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PubMed1993

Spontaneous mutation rates in null and band-morph mutations of enzyme loci in Drosophila melanogaster.

Spontaneous mutations were accumulated for a total of 1,678,388 allele-generations in several hundred replicate second chromosome lines. These lines were compared of a Cy chromosome and one of three different lethal bearing chromosomes from natural populations. Electrophoretic mobility and/or activity change was screened for seven enzyme loci. Forty-four null mutations were detected, but no band-morph mutations were observed. There is significant variation in null mutation rate among enzyme loci and among lethal chromosomes. This may be attributable to differences in the distribution of transposable elements among the lines. The band-morph mutation rate is pooled with previous results and becomes 7.48 x 10(-7) with a 95% confidence limit of 2.04 x 10(-7) to 1.91 x 10(-6) per locus per generation. Similarly, the pooled null mutation rate becomes 1.30 x 10(-5) with 95% confidence limit of 1.15 x 10(-5) to 1.52 x 10(-5) per locus per generation.

Animals↗
PubMed1999

The causes of synonymous rate variation in the rodent genome. Can substitution rates be used to estimate the sex bias in mutation rate?

Miyata et al. have suggested that the male-to-female mutation rate ratio (alpha) can be estimated by comparing the neutral substitution rates of X-linked (X), Y-linked (Y), and autosomal (A) genes. Rodent silent site X/A comparisons provide very different estimates from X/Y comparisons. We examine three explanations for this discrepancy: (1) statistical biases and artifacts, (2) nonneutral evolution, and (3) differences in mutation rate per germline replication. By estimating errors and using a variety of methodologies, we tentatively reject explanation 1. Our analyses of patterns of codon usage, synonymous rates, and nonsynonymous rates suggest that silent sites in rodents are evolving neutrally, and we can therefore reject explanation 2. We find both base composition and methylation differences between the different sets of chromosomes, a result consistent with explanation 3, but these differences do not appear to explain the observed discrepancies in estimates of alpha. Our finding of significantly low synonymous substitution rates in genomically imprinted genes suggests a link between hemizygous expression and an adaptive reduction in the mutation rate, which is consistent with explanation 3. Therefore our results provide circumstantial evidence in favor of the hypothesis that the discrepancies in estimates of alpha are due to differences in the mutation rate per germline replication between different parts of the genome. This explanation violates a critical assumption of the method of Miyata et al., and hence we suggest that estimates of alpha, obtained using this method, need to be treated with caution.

Animals↗
PubMed1995

Biological basis of germline mutation: comparisons of spontaneous germline mutation rates among drosophila, mouse, and human.

Spontaneous mutation rates per generation are similar among the three species considered here--Drosophila, mouse, and human--and are not related to time, as is often assumed. Spontaneous germline mutation rates per generation averaged among loci are less variable among species than they are among loci and tests and between gender. Mutation rates are highly variable over time in diverse lineages. Recent estimates of the number of germ cell divisions per generation are: for humans, 401 (30-year generation) in males and 31 in females; for mice, 62 (9-month generation) in males and 25 in females; and for Drosophila melanogaster, 35.5 (18-day generation) in males and 36.5 (25-day generation) in females. The relationships between germ cell division estimates of the two sexes in the three species closely reflect those between mutation rates in the sexes, although mutation rates per cell division vary among species. Whereas the overall rate per generation is constant among species, this consistency must be achieved by diverse mechanisms. Modifiers of mutation rates, on which selection might act, include germline characteristics that contribute disproportionately to the total mutation rates. The germline mutation rates between the sexes within a species are largely influenced by germ cell divisions per generation. Also, a large portion of the total mutations occur during the interval between the beginning of meiosis and differentiation of the soma from the germline. Significant genetic events contributing to mutations during this time may include meiosis, lack of DNA repair in sperm cells, methylation of CpG dinucleotides in mammalian sperm and early embryo, gonomeric fertilization, and rapid cleavage divisions.

Animals↗
PubMed2017

Single-sperm sequencing reveals the accelerated mitochondrial mutation rate in male Daphnia pulex (Crustacea, Cladocera).

