The effects of postincubation on induced mutation frequency. II. The role of nucleic acid and protein synthesis in survival and mutation frequency.
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Mutation frequency
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PAX3
Haploinsufficiency
Waardenburg syndrome
Microphthalmia-associated transcription factor
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Objective:To investigate the role of mutation in GLUT4gene on the pathogenesis in type2diaˉbetic subjects in Tianjin.Methods:The exon4a of GLUT4was screened by PCR-SSCP in220type2diabetic patients and150control subjects.Results:Four silent mutations(AAC→AAT)at Asn 130 were detected in220diabetic subjects,one is homozygous,the others were heterozygous.The frequency of mutation was1.82%.No mutation was found in normal controls.There was no significant difference in the frequency of mutation between two groups(P0.05).Conclusion:The frequency of gene mutation in GLUT4is low in type2diabetes,imˉplying that it may not be the primary cause in the pathogenesis of type2diabetes.However,type2diabetes is a multigenic disease.Single mutation can interact with other mutations in many of the genetic components of inˉsulin signaling network and environmental risk factors,and increase the susceptibility to type2diabetes.
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Mutants in the Big Blue transgenic mouse system show spontaneous clustered multiple mutations with unexpectedly high frequency, consistent with chronocoordinate events. We tested the prediction that the multiple mutations seen within the lacI mutation target sometimes occur in the context of chronocoordinate multiple mutations spanning multiple kilobases (mutation showers). Additional sequencing of mutants was performed in regions immediately flanking the lacI region (total of 10.7 kb). Nineteen additional mutations were found outside the lacI region ("ectomutations") from 10 mutants containing two or more lacI mutations, whereas only one ectomutation was found in 130 mutants with a single mutation (P < 0.0001). The mutation showers had an average of approximately one mutation per 3 kb. Four mutants showed closely spaced double mutations in the new sequence, and analysis of the spacing between these mutations revealed significant clustering (P = 0.0098). To determine the extent of the mutation showers, regions (8.5 kb total) remote from the lacI region (approximately 16-17 kb away) were sequenced. Only two additional ectomutations were found in these remote regions, consistent with mutation showers that generally do not extend more than approximately 30 kb. We conclude that mutation showers exist and that they constitute at least 0.2% and possibly 1% or more of mutational events observed in this system. The existence of mutation showers has implications for oncogenesis and evolution, raising the possibilities of "cancer in an instant" and "introns as sponges to reduce the deleterious impact of mutation showers."
Lac repressor
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Mutation frequency
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This paper describes a mutator system in the nematode Caenorhabditis elegans var. Bergerac for the gene unc-22. Of nine C. elegans and two C. briggsae strains tested only the Bergerac BO strain yielded mutant animals at a high frequency and the unc-22 IV gene is a preferred mutational target. The forward spontaneous mutation frequency at the unc-22 locus in Bergerac BO is about 1 X 10(-4), and most of these spontaneous unc-22 mutations revert at frequencies between 2 X 10(-3) and 2 X 10(-4). Both the forward mutation frequency and the reversion frequency are sensitive to genetic background. Spontaneous unc-22 mutations derived in a Bergerac background and placed in a primarily Bristol background revert at frequencies of less than 10(-6). When reintroduced into a Bergerac/Bristol hybrid background the mutations once again become unstable. The mutator activity could not be localized to a discrete site in the Bergerac genome. Nor did mutator activity require the Bergerac unc-22 gene as a target since the Bristol unc-22 homolog placed in a Bergerac background also showed high mutation frequency. Intragenic mapping of two spontaneous unc-22 alleles, st136 and st137, place both mutations in the central region of the known unc-22 map. However, these mutations probably recombine with one another, suggesting that the unstable mutations can occur in more than one site in unc-22. Examination of the phenotypic effect of these mutations on muscle structure indicates that they are less severe in their effect than a known amber allele. We suggest that this mutator system is polygenic and dispersed over the nematode genome and could represent activity of the transposable element Tc1.
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The mutation spectrum, together with mutation frequency, is decisive for the size and nature of genetic diversity. We constructed plasmid-encoded probes for specific detection of each and all of the six base substitutions. Using the set of the probes, we analyzed the mutation spectrumon the plasmids caused by different types of mutagens and mutator enzymes/alleles.
