SEARCH · PubMed Health

Results for “Mutations”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources

PubMed1992

X-ray-induced specific-locus mutations in the ad-3 region of two-component heterokaryons of Neurospora crassa. XI. Heterozygous effects of gene/point mutations of genotype ad-3A or ad-3B.

Previous studies on X-ray-induced irreparable adenine-3 mutants (designated ad-3IR), induced in heterokaryon 12 of Neurospora crassa, showed that they were not recessive, and that they demonstrated heterozygous effects in terms of markedly reduced linear growth rates as compared with a wild-type control (de Serres, 1965, 1988). Homology tests on X-ray-induced irreparable mutants showed that they map, in the main part, as a series of overlapping multilocus deletions that extend both proximally and distally into the immediately adjacent genetic regions, as well as into the 'X' region (a region of unknown, but essential, function) between ad-3A and ad-3B (de Serres, 1969, 1989a). Studies on a larger sample of X-ray-induced multilocus deletion mutations of genotype (ad-3A)IR or (ad-3B)IR (de Serres et al., 1992) demonstrated that heterozygous effects are allele specific and that there was no correlation with genotype, radiation dose or complementation map position. Furthermore, the heterozygous effects of multilocus deletions in the ad-3 region can be modified genetically and biochemically (de Serres and Miller, 1988). In the present paper, the heterozygous effects of X-ray-induced gene/point mutations of genotype ad-3AR or ad-3BR, induced in heterokaryon 12 (Webber and de Serres, 1965; de Serres, 1988, 1989a), were determined. The studies presented in this paper show that 8.1% (3/37) of X-ray-induced ad-3AR mutations exhibit heterozygous effects in terms of reduced linear growth rates in forced dikaryons with a gene/point mutant at the ad-3B locus, and 10.8% (4/37) in forced dikaryons with a multilocus deletion mutation covering the ad-3B locus. In addition, 24.3% (9/37) of ad-3AR mutations exhibit heterozygous effects in terms of enhanced linear growth rates in forced dikaryons with a gene/point mutant at the ad-3B locus. Similar studies with X-ray-induced ad-3BR mutations showed that 54.9% (28/51) exhibit heterozygous effects in terms of reduced growth rates in forced dikaryons with a gene/point mutant at the ad-3A locus and 100.0% (48/48) in forced dikaryons with a multilocus deletion covering the ad-3A locus. These studies have also shown that about a 13-fold higher percentage of X-ray-induced multiple-locus mutations of genotype ad-3AR + RLCL have heterozygous effects resulting in reduced growth rates than X-ray-induced single-locus mutations of genotype ad-3AR. The overall data base on X-ray-induced ad-3 gene/point mutations in the present studies demonstrates that heterozygous effects are allele specific, genotype specific, and locus specific.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenine↗

PubMed1992

Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease.

Only about 30% of the cystic fibrosis chromosomes in the Israeli cystic fibrosis patient populations carry the major CF mutation (delta F508). Since different Jewish ethnic groups tended to live as closed isolates until recent times, high frequencies of specific mutations are expected among the remainder cystic fibrosis chromosomes of these ethnic groups. Genetic factors appear to influence the severity of the disease. It is therefore expected that different mutations will be associated with either severe or mild phenotype. Direct genomic sequencing of exons included in the two nucleotide-binding folds of the putative CFTR protein was performed on 119 Israeli cystic fibrosis patients from 97 families. One sequence alteration which is expected to create a termination at residue 1282 (W1282X) was found in 63 chromosomes. Of 95 chromosomes, 57 (60%) are of Ashkenazi origin. Together with the delta F508 (23% in this group), G542X, N1303K, and 1717-1G----A mutations, the identification of 92% of cystic fibrosis chromosomes of Ashkenazi origin becomes possible. Patients homozygous for the W1282X mutation (n = 16) and patients heterozygous for the delta F508 and W1282X mutations (n = 22) had similarly severe disease, reflected by pancreatic insufficiency, high incidence of meconium ileus (37% and 27%, respectively), early age at diagnosis, poor nutritional status, and variable pulmonary function. In conclusion, the W1282X mutation is the most common cystic fibrosis mutation in the Ashkenazi Jewish patient population in Israel. This nonsense mutation is associated with presentation of severe disease.