Mutation rate in the nuclear genome differs between sexes, with males contributing more mutations than females to their offspring. The male-biased mutation rates in the nuclear genome is most likely to be driven by a higher number of cell divisions in spermatogenesis than in oogenesis, generating more opportunities for DNA replication errors. However, it remains unknown whether male-biased mutation rates are present in mitochondrial DNA (mtDNA). Although mtDNA is maternally inherited and male mtDNA mutation typically does not contribute to genetic variation in offspring, male mtDNA mutations are critical for male reproductive health. In this study, we measured male mtDNA mutation rate using publicly available whole-genome sequences of single sperm of the freshwater microcrustacean Daphnia pulex Using a stringent mutation detection pipeline, we found that the male mtDNA mutation rate is 3.32 × 10-6 per site per generation. All the detected mutations are heteroplasmic base substitutions, with 57% of mutations converting G/C to A/T nucleotides. Consistent with the male-biased mutation in the nuclear genome, the male mtDNA mutation rate in D. pulex is approximately 20 times higher than the female rate per generation. We propose that the elevated mutation rate per generation in male mtDNA is consistent with an increased number of cell divisions during male gametogenesis.

Animals↗
PubMed2003

Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases.

I estimate per nucleotide rates of spontaneous mutations of different kinds in humans directly from the data on per locus mutation rates and on sequences of de novo nonsense nucleotide substitutions, deletions, insertions, and complex events at eight loci causing autosomal dominant diseases and 12 loci causing X-linked diseases. The results are in good agreement with indirect estimates, obtained by comparison of orthologous human and chimpanzee pseudogenes. The average direct estimate of the combined rate of all mutations is 1.8x10(-8) per nucleotide per generation, and the coefficient of variation of this rate across the 20 loci is 0.53. Single nucleotide substitutions are approximately 25 times more common than all other mutations, deletions are approximately three times more common than insertions, complex mutations are very rare, and CpG context increases substitution rates by an order of magnitude. There is only a moderate tendency for loci with high per locus mutation rates to also have higher per nucleotide substitution rates, and per nucleotide rates of deletions and insertions are statistically independent on the per locus mutation rate. Rates of different kinds of mutations are strongly correlated across loci. Mutational hot spots with per nucleotide rates above 5x10(-7) make only a minor contribution to human mutation. In the next decade, direct measurements will produce a rather precise, quantitative description of human spontaneous mutation at the DNA level.

Codon, Nonsense↗
PubMed2003

Sex-specific mutation rates in salmonid fish.

If germline mutations arise because of replication errors, the mutation rate may differ between males and females given that they differ in their number of germ cell divisions. As males of many higher organisms produce more gametes than females, this has led to the idea of "male-driven evolution." The extent of such male bias to the mutation rate is currently debated. For human some recent data suggest a very low bias, at a factor 1.7 only, while other approaches have given values of alpha(m) (the male-to-female mutation rate ratio) of 5, which is more close to what might be expected from male and female germ cell biology. Comparative analyses of sex-specific mutation rates in other organisms may be necessary for understanding the generality of an effect of sex and the number of germline DNA replications on the mutation rate. In this study we estimate for the first time sex-specific mutation rates in fish. Comparing the intronic substitution rates of the autosomal GH- 2 gene and its duplicated Y-linked and male-specific copy GH- 2Y (447-468 bp of each gene), we estimate alpha(m) to be 5.35-6.60 in salmonid fish of the genus Oncorhynchus. To the observations previously made among mammals and birds, this adds evidence from another class of vertebrates showing that a majority of mutations are of paternal origin. This would suggest that replication errors play a major role for the generation of new mutations.

Animals↗
PubMed1994

Estimating effective population size or mutation rate using the frequencies of mutations of various classes in a sample of DNA sequences.

Mutations resulting in segregating sites of a sample of DNA sequences can be classified by size and type and the frequencies of mutations of different sizes and types can be inferred from the sample. A framework for estimating the essential parameter theta = 4Nu utilizing the frequencies of mutations of various sizes and types is developed in this paper, where N is the effective size of a population and mu is mutation rate per sequence per generation. The framework is a combination of coalescent theory, general linear model and Monte-Carlo integration, which leads to two new estimators theta xi and theta eta as well as a general Watterson's estimator theta K and a general Tajima's estimator theta tau. The greatest strength of the framework is that it can be used under a variety of population models. The properties of the framework and the four estimators theta K, theta tau, theta xi and theta eta are investigated under three important population models: the neutral Wright-Fisher model, the neutral model with recombination and the neutral Wright's finite-islands model. Under all these models, it is shown that theta xi is the best estimator among the four even when recombination rate or migration rate has to be estimated. Under the neutral Wright-Fisher model, it is shown that the new estimator theta xi has a variance close to a lower bound of variances of all unbiased estimators of theta which suggests that theta xi is a very efficient estimator.