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A compensatory mutation occurs when the fitness loss caused by one mutation is remedied by its epistatic interaction with a second mutation at a different site in the genome. This poorly understood biological phenomenon has important implications, not only for the evolutionary consequences of mutation, but also for the genetic complexity of adaptation. We have carried out the first direct experimental measurement of the average rate of compensatory mutation. An arbitrary selection of 21 missense substitutions with deleterious effects on fitness was introduced by site-directed mutagenesis into the bacteriophage phiX174. For each deleterious mutation, we evolved 8-16 replicate populations to determine the frequency at which a compensatory mutation, instead of the back mutation, was acquired to recover fitness. The overall frequency of compensatory mutation was approximately 70%. Deleterious mutations that were more severe were significantly more likely to be compensated for. Furthermore, experimental reversion of deleterious mutations revealed that compensatory mutations have deleterious effects in a wild-type background. A large diversity of intragenic compensatory mutations was identified from sequencing fitness-recovering genotypes. Subsequent analyses of intragenic mutation diversity revealed a significant degree of clustering around the deleterious mutation in the linear sequence and also within folded protein structures. Moreover, a likelihood analysis of mutation diversity predicts that, on average, a deleterious mutation can be compensated by about nine different intragenic compensatory mutations. We estimate that about half of all compensatory mutations are located extragenically in this organism.
Mutation Accumulation
Reversion
Epistasis
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Suppressor mutation
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Mutations in the gene GJB2, encoding the gap-junction protein connexin-26, have been shown to be a major cause of nonsyndromic recessive deafness (NSRD). A single mutation in the GJB2 gene accounts for the majority of NSRD in many different populations. This mutation represents a deletion of a guanine within a stretch of six Gs between nucleotide positions +30 and +35 of the GJB2 cDNA (35delG). Molecular detection of the 35delG mutation is usually performed by direct sequencing analysis of PCR products, or by allele-specific PCR analysis. To screen for this mutation, we developed an easier and more reliable method, based on the principle of PCR-mediated site-directed mutagenesis (PSDM), followed by a BsiYI digestion. We tested 360 unrelated unaffected Belgian individuals for heterozygosity of the 35delG mutation and found a carrier frequency of 1 in 40 (95% CI, 1 in 30 to 1 in 60). As our new screening method is simple and reliable in use, and detects a mutation responsible for a significant part of NSRD, it may find widespread use in DNA diagnostics.
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Collections of mutants usually contain more mutants bearing multiple mutations than expected from the mutant frequency and a random distribution of mutations. This excess is seen in a variety of organisms and also after DNA synthesis in vitro. The excess is unlikely to originate in mutator mutants but rather from transient hypermutability resulting from a perturbation of one of the many transactions that maintain genetic fidelity. The multiple mutations are sometimes clustered and sometimes randomly distributed. We model some spectra as populations comprising a majority with a low mutation frequency and a minority with a high mutation frequency. In the case of mutants produced in vitro by a bacteriophage RB69 mutator DNA polymerase, mutants with two mutations are in approximately 10-fold excess and mutants with three mutations are in even greater excess. However, phenotypically undetectable mutations seen only as hitchhikers with detectable mutations are approximately 5-fold more frequent than mutants bearing detectable mutations, indicating that they arose in a subpopulation with a higher mutation frequency. Excess multiple mutations may contribute critically to carcinogenesis and to adaptive mutation, including the adaptations of pathogens as they move from host to host. In the case of the rapidly mutating riboviruses, the viral population appears to be composed of a majority with a mutation frequency substantially lower than the average and a minority with a huge mutational load.
Mutation frequency
Suppressor mutation
Mutation Accumulation
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A common goal of tumor sequencing projects is the identification of genes whose mutations are selected for during tumor development. This is accomplished by finding genes that have more nonsynonymous mutations than expected by an estimated background mutation frequency. While this frequency is unknown, it can be estimated using both the observed synonymous mutation frequency, and the nonsynonymous to synonymous mutation ratio. The synonymous mutation frequency can be determined across all genes, or in a gene-specific manner. This choice introduces an interesting tradeoff. A gene-specific frequency is difficult to estimate given small or missing synonymous mutation counts, but adjusts for an underlying mutation load bias. Using a genome-wide synonymous frequency is more robust, but is less suited for adjusting for the same bias. Studying three evaluation criteria for identifying genes with high nonsynonymous mutation burden (preferential selection of expressed genes, genes with mutations in conserved bases, and genes that show loss of heterozygosity), we find that the gene-specific synonymous frequency is superior in the gene expression and conservation tests, while both frequencies perform similarly for the loss of heterozygosity test. In conclusion, we believe that the use of the gene-specific synonymous mutation frequency is well suited for estimating a gene's nonsynonymous mutation burden.
Nonsynonymous substitution
Synonymous substitution
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Silent mutation
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