Cystic Fibrosis↗

PubMed1979

[Comparative study of mutator-gene prv and several other mutator-genes of Escherichia coli K-12].

Mutations prv1, prv2 and mutR34, increasing frequencies of intragenic recombinations, are found not to complement and therefore to be alleles of one gene. Checking for the influence of mutator genes mutS3, mutT1 and uvrE502 on the intragenic recombination in conjugational crossings has shown that mutators mutS3 and uvrE502 increase the frequency of intragenic recombinations while mutT1 does not change it. None of the examined mutator genes influence the conjugational frequencies of recombination. A supplementary analysis for the mutability of the mutant prv1 has been carried out. The prv1 mutation can induce mutations of the frameshift type. Mutations uvrA6, recB21, recC22 and lexA produce no influence on the display of a mutator effect of the prv1 mutation.

Conjugation, Genetic↗

PubMed2026

The shape of fitness functions and the distribution of mutational effect sizes jointly limit adaptation by regulatory mutations.

Mutations in gene regulatory regions have been shown to play a role in rapid adaptation, but the factors determining their contribution are largely unknown. Here, using the metabolic enzyme cytosine deaminase of budding yeast, we examine whether adaptation to 5-fluorocytosine, which requires reduced cytosine deamination and can readily arise from amino acid substitutions, may be reached by single promoter mutations. We generated all single-nucleotide substitutions and indels in the FCY1 promoter and assayed the resulting mutants in presence of 5-fluorocytosine. This revealed that no promoter mutation is sufficient for adaptation to occur. We next investigated how this inaccessibility of adaptation arises by combining large-scale expression measurements with the experimental characterization of the corresponding expression-fitness function. These experiments showed that the shape of this function precludes single promoter mutations from being adaptive. Although 24% of mutations significantly affect expression, the fitness curve is flat around wild-type level. As such, adaptation can only emerge from a severe reduction of expression, which cannot occur from a single mutation in the promoter. Our results show that the contribution of regulatory mutations to rapid adaptation depends not only on the distribution of mutational effect sizes on expression level but also on the shape of the function linking fitness to expression levels.

Promoter Regions, Genetic↗

PubMed1977

Spontaneous and ethyl methanesulfonate-induced mutations controlling viability in Drosophila melanogaster. II. Homozygous effect of polygenic mutations.

Polygenic mutations affecting viability were accumulated on the second chromosome of Drosophila melanogaster by treating flies with EMS in successive generations. The treated chromosomes were later made homozygous and tested for their effects on viability by comparison of the frequency of such homozygotes with that of other genotypes in the same culture. The treated wild-type chromosomes were kept heterozygous in Pm/+ males by mating individual males in successive generations to Cy/Pm females. The number of generations of accumulation was 1 to 30 generations, depending on the concentration of EMS. A similar experiment for spontaneous polygenic mutations was also conducted by accumulating mutations for 40 generations. The lower limit of the spontaneous mutation rate of viability polygenes is estimated to be 0.06 per second chromosome per generation, which is about 12 times as high as the spontaneous recessive lethal mutation rate, 0.005. EMS-induced polygenic mutations increase linearly with the number of treated generations and with the concentration of EMS. The minimum mutation rate of viability polygenes is about 0.017 per 10(-4)m, which is only slightly larger than the lethal rate of 0.013 per 10(-4) m. The maximum estimate of the viability reduction of a single mutant is about 6 to 10 percent of the normal viability. The data are consistent with a constant average effect per mutant at all concentrations, but this is about three times as high as that for spontaneous mutants. It is obvious that one can obtain only a lower limit for the mutation rate, since some mutants may have effects so near to zero that they cannot be detected. The possibility of measuring something other than the lower limit is discussed. The ratio of the load due to detrimental mutants to that caused by lethals, the D/L ratio, is about 0.2 to 0.3 for EMS-induced mutants, as compared to about 0.5 for spontaneous mutants. This is to be expected if EMS treatment produces a large fraction of small deletions and other chromosome rearrangements which are more likely to be lethal.

