Showing papers on "Mutation rate published in 1973"

A model of mutation appropriate to estimate the number of electrophoretically detectable alleles in a finite population

Abstract: A new model of mutational production of alleles was proposed which may be appropriate to estimate the number of electrophoretically detectable alleles maintained in a finite population. The model assumes that the entire allelic states are expressed by integers (…, A−1, A0, A1, …) and that if an allele changes state by mutation the change occurs in such a way that it moves either one step in the positive direction or one step in the negative direction (see also Fig. 1). It was shown that for this model the ‘effective’ number of selectively neutral alleles maintained in a population of the effective size Ne under mutation rate υ per generation is given byWhen 4Neυ is small, this differs little from the conventional formula by Kimura & Crow, i.e. ne = 1 + 4Neυ, but it gives a much smaller estimate than this when 4Neυ is large.

Somatic cell mutation detection and quantification of X-ray-induced mutation in cultured, diploid human fibroblasts

Abstract: We describe a system for detecting somatic cell mutation to 8-azaguanine (8AG) resistance in cultured, diploid human fibroblasts. Hypoxanthine-guanine phosphoribosyltransferase (HG-PRT)-deficient, AG-resistant fibroblasts from boys with the X-chromosomal, Lesch-Nyhan (L-N) mutation served as one type of prototype mutant cells. Both spontaneous and X-ray-induced mutation were studied. Recovery of L-N cells was a function both of density of normal cells and of the AG concentration used for selection. Optimum recovery was achieved at an initial inoculum of 2·10 4 normal cells per 60 mm diameter culture dish and an AG concentration of 8·10 −6 M . Efficiency of recovery was between 39 and 90% and controls to determine this efficiency were included in mutagenesis experiments. Attempts to free normal cell populations of pre-existing AG-resistant mutant cells by pregrowth in HAT medium failed because, unlike L-N mutants, most spontaneous AG-resistant mutants can grow in HAT medium. Although pre-existing mutants probably caused overestimation, the average spontaneous mutation rate derived from our experiments was 4.5·10 −6 per cell generation. Eliminating one large-yieldv experiment reduced this estimate to 1.9·10 −6 . Clonal survival of cultured human fibroblasts as a function of X-ray dose was studied. X-Irradiation increased the mutation rate above spontaneous background. Minimum estimates of the increases were 1.13·10 −9 per R per cell at 75 R, 7.49·10 −8 per R per cell at 125 R, 6.87·10 −8 per R per cell at 150 R and 2.16·10 −7 per R per cell at 250 R. The total mutagenic effect and the induced mutation rate appeared to be dose-dependent. Normal parental cell strains and their derived AG-resistant mutants had similar X-ray sensitivities indicating that X-rays induced mutations rather than selected for pre-existing mutants. Because of the realism of the cultured diploid, human fibroblast model vis-a-vis in vivo human cellular events, the mutation detection system described herein is proposed as being potentially useful for environmental monitoring.

Uniformity of radiation-induced mutation rates among different species.

Abstract: ONE of the major difficulties in estimating thegenetic hazards of ionising radiation to human populations has been our inability to extrapolate with confidence from mutation rate data in lower organisms to man1,2. Experimentally observed mutation rates per locus per rad extend over an enormous range of three orders of magnitude. For instance, the forward mutation rate per locus per rad is 1 × 10−9 in Escherichia coli B/r at two loci for phage T1 resistance, 2.7 × 10−9 in Neurospora at the ad3 locus, 1.4 × 10−8 in Drosophila for eight specific loci (averaged), 1.7 × 10−7 in the mouse for twelve specific loci (averaged), and 1 × 10−6 in barley for three loci.

The Island Model of Population Differentiation: A General Solution

Abstract: The island model deals with a species which is subdivided into a number of discrete finite populations, races or subspecies, between which some migration occurs. If the number of populations is small, an assumption of equal rates of migration between each pair of populations may be reasonable approximation. Mutation at a constant rate to novel alleles may also be assumed.-A general solution is given for the process of population divergence under this model following subdivision of a single parental population, expressed in terms of the observed average frequency of heterozygotes within and between subpopulations at a randomly chosen set of independently segregating loci. No restriction is imposed on the magnitude of the migration or mutation rates involved, nor on the number of populations exchanging migrants.-The properties of two fundamental measures of genetic divergence are deduced from the theory. One is a parameter related to varphi, the coefficient of kinship, and the other, gamma, measures the rate of mutational divergence between the sub-populations.