Base Sequence↗
PubMed1993

Potential problems in estimating the male-to-female mutation rate ratio from DNA sequence data.

It is commonly believed that the rate of mutation is much higher in males than in females because the number of germ-cell divisions per generation is much larger in males than in females. However, the precise magnitude of the male-to-female mutation rate ratio (alpha m) remains unknown. Recently there have been efforts to estimate alpha m by using DNA sequence data from different species. We have studied the potential problems in such an approach. We found that the rate of synonymous substitution varies about fivefold among X-linked genes, as large as the variation among autosomal genes. This large variation makes the assumption of selective neutrality of synonymous changes dubious, so one should be cautious in using the synonymous rates in X-linked and autosomal genes to estimate alpha m. A similar difficulty was also observed in using nonhomologous intron sequences to estimate alpha m. Contrary to the expectation that X-linked sequences should evolve more slowly than autosomal sequences, the Alu repeat in the last intron of the X-linked zinc finger gene has evolved faster than the four autosomal Alu repeats used in this study. It appears that the best way to estimate alpha m is to use homologous sequences. However, such sequences may be involved in gene conversion events. In fact, we found evidence that the Y-linked and X-linked zinc finger genes have been involved in multiple conversion events during primate evolution. Thus, the possibility of gene conversion should be considered when using homologous sequences to estimate alpha m.

Animals↗
PubMed1993

Increased spontaneous mutation rates and prevalence of karyotype abnormalities in highly metastatic human melanoma cell lines.

Previous studies have suggested that increased malignant potential might be related to increased genomic instability, but this issue still remains controversial. We tested this hypothesis in a human tumour spontaneous metastasis model, using six clones and variants isolated from the parental poorly metastatic M4Be melanoma cell line, and expressing various metastatic abilities. The spontaneous rates of mutation to ouabain resistance measured in these cells by Luria and Delbrück fluctuation analysis correlated with the metastatic ability of the cells: moderately and highly metastatic cells showed spontaneous mutation rates 10 to 50 times higher than those of poorly metastatic cells. Genomic instability at the chromosome level was assessed by searching for accumulated structural abnormalities in the moderately and highly metastatic cell lines. All the cell lines appeared hypertriploid, and showed comparable modal numbers and great chromosome dispersion. Unstable DNA amplification in the form of double minute chromosomes was shown in one of the four poorly metastatic cell lines, and in a significantly higher proportion of the cells of two of the three metastatic cell lines. Abnormal chromosomes were demonstrated in all cell lines, with markers involving specific rearrangements of chromosomes 1, 6, 7, 8, 9, 11, 14 and 15, as frequently observed in human melanoma cells. Clonal markers were present in all cell lines, documenting the common origin of all variants and clones, and specific marker amplification was noticed in highly metastatic cells compared to poorly metastatic lines. These results suggest that human tumour progression might be accompanied both by an increase in genomic instability and by accumulation of karyotypic abnormalities.

Cell Division↗
PubMed1998

The mutation rate and cancer.

The stability of the human genome requires that mutations in the germ line be exceptionally rare events. While most mutations are neutral or have deleterious effects, a limited number of mutations are required for adaptation to environmental changes. Drake has provided evidence that DNA-based microbes have evolved a mechanism to yield a common spontaneous mutation rate of approximately 0.003 mutations per genome per replication (Drake 1991). In contrast, mutation rates of RNA viruses are much larger (Holland et al. 1982) and can approach the maximum tolerable deleterious mutation rate of one per genome (Eigen and Schuster 1977; Eigen 1993). Drake calculates that lytic RNA viruses display spontaneous mutation rates of approximately one per genome while most have mutation rates that are approximately 0.1 per genome (Drake 1993). This constancy of germline mutation rates among microbial species need not necessarily mean constancy of the somatic mutation rates. Furthermore, there need not be a constant rate for somatic mutations during development. In this review, we consider mutations in cancer, a pathology in which there appears to be an increase in the rate of somatic mutations throughout the genome. Moreover, within the eukaryotic genome, as in microbes, there are "hot-spots" that exhibit unusually high mutation frequencies. It seems conceivable to us that many tumors contain thousands of changes in DNA sequence. The major question is: how do these mutations arise, and how many are rate-limiting for tumor progression?