Animals↗

PubMed1975

mut-25, a mutation to mutator linked to purA in Escherichia coli.

The mutation mut-25 that results in a mutator phenotype is closely linked to purA on the chromosome of Escherichia coli. The gene order in this region is ampA mut-25 purA. purA mut-25 double mutants retained mutator activity indicating that mut-25 is not a mutation in the purA gene. The repair mutations uvrA6, recA56, and exrA1 had no effect on mutation frequencies in mut-25 strains, and mut-25 strains were normally resistant to ultraviolet irradiation. Frequencies of host range mutations were not increased in phages T1, T2, and T7 grown on mut-25 strains. mut-25 could act trans, reverting the trpA46 mutation either on the chromosome or on an F episome. The transitions AT yields GC (adenine-thymine yields guanine-cytosine) and GC yields AT were induced by mut-25.

Base Sequence↗

PubMed1992

DNA mutation associated with the human butyrylcholinesterase K-variant and its linkage to the atypical variant mutation and other polymorphic sites.

Genomic DNA from two families exhibiting the K-variant phenotype of serum butyrylcholinesterase was amplified by PCR and sequenced to determine the molecular basis of this variant. The K-variant phenotype was found to be associated with a DNA transition from guanine to adenine at nucleotide 1615, which caused an amino acid change from alanine 539 to threonine (GCA----ACA; Ala539----Thr). There was a 30% reduction of serum butyrylcholinesterase activity associated with this mutation. Amplification and sequencing of DNA from a random sample of 47 unrelated people gave a frequency of .128 for the K-variant allele. Thus, 1 person in 63 should be homozygous for the K-variant, making the K-variant the most common butyrylcholinesterase variant. The K-variant mutation was also found to be present in 17 (89%) of 19 butyrylcholinesterase genes containing the point mutation which causes the atypical phenotype of butyrylcholinesterase (GAT----GGT; Asp70----Gly). The presence of the K-variant in the same molecule as the atypical variant does not contribute to the qualitative change in the atypical enzyme, but it most likely accounts for the approximately one-third reduction in Vmax of butyrylcholinesterase activity in atypical serum. Two additional point mutations located in noncoding regions of the gene were also observed to be in linkage disequilibrium with the K-variant mutation. As many as four different point mutations have been identified within a single butyrylcholinesterase gene. Inhibition tests of the enzyme in plasma are usually used to distinguish the K-variant from the usual enzyme when the former is present with the heterozygous atypical variant (AK phenotype vs. UA phenotype). Inhibition tests were performed on plasma enzyme from the four possible genotypic combinations of the heterozygous atypical mutation with or without the K-variant mutation on either allele; we found that the AK phenotype was caused by three genotypes (A/K, AK/K, and U/A) and that the UA phenotype was caused by two genotypes (U/A and U/AK).

Amino Acid Sequence↗

PubMed2024

Non-hypermutator cancers access driver mutations through reversals in germline mutational bias.

Cancer is an evolutionary disease driven by mutations in asexually-reproducing somatic cells. In asexual microbes, bias reversals in the mutation spectrum can speed adaptation by increasing access to previously undersampled beneficial mutations. By analyzing tumors from 20 tissues, along with normal tissue and the germline, we demonstrate this effect in cancer. Non-hypermutated tumors reverse the germline mutation bias and have consistent spectra across tissues. These spectra changes carry the signature of hypoxia, and they facilitate positive selection in cancer genes. Hypermutated and non-hypermutated tumors thus acquire driver mutations differently: hypermutated tumors by higher mutation rates and non-hypermutated tumors by changing the mutation spectrum to reverse the germline mutation bias.

Journal Article↗

PubMed1992

Somatic mutation of the APC gene in gastric cancer: frequent mutations in very well differentiated adenocarcinoma and signet-ring cell carcinoma.