Ultraviolet-Sensitive Mutator Strain of Escherichia coli K-12

Abstract: An ultraviolet (UV)-sensitive mutator gene, mutU, was identified in Escherichia coli K-12. The mutation mutU4 is very close to uvrD, between metE and ilv, on the E. coli chromosome. It was recessive as a mutator and as a UV-sensitive mutation. The frequency of reversion of trpA46 on an F episome was increased by mutU4 on the chromosome. The mutator gene did not increase mutation frequencies in virulent phages or in lytically grown phage λ. The mutU4 mutation predominantly induced transitional base changes. Mutator strains were normal for recombination and host-cell reactivation of UV-irradiated phage T1. They were normally resistant to methyl methanesulfonate and were slightly more sensitive to gamma irradiation than Mut+ strains. UV irradiation induced mutations in a mutU4 strain, and phage λ was UV-inducible. Double mutants containing mutU4 and recA, B, or C were extremely sensitive to UV irradiation; a mutU4 uvrA6 double mutant was only slightly more sensitive than a uvrA6 strain. The mutU4 uvrA6 and mutU4 recA, B, or C double mutants had mutation rates similar to that of a mutU4 strain. Two UV-sensitive mutators, mut-9 and mut-10, isolated by Liberfarb and Bryson in E. coli B/UV, were found to be co-transducible with ilv in the same general region as mutU4.

"Private" genetic variants and the frequency of mutation among South American Indians.

Abstract: Electrophoretic studies were performed on 15 proteins of blood serum and of erythrocytes, from blood specimens from 72 villages of six relatively unacculturated and genetically pure Indian tribes of South America, for a total of 56,237 determinations. At least 10 different “private” variants were encountered, in 131 people. Two previously recognized genetic polymorphisms of these 15 proteins were also encountered. On the assumption that these variants are neutral from the standpoint of natural selection, and that only one-third of amino-acid substitutions in proteins result in electrophoretically detectable variants, the mutation rate is estimated from a formulation of Kimura and Ohta to be about 8 × 10-5 per locus per generation. The calculation involves several approximations which can be improved by further investigations; if confirmed, then for this class of mutations Indian mutation rates are roughly an order of magnitude higher than commonly envisioned.

X-ray-induced specific-locus mutation rate in newborn male mice

Abstract: The specific-locus mutation frequency resulting from 300 R of acute X-irradiation has been determined for the germ cells present in newborn male mice. The frequency is 13.7·10−8 mutations/locus/R, which is statistically significantly lower than that of 29.1·10−8 mutations/locus/R found earlier for the same loci in spermatogonia of the adult male by W. L. Russell . The mutation rate for newborn males does not differ significantly from the induced specific-locus frequency reported for fetal males by T. C. Carter et al. The incidence of clusters of specific-locus mutations found following the irradiation of the newborn males was statistically significantly higher than the cluster incidence reported by W. L. Russell for similar irradiation of adult males. This presumably indicates the survival of relatively fewer reproductive cells following irradiation of the day-o testis. Although there are suggestions that the distribution of mutations among the loci following irradiation of the newborn males may be different from that of the irradiated adults, no statistically significant differences are demonstrated. It is quite possible that the testis of the newborn mouse may be comparable to the relatively undifferentiated human testis which persists for approx. 10 years. Until the present research was undertaken, no attempt had been made to determine the specific-locus mutation frequency resulting from X-irradiation of newborn male mice. Although some important questions still remain concerning the explanation for the lower mutational response of the newborn mouse testis, from the hazard standpoint it is reassuring that the mutation frequency of the newborn male is statistically significantly lower than that of the adult.

