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Escherichia coli cells growing slowly as a result of the overexpression of a cloned foreign gene were shown to exhibit an increased mutation rate in the foreign gene as well as in several non-selected markers. This phenomenon is discussed in terms of the model proposed by Hall (1990).
The reversion rates of two isogenic Escherichia coli K-12 auxotrophs differing only in relA have been determined in the absence or presence of serine hydroxamate, which provokes the stringent response. Reversion rates of leuB- and argH- were significantly higher in the relA+ than in the relA- strain, and the reversion rates in both strains were enhanced by serine hydroxamate. A positive correlation was established between reversion rates and the synthesis of guanosine-5'-diphosphate-3'-diphosphate in the absence and presence of serine hydroxamate. It is proposed that mutation rates are dependent upon rates of transcription and upon the genes which regulate the level of the signal nucleotide, guanosine tetraphosphate.
We present a new way to make a maximum likelihood estimate of the parameter 4N mu (effective population size times mutation rate per site, or theta) based on a population sample of molecular sequences. We use a Metropolis-Hastings Markov chain Monte Carlo method to sample genealogies in proportion to the product of their likelihood with respect to the data and their prior probability with respect to a coalescent distribution. A specific value of theta must be chosen to generate the coalescent distribution, but the resulting trees can be used to evaluate the likelihood at other values of theta, generating a likelihood curve. This procedure concentrates sampling on those genealogies that contribute most of the likelihood, allowing estimation of meaningful likelihood curves based on relatively small samples. The method can potentially be extended to cases involving varying population size, recombination, and migration.
The Down syndrome phenotype may be associated with, among other genotypes, an unbalanced Robertsonian translocation producing an "interchange trisomy" with 46 chromosomes, or 47, trisomy 21. Translocations, like specificlocus point mutations, result from a direct change in structural chromosome elements. In contrast 47, trisomy 21 results from meiotic non-disjunction. Mutation rates for interchange trisomies may be followed indirectly by determining the ratio of instances of Down syndrome associated with a new translocation mutation to those produced by 47, trisomy 21, which accounts for the bulk of the Down syndrome phenotype. This genotypic ratio can be analyzed in data from cytogenetic laboratories, clinics, and chromosome registries and does not depend upon intensive chromosome screening of newborn populations. A similar approach can be adopted to follow trends in Patau syndrome. The genotypic ratio, stratified by maternal age, may in addition, provide a sentinel index for changes in human specific-locus mutations and perhaps other adverse health consequences. Analysis of data from the New York State-North-eastern chromosome registry revealed a two- to three-fold increase in the genotypic ratio for both Down syndrome and Patau syndrome for individuals born in 1973, 1974 and 1975 compared to those born in earlier years.
Four mutations resulting in opal stop codons were individually engineered into a plasmid-borne chloramphenicol-resistance (cat) gene driven by the lac promoter. These four mutations were located at different sites in secondary structures. The mutations were analysed with the computer program mfg, which predicted their relative reversion frequencies. Reversion frequencies determined experimentally correlated with the mutability of the bases as predicted by mfg. To examine the effect of increased transcription on reversion frequencies, the lac promoter was replaced with the stronger tac promoter, which resulted in 12- to 30-fold increases in reversion rates. The effect of increased and decreased supercoiling was also investigated. The cat mutants had higher reversion rates in a topA mutant strain with increased negative supercoiling compared with wild-type levels, and the cat reversion rates were lower in a topA gyrB mutant strain with decreased negative supercoiling, as predicted.
The theoretical justifications for using the number of rare alleles observed in a sample and the heterozygosity contributed by such alleles to estimate the relative electrophoretic mutation rate (REMR) are given in this note. It is shown that the estimator using the number of alleles has comparatively less bias. While the total heterozygosity contributed by all alleles at a locus has been previously used to estimate REMR with success, an analogous estimator with only rare alleles has large bias over a wide range of effective population size and sample size.
Human minisatellites consist of tandem arrays of short repeat sequences, and some are highly polymorphic in numbers of repeats among individuals. Since these loci mutate much more frequently than coding sequences, they make attractive markers for screening populations for genetic effects of mutagenic agents. Here we report the results of our analysis of mutations at eight hypervariable minisatellite loci in the offspring (61 from exposed families in 60 of which only one parent was exposed, and 58 from unexposed parents) of atomic bomb survivors with mean doses of >1 Sv. We found 44 mutations in paternal alleles and eight mutations in maternal alleles with no indication that the high doses of acutely applied radiation had caused significant genetic effects. Our finding contrasts with those of some other studies in which much lower radiation doses, applied chronically, caused significantly increased mutation rates. Possible reasons for this discrepancy are discussed.