We searched for somatic mutations of the adenomatous polyposis coli (APC) gene in DNA samples isolated from 57 sporadic gastric cancers, by means of a ribonuclease (RNase) protection analysis coupled with DNA amplification by the polymerase chain reaction (PCR). Examining 30% of the APC coding region, including a region where somatic mutations in colorectal tumors are known to be clustered, we detected somatic mutations in 12 tumors; seven in 17 very well differentiated adenocarcinomas, two in 19 well or moderately differentiated adenocarcinomas, and three in ten signet-ring cell carcinomas. So far, no somatic mutations have been identified in 11 poorly differentiated adenocarcinomas. Eight of the 17 somatic mutations found in 12 tumors caused truncation of the gene product due to a nonsense mutation and a 1-, 2- or 5-bp deletion; nine others were point mutations that altered amino acids. Our results suggest that inactivation of APC plays a role in development of some gastric cancers, particularly very well differentiated adenocarcinomas and signet-ring cell carcinomas.

Adenocarcinoma↗

PubMed1979

Characterization of the mutator mutation mut5-1.

The mutator mutation mut5-1 has been characterized with respect to a range of parameters which have been used to describe DNA repair mutants of yeast. No marked effect of the mutation on UV-mutability at lower doses was apparent. Diploids homozygous for the mutation are deficient in UV-induced recombination between the alleles his1-1 and hist1-315, mutation being sufficient to account for all the UV-induced histidine prototrophs. Complementation and mapping studies indicate that mut5-1 is allelic to rad51-1, supporting the conclusion of Hastings et al. (1976) that a mutator may increase spontaneous mutation by modifying repair parameters. Both mut5-1 homozygous and heterozygous diploids give rise to spontaneous or UV-induced segregants which appear to be the products of nondisjunction events. The levels of parameiotic recombination (see Sherman and Roman, 1963; Esposito and Esposito, 1974), sporulation and spore viability observed in mut5-1/mut5-1 diploids indicate that the function encoded by RAD51 is required at 2 times during meiosis. An essential role of the function encoded by RAD51 in mitotic and meiotic recombination is indicated.

DNA Repair↗

PubMed1992

G:C-->T:A and G:C-->C:G transversions are the predominant spontaneous mutations in the Escherichia coli supF gene: an improved lacZ(am) E. coli host designed for assaying pZ189 supF mutational specificity.

Escherichia coli K12 strain KS40 and plasmid pKY241 were designed for easy screening of supF mutations in plasmid pZ189. KS40 is a nalidixic acid-resistant (gyrA) derivative of MBM7070 (lacZ(am)CA7020). Using in vitro mutagenesis, an amber mutation was introduced into the cloned gyrA structural gene, of E. coli, to give pKY241, a derivative of pACYC184. When KS40 containing pKY241 (designated KS40/pKY241) is transformed with pZ189, nalidixic acid-resistant GyrA protein is produced from the chromosomal gyrA gene and wild-type GyrA protein from pKY241 because of the suppression of the gyrA amber mutation by supF. It is known that the wild-type, otherwise nalidixic acid-sensitive, phenotype is dominant over the nalidixic acid-resistant phenotype. Thus, KS40/pKY241 gives rise to nalidixic acid-sensitive colonies when it carries a pZ189 plasmid with an active supF suppressor tRNA. If the supF gene on the plasmid carries an inactivating mutation then KS40/pKY241 will form nalidixic acid-resistant colonies. By using this system, the spontaneous mutational frequency of the supF gene on pZ189 was calculated to be 3.06 x 10(-7) per replication. Among 51 independent supF mutations analyzed by DNA sequencing, 63% were base substitutions, 25% IS element insertions, 9.6% deletions and 1.9% single-base frameshifts. The base substitutions included both transversions (84.8%) and transitions (15.2%), the largest single group being G:C to T:A transversions (45.4% of the base substitutions). These results demonstrate that the KS40/pKY241 system we have developed can be used to characterize the DNA sequence changes induced by mutagens that give very low mutational frequencies.

Base Composition↗

PubMed1977

Validation of the in vivo somatic mutation method in the mouse as a prescreen for germinal point mutations.