Clone-selection and optimal rates of mutation

Abstract: The paper employs methods of multitype branching processes to evaluate the probability of survival of mutable clones under environmental conditions which are unfavorable to the original parent of the clone. When other factors are taken to be constant, the long-term survival probability of a clone is implicitly demonstrated as a function of the intrinsic rate of mutation carried by this clone. The existence of a mutation rate which maximizes clone survival probability is shown and the effects of environmental deterioration on this optimal rate are studied. Finally, rigorous quantitative results are obtained for the classical situation of a Poisson distribution of offspring numbers. These results are then applied to the biological problem of indirect selection (Eshel (1972)).

Integration Efficiencies of Spontaneous Mutant Alleles of amiA Locus in Pneumococcal Transformation

Abstract: The distribution of integration efficiencies of independent mutations spontaneously occurring in the amiA locus was determined in two strains of pneumococcus. Strain Cl3 integrates genetic markers with different efficiencies during transformation, whereas strain 401, isogenic with strain Cl3, does not discriminate between markers and integrates all markers with the same high efficiency. The discriminating strain Cl3 gives rise to spontaneous mutations in the locus amiA, which fall into four classes with respect to their individual integration efficiencies. Mutations with a low efficiency of integration are equal in number to mutations with a high efficiency. Mutations from the two other classes corresponding to intermediate and very high efficiencies are about five times less frequent. The same four classes were also found among amiA mutants spontaneously occurring in strain 401. However, the two distributions of integration efficiencies of amiA mutants arisen either in strain Cl3 or strain 401 are significantly different. The number of spontaneous amiA mutants, estimated by two methods, was found to be higher in strain 401 than in strain Cl3. The increase of the mutation rate in strain 401 could be accounted for by the excess of mutations falling in the two less-efficient classes observed in this strain. The discriminating process which acts during transformation presumably also intervenes in the appearance of spontaneous mutations.

The measurement of fitness and mutation rate in human populations.

Abstract: Human geneticists often wish to estimab the relative fitnesses of two or more genotypes, especially in connexion with the ‘indirect method’ of measuring the rate of mutation of a gene controlling a deleterious trait. Various methods for measuring relative genotypic fitnesses have been proposed by a number of authors (e.g. Reed & Neel, 1955; Krooth, 1955; Reed, 1959, Crow, 1962). The differences between these methods are not merely differences in approach to the statistical problems of estimation of the same parameter ‘fitness ’; different parameters are being estimated, and the relations between them are by no means clear. This confusion arises from the fact that the standard models of population genetics are precisely defined only for populations where generations are distinct. In such populations, the fitness wi of a genotype i is defined as its expected number of offspring (parents and offspring being counted at the same stage in the lifecycle). The fitness of genotype i relative to that of a standard genotype j is measured as wi/wj. Relative genotypic fitnesses can be substituted into equations describing different genetic situations, and the course of genetic change, or the composition of equilibrium populations, can then be calculated. With populations such as the human one, where generations overlap, it is not easy to arrive at a simple measure of fitness which can be used in equations describing the course of change of the genetic make-up of a population. Until recently, the most widely used method has been Fisher’s (1 930) Malthusian parameter approach, which is an approximation whose derivation by Fisher is difficult to follow. For equilibrium populations, a measure of fitness with the same degree of exactness as the measure used in discrete generation models has been devised by Charlesworth (1972). In this paper, we will discuss the application of this fitness measure to human population data, particularly in the context of the indirect method of measuring mutation rates. We wil l also consider its relationships with other fitness measures which have been proposed.

A case of high rate of spontaneous mutation affecting viability in drosophila melanogaster

Abstract: A spontaneous lethal mutation rate approximately twenty to thirty times greater than normal has been discovered in second and third chromosomes derived from an irradiated isogenic line and paired with marked inversion chromosomes. Mutations resulting in reductions of viability of varying magnitude short of complete lethality apparently also occur at a very high rate in the third but not in the second chromosome. The pattern of accumulation of lethal mutations over several generations and viability frequency distributions within generations have been studied in a number of independent experiments. High mutation rate occurs in heterozygous isogenic-derived second and third chromosomes, either together or apart, irrespective of the genetic constitution of nonhomologous chromosomes. High mutation rates were not observed using the same methods with chromosomes of an inbred line from a different source. The possible mechanisms responsible for these results are discussed.