Animals↗
PubMed1992

Direct determination of the point mutation rate of a murine retrovirus.

The point mutation rate of a murine leukemia virus (MuLV) genome (AKV) was determined under conditions in which the number of replicative cycles was carefully controlled and the point mutation rate was determined by direct examination of the RNA genomes of progeny viruses. A clonal cell line infected at a low multiplicity of infection (2 x 10(-3)) was derived to provide a source of virus with high genetic homogeneity. Virus stocks from this cell line were used to infect cells at a low multiplicity of infection, and the cells were seeded soon after infection to obtain secondary clonal cell lines. RNase T1-oligonucleotide fingerprinting analyses of virion RNAs from 93 secondary lines revealed only 3 base changes in nearly 130,000 bases analyzed. To obtain an independent assessment of the mutation rate, we directly sequenced virion RNAs by using a series of DNA oligonucleotide primers distributed across the genome. RNA sequencing detected no mutations in over 21,000 bases analyzed. The combined fingerprinting and sequencing analyses yielded a mutation rate for infectious progeny viruses of one base change per 50,000 (2 x 10(-5)) bases per replication cycle. Our results suggest that over 80% of infectious progeny MuLVs may be replicated with complete fidelity and that only a low percentage undergo more than one point mutation during a replication cycle. Previous estimates of retroviral mutation rates suggest that the majority of infectious progeny viruses have undergone one or more point mutations. Recent studies of the mutation rates of marker genes in spleen necrosis virus-based vectors estimate a base substitution rate lower than estimates for infectious avian retroviruses and nearly identical to our determinations with AKV. The differences between mutation rates observed in studies of retroviruses may reflect the imposition of different selective conditions.

Animals↗
PubMed1973

Ligase-defective bacteriophage T4. I. Effects on mutation rates.

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.

Acridines↗
PubMed1988

Determination of the mutation rate of a retrovirus.

The mutation rate of Rous sarcoma virus (RSV) was measured. Progeny descended from a single virion were collected after one replication cycle, and seven regions of the genome were analyzed for mutations by denaturing-gradient gel electrophoresis. In all, 65,250 nucleotides were screened, yielding nine mutations, and the RSV mutation rate was calculated as 1.4 x 10(-4) mutations per nucleotide per replication cycle. These results indicate that RSV is an extremely mutable virus. We speculate that the mutation rate of a virus may correlate inversely with the effectiveness of vaccination against a given virus and suggest that prevention of retrovirus-mediated disease via vaccination may prove difficult.

Animals↗
PubMed1994

Evolution of mutation rate and virulence among human retroviruses.

High mutation rates are generally considered to be detrimental to the fitness of multicellular organisms because mutations untune finely tuned biological machinery. However, high mutation rates may be favoured by a need to evade an immune system that has been strongly stimulated to recognize those variants that reproduced earlier during the infection. HIV infections conform to this situation because they are characterized by large numbers of viruses that are continually breaking latency and large numbers that are actively replicating throughout a long period of infection. To be transmitted, HIVs are thus generally exposed to an immune system that has been activated to destroy them in response to prior viral replication in the individual. Increases in sexual contact should contribute to this predicament by favouring evolution toward relatively high rates of replication early during infection. Because rapid replication and high mutation rate probably contribute to rapid progression of infections to AIDS, the interplay of sexual activity, replication rate, and mutation rate helps explain why HIV-1 has only recently caused a lethal pandemic, even though molecular data suggest that it may have been present in humans for more than a century. This interplay also offers an explanation for geographic differences in progression to cancer found among infections due to the other major group of human retroviruses, human T-cell lymphotropic viruses (HTLV). Finally, it suggests ways in which we can use natural selection as a tool to control the AIDS pandemic and prevent similar pandemics from arising in the future.

Biological Evolution↗
PubMed2000

The mutation rate in the human mtDNA control region.