The in-vivo somatic mutation method developed by us in an earlier X-ray experiment was tested for its usefulness in chemical mutagenesis work, specifically in the prescreening for germinal point mutations. In order to explore possible parallelisms, the 7 compounds chosen for study, as well as the genetic markers used, were those with which large-scale specific-locus mutation-rate experiments in germcells had been conducted in the past or were in progress. From 1--3 dose levels were tested for each compound. On day 10 1/4 after copulation of C57BL females with T males, a single injection of the test compound was administered, and about 2000 offspring altogether were subsequently scored for survival, morphology, and presence of spots of various types. In accordance with our earlier results we found 3 types of spots: white near midline ventral spots (WMVS) which probably result from killing of melanocyte precursor cells; spots resulting from misdifferentiation; and the remainder, which probably result from expression of the recessive by one of several mechanisms (RS). Induction of teratogenic effects, which were stage-specific rather than agent-specific, generally paralleled induction of WMVS's. Both are interpreted as resulting from cell killing. Induction of RS's did not always parallel induction of WMVS's, but roughly paralleled relative frequencies of specific-locus mutations induced in spermatogonia by the same compounds. Even though the in vivo somatic-mutation method probably detects genetic changes additional to point mutations, the results indicate that it may be a useful prescreen for germinal specific-locus mutations, provided care is taken to distinguish between the 3 types of spots, only one of which (RS) is indicative of expression of the recessive.

Animals↗

PubMed1976

Mapping of mutations affecting synthesis of exocellular enzymes in Bacillus subtilis. Identity of the sacUh, amyB and pap mutations.

The sacUh, amyB and pap mutations are identical with respect to their pleiotropic phenotype and their genetic location. Strains bearing these mutations overproduce several exocellular enzymes: alpha amylase, lavansucrase and proteases, they are poorly or not at all transformable and most of them are devoid of flagella. These mutations are tightly linked to the sacU- mutations by transformation and therefore lie between the hisA1 and gtaB290 markers. It is possible that the sacUh, amyB and pap mutations on one hand and the sacU- mutations on the other are two different classes of alterations of the same regulatory gene controlling the synthesis of some exocellular enzymes and several other cellular functions. Furthermore an amy- mutation, leading to the lack of alpha-amylase activity, was mapped between the lin2 and aroI906 markers which are not linked to the sacU locus.

Amylases↗

PubMed1976

Spontaneous chromosome mutation and screening of mutator factors in Drosophila melanogaster.

(1) The marked inversion technique was used, and 38 major autosome sets of Drosophila melanogaster were extracted from populations of Jugoslavia, Taiwan and Japan. Spontaneous mutations were allowed to accumulate on the major chromosomes for 25 generations. Then the second chromosomes were tested to determine whether or not they were associated with such known mutator factors as the male crossing-over factor, SD, and the extrachromosomal element delta. Chromosome mutations were examined by salivary gland chromosome analysis, and viability mutations were done by the marked autosomal translocation method. (2) In 8 out of 38 major autosome lines, 5 inversions occurred in the second chromosomes, 4 inversions in the third chromosomes, and 1 reciprocal translocation between the second and the third chromosomes. Chromosome mutation rates were, therefore, 0.0063 per second chromosome per generation and 0.0053 per third chromosome per generation. Since there was no signficant difference in the rates, chromosome mutations seem to be occurring approximately equally in both major autosomes. (3) Lethal mutation rates were estimated to be 0.0097 per major autosome per generation. (4) Twenty-four second chromosome lines out of 37 demonstrated male crossing-over among the cinnabar and brown interval; the average frequencies were 0.0031 for all lines and 0.0034 when non-recombination lines were excluded. (5) One second chromosome exhibited delta retaining ability (ID), but no second chromosome carried SD.

Animals↗

PubMed1992

Mutational spectrometry: a general approach for hot-spot point mutations in selectable genes.