X-ray-induced specific-locus mutation rates in young male mice.

Abstract: The specific-locus mutation frequency resulting from 300 R of acute X-irradiation has been determined for the germ cells present in male mice at 2, 4, 6, 8, 10, 14, 21, 28, and 35 days of age. The sample size was large enough for each of these nine age groups to ensure that a high mutation rate would be noticed. The testis of the mouse undergoes many developmental changes between birth, when most or all germ cells are gonocytes, and 35 days, when the cell population has come to resemble that of the adult. It was important to know if the germ cells present in these developmental stages of immature male mice yield the same mutation frequency as that found earlier for spermatogonia in the adult by W. L. Russell . None of the nine age groups has a mutation rate statistically significantly higher than that of the adult. Taken together, the nine groups of males have an average mutation frequency quite to that of the adult. This does not rule out the possibility that individual age groups may have a mutation frequency somewhat different from that of the adult. The distribution of mutations among the loci seems to be similar to that found for mutations induced in spermatogonia of the adult. Clusters of specific-locus mutations were found only on day 21. This paper and that presented earlier on the newborn report the first specific-locus mutation-rate studies on male mice irradiated between birth and adulthood. If the results can be carried over to man, it can be concluded that irradiation of the immature testis, from birth to puberty, will not present any greatly increased genetic hazard over that from irradiation of the adult testis. In fact, as the data stand in the mouse, they indicate a mutation rate similar to the adult for all but the earlier stages tested and, for these stages, a probably lower rate, representing a transition from the significantly lower rate reported earlier for newborns.

Ligase-Defective Bacteriophage T4 I. Effects on Mutation Rates

Abstract: Temperature-sensitive mutations in bacteriophage T4 gene 30 (polynucleotide ligase) were examined for their effects on spontaneous and proflavine-induced frameshift mutagenesis in the rII and ac (acridine resistance) cistrons. Only small (fourfold or less) effects on mutation rates were observed, even when selection artifacts involving suppression of gene 30 mutations by rII mutations were taken into account. The deoxyribonucleic acid ligase gene of T4 therefore appears to be only a minor determinant of frameshift mutation rates. This result is consistent with the particular nature of frameshift mutagenesis in bacteriophage T4.

History of Research on Chemical Mutagenesis

Abstract: The interest in mutation is as old as the modern science of genetics. It is well known that the term “mutation” was coined by de Vries for sudden hereditary changes in Oenothera; although we now realize that these changes were not mutations sensu stricto, the term has been retained. De Vries was also the first to dream of the induction of “directed mutations” that would provide man with “unlimited power over Nature.” This dream has been a major spur to the search for chemical mutagens. In 1914, T. H. Morgan reported on unsuccessful attempts to produce mutations in Drosophila by treatment with alcohol or ether. Mann, in 1923, likewise failed to obtain mutations from treatment of Drosophila with a variety of chemicals, including morphine, quinine, and a number of metal salts. During the 1920s, mutation research was put on a firm basis by H. J. Muller, who developed the concept of “mutation rate” and devised objective, efficient, and quantitative techniques for its measurement. These techniques proved their value first in the discovery and analysis of the mutagenic action of ionizing radiation, but they were soon applied also to tests of chemicals. Muller himself obtained negative results with several chemicals, but Russian workers (Lobashov, Saccharov, Magrzhikovskaya) claimed success for ammonia, iodine, potassium permanganate, and copper sulfate; for the last-named substance, confirmatory data were published by Law in the United States. Although in these experiments the differences between the frequencies of sex-linked lethals in control and treated flies were statistically significant, treatment effects were always small and rarely reached or exceeded 1% lethals. Since at that time the striking differences between spontaneous mutation frequencies in successive broods were not known, one cannot exclude the possibility that the effective treatments had acted simply by altering the rate of sperm utilization. It would be interesting to repeat some of these experiments with a rigorous brood pattern technique.

Base pair substitutions caused by the uvr502 mutation affecting mutation rates and UV-sensitivity of Escherichia coli.

