Salmonella typhimurium fliG and fliN mutations causing defects in assembly, rotation, and switching of the flagellar motor
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FliG, FliM, and FliN are three proteins of Salmonella typhimurium that affect the rotation and switching of direction of the flagellar motor. An analysis of mutant alleles of FliM has been described recently (H. Sockett, S. Yamaguchi, M. Kihara, V. M. Irikura, and R. M. Macnab, J. Bacteriol. 174:793-806, 1992). We have now analyzed a large number of mutations in the fliG and fliN genes that are responsible for four different types of defects: failure to assembly flagella (nonflagellate phenotype), failure to rotate flagella (paralyzed phenotype), and failure to display normal chemotaxis as a result of an abnormally high bias to clockwise (CW) or counterclockwise (CCW) rotation (CW-bias and CCW-bias phenotypes, respectively). The null phenotype for fliG, caused by nonsense or frameshift mutations, was nonflagellate. However, a considerable part of the FliG amino acid sequence was not needed for flagellation, with several substantial in-frame deletions preventing motor rotation but not flagellar assembly. Missense mutations in fliG causing paralysis or abnormal switching occurred at a number of positions, almost all within the middle one-third of the gene. CW-bias and CCW-bias mutations tended to segregate into separate subclusters. The null phenotype of fliN is uncertain, since frameshift and nonsense mutations gave in some cases the nonflagellate phenotype and in other cases the paralyzed phenotype; in none of these cases was the phenotype a consequence of polar effects on downstream flagellar genes. Few positions in FliN were found to affect switching: only one gave rise to the CW mutant bias and only four gave rise to the CCW mutant bias. The different properties of the FliM, FliG, and FliN proteins with respect to the processes of assembly, rotation, and switching are discussed.Objective To explore germline mutation frequencies and features of mismatch repaired gene MSH6 in persons with different kinds of endometrial cancer.Methods The papers about MSH6 mutations were reviewed and information was derived from studies published between 1997 and 2008,data were analyzed by statistical methods.Results MSH6 mutation in all endometrial cancer patients was 9.77%;Substitute mutation and frameshift mutation were the main types of the mutation,and each mutation frequency was 1.70%;exon 4 was the main mutable site,and the mutation frequency was 3.69%;the mean age at onset of MSH6 mutation carriers was(54.8±2.8) years old.Conclusions The mutation frequencies of MSH6 in persons with different kinds of endometrial cancer were higher;substitute mutation and frameshift mutation were the main types of the mutation,exon 4 was the main mutable site,the mean age of onset was higher.
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Idiopathic congenital nystagmus (ICN) is a common oculomotor disorder characterized by bilateral involuntary, periodic, and predominantly ocular oscillations. X-linked ICN (XLICN) with incomplete penetrance in females is the most common inheritance form, and FERM domain containing (FRMD7) mutation is the major reason for XLICN families. To date, 39 FRMD7 mutations have been identified, and 50% of the XLICN pedigrees have yielded FRMD7 mutations in the Western population. In this study, we identified a novel frameshift mutation (c.1274–1275delTG) in the FRMD7 gene in six XLICN pedigrees. Incorporated with data reported from other two Chinese groups, approximately 47% XLICN pedigrees were caused by the FRMD7 mutation in China. Therefore, this study showed that mutation analysis of the FRMD7 gene had diagnostic value not only in the Western population but also in one of the biggest Eastern populations, Chinese XLICN families. In addition, the results indicated the type of FRMD7 mutation associated with the penetrance of female carriers of XLICN.