To observe point mutational spectra with a high degree of precision, independent large cultures of human lymphoblastoid cells were treated with a mutagen, benzo[a]pyrene diol epoxide, and mutants at the HPRT gene were selected en masse by 6-thioguanine resistance. An average of 1.6 x 10(4) 6-thioguanine-resistant mutants were created per experiment and the kinds, positions, and numbers of the most frequent mutations were examined in exon 3 of the HPRT gene by using a high-fidelity polymerase chain reaction and denaturing gradient gel electrophoresis. Sixteen exon 3-specific mutations were found to be predominantly G----T transversions and corresponded to an average of 3500 induced mutants per experiment. Of these mutations, 6 occurred within a run of 6 guanines and 5 occurred in the sequence 5'-GAAGAG-3'. The variation among independent experiments is consistent with the numerical expectation that all 16 mutations fulfill reasonable statistical criteria for mutational hot spots. The agreement with data from various systems using clone-by-clone analysis shows that the protocol reported herein can be a useful tool to study hot-spot point mutational spectra for DNA sequences for which phenotypic selection systems exist.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed1992

ras mutations in endocrine tumors: mutation detection by polymerase chain reaction-single strand conformation polymorphism.

To elucidate the molecular basis for endocrine tumorigenesis, ras mutations in human endocrine tumors were analyzed using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Mutations of the H-, K-, N-ras genes were examined in genomic DNAs from 169 successfully amplified primary endocrine tumors out of 189 samples. Four out of 24 thyroid follicular adenomas analyzed contained mutated N-ras codon 61, and one contained the mutated H-ras codon 61. One of the 19 pheochromocytomas revealed mutation of the H-ras codon 13. No mutations of the ras gene were detected in pituitary adenomas, parathyroid tumors, thyroid cancers, endocrine pancreatic tumors, and adrenocortical tumors. Based on these findings we conclude that activation of the ras gene may play a role in the tumorigenesis of a limited number of thyroid follicular adenomas and pheochromocytomas, and that mutation of the ras gene is not frequent in other human endocrine tumors.

Adult↗

PubMed1976

Suppression of polarity of insertion mutations in the gal operon and N mutations in bacteriophage lambda.

Bacterial mutations (psuA and psu) known for their ability to suppress the polarity on nonsense mutations are shown to suppress the polarity of certain insertion mutations in the gal operon. The short insertion, IS1 (800 nucleotide pairs), is about 15 to 50% suppressed, whereas longer insertions, IS2 (1,400 nucleotide pairs), and IS3 (1,200 nucleotide pairs), are not. Some of the polarity suppressor mutations (psu-1, psu-2, and psu-3) are at least partially permissive for N-gene mutations (N7 and N53) of bacteriophage lambda, suggesting a relationship between natural and mutational polar signals. That this relationship may be complex is indicated by the fact that other suppressor mutations, effective in suppressing nonsense or insertion polarity, fail entirely to permit the growth of lambda N mutants.

Cell-Free System↗

PubMed1992

Correlations of language abnormalities with localization of mutations in the beta-thyroid hormone receptor in 13 kindreds with generalized resistance to thyroid hormone: identification of four new mutations.

Generalized resistance to thyroid hormone is an inherited disease characterized by unresponsiveness of pituitary and peripheral tissues to thyroid hormone. Genetic analysis of several kindreds linked this syndrome to the gene for the beta-form of the thyroid hormone receptor, and this led to the subsequent identification of various mutations in the ligand-binding domain of this receptor. In this region we now have found 4 new point mutations with reduced T3-binding affinities from separate kindreds by direct sequencing of polymerase chain reaction products. Similar to previously studied kindreds, the reduction in T3 binding of these four kindreds ranged from 2.5- to 5-fold, indicating that these are not neutral polymorphisms. Furthermore, the pattern of inheritance of these 4 kindreds is familial in 2, sporadic in 1, and unknown in 1. To date, 20 distinct mutations have been identified, of which 18 are clustered in 2 distinct topographical regions: 11 are within the tau i/dimerization subdomains of exon 9, and 7 are within the L2 subdomain of exon 10. The 4 newly identified mutations coupled to the 9 mutations our laboratory has previously identified provide new insights into the clinical aspects of generalized resistance to thyroid hormone. Kindreds with mutations in exon 9 compared with those in exon 10 have significantly more problems in language development, as manifested by articulation problems and/or wide discrepancies in verbal and performance IQs. Interestingly, marked variability in language deficiency as well as other clinical patterns were seen not only between kindreds but also within a kindred. Further identification and clinical correlations of new mutations will continue to enhance our understanding of the structure/function relationships and physiological role of the human thyroid hormone receptor.

Adolescent↗