Abstract: The types of base pair substitutions induced by the uvr502 mutator activity were studied using the isogenic uvr+ and uvr502 strains bearing an ochre or missense mutations in the trp operon. It was found that the uvr502 mutation increased the frequency of both structural gene (true) reversions and suppressor mutations in the trpoc−mutant. The trpA58 missense mutation was also reverted by the uvr502 allele and 5-methyl tryptophane resistant as well as 5-methyl tryptophane sensitive Trp+ revertants were formed. However the uvr502 mutation was unable to increase significantly the frequency of Trp+ revertants in the rpA78 mutant. With the help of key of Yanofsky et al. (1966b) and codon catalogue it could be concluded that the uvr502 mutation induces transitions in both directions but not A:T→C:G and probably not G:C→T:A transversions. Incubation of the uvr502 mutant with either of four deoxyribonucleosides has no effect on its spontaneous mutability while deoxyguanosine and deoxyadenosine reduce the mutagenic effect of 2-aminopurine in the uvr+ strain, suggesting that the mutator effect of the uvr502 mutation has nothing to do with the formation of mutagenic base analogue or insufficient synthesis of bases.

Techniques for Monitoring and Assessing the Significance of Mutagenesis in Human Populations

Abstract: Monitoring for mutagenesis in man would not by itself indicate the significance of the changes in mutation rate that are observed. Since the stated purpose of these volumes is to help “avert significant human exposure to mutagenic agents” (p. ix of Volume 1), it is therefore necessary to consider, not only the problem of detecting increases in mutation rate, but also that of assessing their significance in terms of human health. The latter of these two related problems is more difficult than is generally recognized.

Somatic mutational transients. iii. response by two genes in a clone of nicotiana to 24 roentgens of gamma radiation applied at various intensities

Abstract: Somatic effects of radiation intensity on the mutable V and stable R genes were detected in plants of a heterozygous clone ( v S3 /v s , R/r ) subjected to the same dose at four rates. The effects were compared by counting speckled and purple sectors in flowers from irradiated and control plants. Response curves were estimated from the mutant sector averages, observed over a period of transient response for successive mature flowers. A structure for integrating the mutational contributions from different flowers was provided by models. The average control mutation rates are 8,110 per 10 7 cells for the V gene, and 49.45 for R . At a constant intensity of 4320 roentgens/hour, average induced mutation rates per 10 7 cells per roentgen for V increase from 194 (at 24 r total dose) to 1,116 (at 3 r dose); the corresponding rates for R increase from 7.24 to 27.65. With these responses as standards, both genes at corresponding total doses yield lower rates at lower intensities. For the series of intensities 1.2, 0.6, 0.3 and 0.15 roentgens/hour, the decreases in mutation rate for the V gene are, respectively, 66, 148, 315, and 617 per 10 7 cells per roentgen. The corresponding decrements for R are 4.86, 8.70, 14.61, and 23.51. These effects are non-linear functions of intensity for both genes, but V is at least 13 times as sensitive as R. Radiation operating to extinguish a buffering system against final mutation can account for the dose and dose-rate effects observed.

A potential hazard: explosive production of mutations by induction of mutators.

Abstract: A systematic study of the genes that control mutation rates began about five years ago both in prokaryotic and eukaryotic organisms. Before this, mutator mutants generally were regarded as freaks, causing their mutagenicity possibly by the build-up of a product of intermediary metabolism which was a mutagen. The concept of differences in the spontaneous mutation rate as a natural phenomenon was suggested by Ives (1) in 1950, but it was not until 1962 that mutation rate enhancement was recognized as a natural component of the meiotic process by Magni and von Borstel (2). In 1966, defective DNA polymerase was noted to have mutator activity (3), and in the following two years defective enzymes associated with DNA repair were implicated in a large variety of organisms (4). Still, the isolation and identification of mutator mutants were difficult at best, although Liberfarb and Bryson (5) were able to isolate a number in E. coli. Cox and his collaborators (6) have been studying these and other mutators in E. coli, and Drake (7) has been examining likely candidates for mutator activity among genes encoding known biochemical functions in the bacteriophage T4. Mutator mutants were induced and selected in the yeast Saccharomyces (8). The unex-