and predominantly G:C→A:T and A:T→G:C mutator phenotype typical for MNNG-induced unrepaired lesions. (aacrjournals.org)
  • These two mutations also provide the first genetic evidence that link TRPM3 to a pain phenotype in humans," adds Vriens. (vib.be)
  • Mutations T1031A and T1040C in one of the WD40 repeats of Eed, which account for the hypomorphic and lethal phenotype of eed in mouse development, blocked binding of Ezh2 to Eed in a two-hybrid interaction in yeast and in mammalian cells. (asm.org)
  • Recombination experiments confirmed that in the cases tested, the mutations identified were indeed responsible for the extended host range phenotype. (pasteur.fr)
  • The predictive power of MAESTRO for single point mutations and stabilizing disulfide bonds is comparable to similar methods. (nih.gov)
  • The prediction error is defined as the absolute difference between the experimental determined Δ Δ G and the predicted Δ Δ G. Data are given for the three main single point mutation sets (SP1, SP3, SP4) as well as the multi-point mutation set (MP). (nih.gov)
  • from a food safety perspective, a single point mutation with the potential to induce such dramatic shifts in cell growth and survival at low temperatures-making an already dangerous pathogen even more formidable-raises significant food-safety concerns which need to be addressed. (science20.com)
  • The paper, "A single point mutation in the listerial betL σA-dependent promoter leads to improved osmo- and chill-tolerance and a morphological shift at elevated osmolarity," will be published in the November/December 2013 issue of Bioengineered but is available open access now . (science20.com)
  • A single-point mutation, V328A, turn the (S)-selective omega-transaminase into an (R)-selective enzyme. (diva-portal.org)
  • Single point mutations may affect the serotype reactivity of serotype G11 porcine rotavirus strains: a widening spectrum? (asm.org)
  • 1. "We used a series of regional replacements and single-point mutations, coupled with functional analyses, to demonstrate that two single-point mutations located in the transmembrane regions of the molecule together determine their ligand selectivity. (elifesciences.org)
  • 1. "Its ortholog HarmOr14b is specific for Z9-14:Ald in H. armigera and we further demonstrate that two single-point mutations, F232I and T355I, located in the transmembrane domains of the receptor, together determine the functional shift between orthologs in the two closely related species. (elifesciences.org)
  • 4. "We systematically identify two single-point mutations, F232I and T355I, located in the transmembrane regions of HassOr14b that together determine the functional shift to its ortholog, HarmOr14b, in H. armigera . (elifesciences.org)
  • A single point mutation of the negatively charged pore loop (P-loop) glutamate (E342) to either a positively charged lysine or arginine resulted in functional channels, which consistently responded to cGMP, although the currents were generally extremely small. (rupress.org)
  • We used Red ® /ET ® Recombination in combination with rpsL counter-selection to introduce a single point mutation into the E. coli MG1655 genome, one of the widely used bacterial model strains in systems biology. (biomedcentral.com)
  • We used rpsL counter-selection in combination with Red ® /ET ® Recombination to introduce a single point mutation into the kdpA gene locus of the MG1655 strain genome. (biomedcentral.com)
  • Introduction of a single point mutation into kdpA was chosen to demonstrate rpsL based counter-selection in combination with Red ® /ET ® Recombination on the E. coli chromosome. (biomedcentral.com)
  • Together with TaqMan ® SNP Genotyping Assays , the resulting QuantStudio™ 3D rare mutation analysis solution helps achieve the high levels of performance required to detect and absolutely quantify mutations present at a very low frequency. (thermofisher.com)
  • Dr. Iain Russell, Sr. Product Manager for TaqMan ® Assays , spoke of the most recent QuantStudio™ 3D enhancements to benefit rare mutation analysis in an interview at the American Society for Human Genetics (ASHG) 2014 annual meeting. (thermofisher.com)
  • Functional studies, including chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays and Surface Plasmon Resonance analysis, of the GDF5 W-414R variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gain-and loss-of-function at the same time. (uni-wuerzburg.de)
  • We recently described a family with neurological findings similar to HSAN (Hereditary sensory and autonomic neuropathy) type V having a point mutation in the Nerve growth factor beta (NGFB) gene. (bmj.com)
  • Point mutations affecting PMP22 can cause hereditary demyelinating and dysmyelinating peripheral neuropathies. (uzh.ch)
  • CGH analysis and VHL mutation analysis of sporadic and hereditary hemangioblastomas point to genetic heterogeneity. (ru.nl)
  • The importance of the TRPV4 channel for human physiology has been highlighted in recent years with the identification of an increasing number of hereditary diseases associated with mutations of this channel. (kuleuven.be)
  • Using gene-targeting technology, we generated mice harboring a subtle point mutation (N265M) in the second transmembrane region of the beta3 subunit of the GABA(A) receptor. (uzh.ch)
  • Coexpression of the A53T and E46K mutations was unable to rescue MSA prion infection in vitro, establishing that MSA α-synuclein prions are conformationally distinct from the misfolded α-synuclein in PD patients. (pnas.org)
  • A male infertility-linked human PLCζ (phospholipase Cζ) mutation introduced into mouse PLCζ completely abolishes both in vitro PIP 2 (phosphatidylinositol 4,5-bisphosphate) hydrolysis activity and the ability to trigger in vivo Ca 2+ oscillations in mouse eggs. (portlandpress.com)
  • In the exhaustive study of 42 new FOXF1 mutations in patients with this disorder, most were sporadic and not inherited from parents. (bcm.edu)