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Transgenic mutation assays generally use mutant frequencies to estimate mutation frequencies but the degree to which clonal expansion inflates mutant frequencies is largely unknown. Mutant frequency is defined as the fraction of cells carrying mutations in the gene of interest and, according to the standard Big Blue protocol, is determined by dividing the number of mutant plaques by the total number of plaques screened. Mutation frequency is determined as the fraction of cells carrying definitely independent mutations and therefore requires correction for clonal expansion. Mutant and mutation frequencies were determined for brain, thymus and male germ cells of four mice from two age groups (3-versus 10-month old). The mutant frequency in thymus differed significantly between 3- and 10-month old mice (P < 0.05). By sequencing all mutants, the mutation frequency (i.e., corrected for jackpot mutations) in thymus was determined and was not significantly different between 3- and 10-month old mice. Mutant frequency does not fit a Poisson distribution, but mutation frequency corrected for jackpot mutations is substantially less variable and does fit a Poisson distribution.
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Transgenic mutation assays generally use mutant frequencies to estimate mutation frequencies but the degree to which clonal expansion inflates mutant frequencies is largely unknown. Mutant frequency is defined as the fraction of cells carrying mutations in the gene of interest and, according to the standard Big Blue® protocol, is determined by dividing the number of mutant plaques by the total number of plaques screened. Mutation frequency is determined as the fraction of cells carrying definitely independent mutations and therefore requires correction for clonal expansion. Mutant and mutation frequencies were determined for brain, thymus and male germ cells of four mice from two age groups (3- versus 10-month old). The mutant frequency in thymus differed significantly between 3- and 10-month old mice (P < 0.05). By sequencing all mutants, the mutation frequency (i.e., corrected for jackpot mutations) in thymus was determined and was not significantly different between 3- and 10-month old mice. Mutant frequency does not fit a Poisson distribution, but mutation frequency corrected for jackpot mutations is substantially less variable and does fit a Poisson distribution. © 1996 Wiley-Liss, Inc.
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A novel heterozygous mutation (c.325dup) was identified in EXT1 gene from the proband and the affected family members; this mutation was absent in all the unaffected family members. The identification of the novel frameshift insertion mutation (c.325dup) expands the mutation spectrum of HME, which provides new evidence for HME diagnosis.
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Hereditary multiple exostoses
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"Adaptive mutation" denotes a collection of processes in which cells respond to growth-limiting environments by producing compensatory mutants that grow well, apparently violating fundamental principles of evolution. In a well-studied model, starvation of stationary-phase lac(-)Escherichia coli cells on lactose medium induces Lac(+)revertants at higher frequencies than predicted by usual mutation models. These revertants carry either a compensatory frameshift mutation or a greater than 20-fold amplification of the leaky lac allele. A crucial distinction between alternative hypotheses for the mechanisms of adaptive mutation hinges on whether these amplification and frameshift mutation events are distinct, or whether amplification is a molecular intermediate, producing an intermediate cell type, in colonies on a pathway to frameshift mutation. The latter model allows the evolutionarily conservative idea of increased mutations (per cell) without increased mutation rate (by virtue of extra gene copies per cell), whereas the former requires an increase in mutation rate, potentially accelerating evolution. To resolve these models, we probed early events leading to rare adaptive mutations and report several results that show that amplification is not the precursor to frameshift mutation but rather is an independent adaptive outcome. (i) Using new high-resolution selection methods and stringent analysis of all cells in very young (micro)colonies (500-10,000 cells), we find that most mutant colonies contain no detectable lac-amplified cells, in contrast with previous reports. (ii) Analysis of nascent colonies, as young as the two-cell stage, revealed mutant Lac(+)cells with no lac-amplified cells present. (iii) Stringent colony-fate experiments show that microcolonies of lac-amplified cells grow to form visible colonies of lac-amplified, not mutant, cells. (iv) Mutant cells do not overgrow lac-amplified cells in microcolonies fast enough to mask the lac-amplified cells. (v)lac-amplified cells are not SOS-induced, as was proposed to explain elevated mutation in a sequential model. (vi) Amplification, and not frameshift mutation, requires DNA polymerase I, demonstrating that mutation is separable from amplification, and also illuminating the amplification mechanism. We conclude that amplification and mutation are independent outcomes of adaptive genetic change. We suggest that the availability of alternative pathways for genetic/evolutionary adaptation and clonal expansion under stress may be exploited during processes ranging from the evolution of drug resistance to cancer progression.
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