The mutation rate of the mitochondrial control region has been widely used to calibrate human population history. However, estimates of the mutation rate in this region have spanned two orders of magnitude. To readdress this rate, we sequenced the mtDNA control region in 272 individuals, who were related by a total of 705 mtDNA transmission events, from 26 large Icelandic pedigrees. Three base substitutions were observed, and the mutation rate across the two hypervariable regions was estimated to be 3/705 =.0043 per generation (95% confidence interval [CI].00088-.013), or.32/site/1 million years (95% CI.065-.97). This study is substantially larger than others published, which have directly assessed mtDNA mutation rates on the basis of pedigrees, and the estimated mutation rate is intermediate among those derived from pedigree-based studies. Our estimated rate remains higher than those based on phylogenetic comparisons. We discuss possible reasons for-and consequences of-this discrepancy. The present study also provides information on rates of insertion/deletion mutations, rates of heteroplasmy, and the reliability of maternal links in the Icelandic genealogy database.

Base Sequence↗
PubMedDate not supplied

Mutation rate of avian intestinal coliform bacteria when pressured with fluoroquinolones.

The purpose of this study was to determine the rate at which resistance developed in avian coliform bacteria when exposed to nalidixic acid, sarafloxacin, or enrofloxacin. In in vitro studies, the rates of mutation of avian isolates of Escherichia coli and Salmonella were determined following nalidixic acid, sarafloxacin, or enrofloxacin pressure. The rates of mutation were similar for nalidixic acid and sarafloxacin, whereas a lower rate of mutation was seen after enrofloxacin pressure. In in vivo studies, the quinolones were administered in the drinking water to broiler chickens at a concentration of 40 ppm for five consecutive days. Samples of feces were inoculated onto appropriate media and the frequency of resistance was determined. The frequency rates of resistance to nalidixic acid and sarafloxacin were similar. Enrofloxacin-medicated birds did not develop enrofloxacin-resistant coliform bacteria. The in vitro and in vivo data appear to correlate.

Animals↗
PubMed1998

Mutation rate of a microsatellite sequence in normal human fibroblasts.

Dinucleotide repeats, because of their repetitive nature, are prone to frameshift mutations, most likely via a DNA-polymerase slippage mechanism. Mutation rates in microsatellite DNA sequences are high in mismatch repair-defective cells. In normal cells, only estimates of maximal rates of mutation in microsatellites have been possible previously, because of the low sensitivity of screening assays for mutations in endogenous sequences. We have measured the spontaneous mutation rate of a dinucleotide repeat in diploid human foreskin fibroblasts. In our system, the mutation target is a (CA)17 repeat contained within a stably integrated plasmid. The repeat disrupts the reading frame of a neomycin (neo) resistance gene within the plasmid. Cells containing frameshift mutations in the CA repeat that correct the reading frame of the neo gene are selected using the neo analogue G418. This system of measuring microsatellite mutation rates is highly sensitive, because there is a specific target within which mutations can be selected. Fluctuation analysis of cells containing the target DNA yielded mutation rates of <3.1 x 10(-8) to 44.8 x 10(-8) mutations/cell/generation. This is the first report of a direct measurement of a spontaneous mutation rate of a microsatellite sequence in normal human cells.

Cells, Cultured↗
PubMed1997

Relative mutation rates at di-, tri-, and tetranucleotide microsatellite loci.

Using the generalized stepwise mutation model, we propose a method of estimating the relative mutation rates of microsatellite loci, grouped by the repeat motif. Applying ANOVA to the distributions of the allele sizes at microsatellite loci from a set of populations, grouped by repeat motif types, we estimated the effect of population size differences and mutation rate differences among loci. This provides an estimate of motif-type-specific mutation rates up to a multiplicative constant. Applications to four different sets of di-, tri-, and tetranucleotide loci from a number of human populations reveal that, on average, the non-disease-causing microsatellite loci have mutation rates inversely related to their motif sizes. The dinucleotides appear to have mutation rates 1.5-2 times higher than the tetranucleotides, and the non-disease-causing trinucleotides have mutation rates intermediate between the di- and tetranucleotides. In contrast, the disease-causing trinucleotides have mutation rates 3.9-6.9 times larger than the tetranucleotides. Comparison of these estimates with the direct observations of mutation rates at microsatellites indicates that the earlier suggestion of higher mutation rates of tetranucleotides in comparison with the dinucleotides may stem from a nonrandom sampling of tetranucleotide loci in direct mutation assays.

Analysis of Variance↗