An attempt was made to ascertain all the dwarfs in the State of Victoria. The incidence of achondroplasia proved to be approximately 1 in 26,000 live births in the period 1969 to 1975 when ascertainment was nearly complete. This indicates a mutation rate of 1.93 X 10(-5) per generation in this locus. Paternal age was shown to influence mutation. Ascertainment in earlier years of the study was low despite the very great effort made to find all cases. Patients with hypochondroplasia were particularly difficult to find. However, 25 cases were found for study. Overlap between hypochondroplasia and achondroplasia was found in all features except the facial appearance (which was the basis of definition). Achondroplasia was more severe in all regards, but some individuals with hypochondroplasia were very short and some had extreme degrees of spinal canal stenosis. The classical measurements used to describe the skull changes in acondroplasia failed to distinguish this condition from hypochondroplasia. More efficient indices were devised, but visual assessment of the size of the facial region compared to that of the cranial valult proved more reliable than any index. The clinical distinction based upon facial appearance remains the arbitrary basis of definition.
This note discusses a minor mathematical error and a problematic mathematical assumption in Luria and Delbrück's (1943) classic article on fluctuation analysis. In addition to suggesting remedial measures, the note provides information on the latest development of techniques for estimating mutation rates using data from fluctuation experiments.
An algorithm is described for calculating the probability distribution of the number of mutant colonies arising in a Luria-Delbrück fluctuation experiment subject to a plating efficiency of less than 100%. A table is constructed to facilitate the estimation of spontaneous mutation rates taking into account the plating efficiency.
Hereditary non-polyposis colorectal cancer (HNPCC), the most common type of hereditary colorectal cancer, is thought to be a simple Mendelian disease involving DNA mismatch repair genes. The majority of mutations associated with HNPCC occur in the hMSH2 and hMLH1 genes. The reported incidence of mismatch repair gene mutations in HNPCC kindreds varies considerably (from 22 to 86%), and most mutations are unique. This study aimed to determine the genetic basis of Taiwanese HNPCC kindreds, focusing on the two major genes involved in this disease. A total of 15 Taiwanese HNPCC kindreds meeting the Amsterdam criteria, including 72 affected individuals among a total of 266 individuals, were analyzed using both RNA- and DNA-based methods. The mutation rate of hMSH2 and hMLH1 in these 15 kindreds was 0% and 20%, respectively, which is lower than that reported in other countries. Two novel mutations were discovered in hMLH1: one was an allelic loss of a 5.2-kb genomic fragment causing exon 16 deletion; and the other was a two-nucleotide deletion that resulted in a frameshift mutation of exon 3. We also identified one hMLH1 exon 4 mutation (a C to T transition in codon 117), which had been reported previously in western countries. This is the first genetic study of HNPCC from Taiwan.
Although we do not know why sex evolved, the twofold cost of meiosis for females provides a standard against which postulated benefits of sex can be evaluated. The most reliable benefit is sex's ability to reduce the impact of deleterious mutations. But deleterious mutations may themselves generate a large and previously overlooked female-specific cost of sex. DNA sequence comparisons have confirmed Haldane's suggestion that most mutations arise in the male germ line; recent estimates of a, the ratio of male to female mutation rates, are ten, six and two in humans, primates and rodents, respectively. Consequently, male gametes may give progeny more mutations than the associated sexual recombination eliminates. Here I describe computer stimulations showing that the cost of male mutations can easily exceed the benefits of recombination, causing females to produce fitter progeny by parthenogenesis than by mating. The persistence of sexual reproduction by females thus becomes even more problematic.
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A single transport system was found to accumulate l- and d-alanine, glycine and d-serine in Mycobacterium tuberculosis. The results of inhibition experiments suggested that the antibiotics d-cycloserine and O-carbamyl-d-serine were also transported by the alanine-glycine-d-serine system. A d-cycloserine-resistant permease-competent (d-CS(r)/perm(+)) mutant and a d-cycloserine-resistant permease-defective (d-CS(r)/perm(-)) mutant were isolated. The d-CS(r)/perm(-) mutant was not found to be more resistant to the drug than was the d-CS(r)/perm(+) mutant. The data were consistent with the conclusion that resistance to d-cycloserine in the tubercle bacilli is primarily due to mutations in the gene(s) controlling the enzyme d-alanyl-d-alanine synthetase. The mutation rate was calculated to be about 10(-10) mutations per bacterium per generation.
The fidelity of poliovirus RNA-dependent RNA polymerase (3D(pol)) was determined using a system based on the fidelity of synthesis of the alpha-lac gene which codes for a subunit of beta-galactosidase. Synthesis products are screened for mutations by an alpha-complementation assay, in which the protein product from alpha-lac is used in trans to complement beta-galactosidase activity in bacteria that do not express alpha-Lac. Several polymerases have been analyzed by this approach allowing comparisons to be drawn. The assay included RNA synthesis by 3D(pol) on an RNA template that coded for the N-terminal region of alpha-Lac. The product of this reaction was used as a template for a second round of 3D(pol) synthesis and the resulting RNA was reverse transcribed to DNA by MMLV-RT. The DNA was amplified by PCR and inserted into a vector used to transform Escherichia coli. The bacteria were screened for beta-galactosidase activity by blue-white phenotype analysis with white or faint blue colonies scored as errors made during synthesis on alpha-lac. Results showed a mutation rate for 3D(pol) corresponding to approximately 4.5x10(-4) errors per base (one error in approximately 2200 bases). Analysis of mutations showed that base substitutions occurred with greater frequency than deletions and insertions.