  • DGGE screening of 32 apparently unrelated heterozygous FH patients revealed 16 unique different aberrant DGGE patterns in 27 patients, while in a group of 32 normal subjects none of these DGGE patterns could be observed, suggesting that the aberrant patterns represent disease-causing mutations. (tudelft.nl)
  • Analysis of baseline samples from 982 patients revealed that mutations in the BCL2 family are relatively rare events. (bloodjournal.org)
  • Mutational analysis of the PMP22 coding region in two unrelated Dejerine-Sottas patients identified individual missense point mutations present in the heterozygous state. (biomedsearch.com)
  • 26 patients heterozygous for the NGFB-mutation (12 men, mean age 50 (13-90) years) were examined clinically and answered a health status questionnaire, including the Michigan Neuropathy Screening Instrument (MNSI). (bmj.com)
  • However, only about 40 percent of patients with short telomeres have one of these known mutations. (laboratoryequipment.com)
  • The team discovered ALK mutations in 8% of the tumors, with a higher rate among tumors from older patients and those with high-risk neuroblastoma. (oncologynurseadvisor.com)
  • This will allow easier diagnosis of patients with Parkinson s disease due to mutations in this gene. (michaeljfox.org)
  • It can be a useful tool for other research groups, and could be especially important for recruitment of patients with GBA mutations to clinical trials, because this method, unlike other methods, will be able to identify all forms of GBA mutations. (michaeljfox.org)
  • METHODS 23 patients with FMF and ESRD were analysed for their MEFV mutations and correlated with their corresponding rectal and renal biopsies. (bmj.com)
  • Our findings imply that reduced stability and enhanced dynamics of MBD1 or MBD6 is the origin of ATP7B dysfunction in Wilson disease patients with the G85V or G591D mutation. (diva-portal.org)
  • BCR-ABL Mutations in Chronic Myeloid Leukemia (CML) Patients (pts) with Failure and Warning to First- and Second-Line Tyrosine Kinase Inhibitor (TKI) Therapy: What Is the Advantage of Next-Generation Sequencing (NGS) over Conventional Sequencing? (linkos.cz)
  • CODE PK', vers un registre national des patients déficitaires en pyruvate kinase intraérythrocytaire. (semanticscholar.org)
  • MPL mutations were identified in 8.5% of JAK2 V617F(-) patients and a single V617F(+) patient. (ox.ac.uk)
  • Compared with V617F(-) patients, those with MPL mutations were older with reduced bone marrow cellularity but could not be identified as a discrete clinicopathologic subgroup. (ox.ac.uk)
  • In both mouse and man the mutations lie within the dystrophin gene, but the phenotypic differences of the disease in the two species confer much interest on the molecular basis of the mdx mutation. (sciencemag.org)
  • Consequently, our study assembles another part of the molecular puzzle of how loss and gain of function mutations in GDF5 affect bone development in hands and feet resulting in specific types of brachydactyly and SYNS2. (uni-wuerzburg.de)
  • Molecular dynamic simulations demonstrated that the mutations increased backbone fluctuations that extended throughout the domain. (diva-portal.org)
  • Point mutation in the pribnow box, the molecular basis of beta-lactamase overproduction in Klebsiella oxytoca. (asm.org)
  • In particular, non-optimal achievement of the key molecular response milestones (10%, 1%, 0.1%) on 1st-line therapy was mostly not associated with BCR-ABL mutations, indicating that other mechanisms of molecular disease persistence have to be investigated in an attempt to optimize therapeutic outcomes. (linkos.cz)
  • The influence of p53 status on the efficiency of the principal steps of this repair pathway was investigated after UV-C irradiation in the human ovarian carcinoma cell line IGROV-1 (expressing wild-type p53) and in the derived clone IGROV-1/Pt1 (with p53 mutations at codons 270 and 282). (tudelft.nl)
  • Repotrectinib was found to have 10-fold or higher increased potency when compared to proxy investigational and the currently approved TRK inhibitors against wildtype (WT) TRK fusions and solvent-front mutations. (businesswire.com)
  • However, we began to functionally characterize these mutations by taking advantage of an anomaly in the development of inhibitors of human MCL1. (bloodjournal.org)
  • Access to time- and tissue-restricted point mutant models. (genoway.com)
  • 10 As a result of this mutation, about 20% of the mutant pre-mRNAs are processed at the normal splice site, whereas the remaining 80% are spliced at cryptic sites. (bloodjournal.org)
  • point mutation in Pmp22) mutant mice were analyzed at two developmental stages: (i) at postnatal day (P)4, when normal myelination has just started and primary causative defects of the mutations are expected to be apparent, and (ii) at P60, with the goal of obtaining information on secondary disease effects. (uzh.ch)
  • E. coli strain PPA305, which has a wild-type PTS system, and PPA316, which utilizes a proton-galactose symport system for glucose uptake, were used as host strains to harbor a phenylalanine overprodn. (epfl.ch)
  • 2. Several recombinants were picked from matings between a single F − p + strain and Hfr strains carrying mutations L8 and L29. (biochemj.org)
  • 5. The same diploid strains were used in experiments to show whether mutations L8 and L29 alleviate the severe catabolite repression caused by growth in glucose plus gluconate. (biochemj.org)
  • Instead, both mutations caused a reduction of phosphatidylcholine secretion compared with the wild-type transfected cell lines. (uniprot.org)
  • Due to the complexity of the biosynthesis, assembly and secretion, collagen II is highly susceptible to mutations leading to disease states which are broadly classified as chondrodysplasias. (uni-koeln.de)