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PubMed1999

Spontaneous mutation rate of measles virus: direct estimation based on mutations conferring monoclonal antibody resistance.

High mutation rates typical of RNA viruses often generate a unique viral population structure consisting of a large number of genetic microvariants. In the case of viral pathogens, this can result in rapid evolution of antiviral resistance or vaccine-escape mutants. We determined a direct estimate of the mutation rate of measles virus, the next likely target for global elimination following poliovirus. In a laboratory tissue culture system, we used the fluctuation test method of estimating mutation rate, which involves screening a large number of independent populations initiated by a small number of viruses each for the presence or absence of a particular single point mutation. The mutation we focused on, which can be screened for phenotypically, confers resistance to a monoclonal antibody (MAb 80-III-B2). The entire H gene of a subset of mutants was sequenced to verify that the resistance phenotype was associated with single point mutations. The epitope conferring MAb resistance was further characterized by Western blot analysis. Based on this approach, measles virus was estimated to have a mutation rate of 9 x 10(-5) per base per replication and a genomic mutation rate of 1.43 per replication. The mutation rates we estimated for measles virus are comparable to recent in vitro estimates for both poliovirus and vesicular stomatitis virus. In the field, however, measles virus shows marked genetic stability. We briefly discuss the evolutionary implications of these results.

Animals↗
PubMed2026

Mutation rate heterogeneity biases variant effect prediction and reveals genuine mutational robustness.

Variant effect predictors (VEPs) are widely used to interpret the functional consequences of human genetic variation. Because most methods rely on sequence conservation, they implicitly treat conservation as evidence of functional constraint. However, substitution patterns across a phylogeny reflect not only selection but also differences in underlying mutation rates. Here, we show that this creates a systematic confounding: most VEPs capture mutation rate variation and misinterpret it as variation in functional importance. Widely used conservation metrics exhibit a related bias; in particular, phyloP scores correlate strongly with mutation rate even at putatively neutral sites. Consequently, variants at low-mutation-rate sites tend to be predicted as more damaging, and variants at highly mutable sites as more tolerated, than warranted by their true functional impact. We also identify a distinct biological signal in experimental measurements of mutational effects on protein stability: amino acid substitutions that are more likely to arise are, on average, less destabilizing than rarer substitutions. This provides empirical support for mutational robustness in the context of protein stability. However, this relationship is insufficient to explain the mutation-rate dependence observed in current VEP outputs. Together, our findings show that mutation rate heterogeneity systematically biases current variant effect prediction frameworks, highlight the need to model mutation probabilities explicitly in future VEPs, and reveal a genuine biological signal of mutational robustness.

conservation scores↗
PubMed1995

Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase.

The level of genetic variation of human immunodeficiency virus type 1 (HIV-1), a member of the lentivirus genus of the Retroviridae family, is high relative to that of retroviruses in some other genera. The high error rates of purified HIV-1 reverse transcriptase in cell-free systems suggest an explanation for this high genetic variation. To test whether the in vivo rate of mutation during reverse transcription of HIV-1 is as high as predicted by cell-free studies, and therefore higher than that rates of mutation of retroviruses in other genera, we developed an in vivo assay for detecting forward mutations in HIV-1, using the lacZ alpha peptide gene as a reporter for mutations. This system allows the rates and types of mutations that occur during a single cycle of replication to be studied. We found that the forward mutation rate for HIV-1 was 3.4 x 10(-5) mutations per bp per cycle. Base substitution mutations predominated; G-to-A transition mutations were the most common base substitution. The in vivo mutation rates for HIV-1 are three and seven times higher than those previously reported for two other retroviruses, spleen necrosis virus and bovine leukemia virus, respectively. In contrast, our calculated in vivo mutation rate for HIV-1 is about 20-fold lower than the error rate of purified HIV-1 reverse transcriptase, with the same target sequence. This finding indicates that HIV-1 reverse transcription in vivo is not as error prone as predicted from the fidelity of purified reverse transcriptase in cell-free studies. Our data suggest that the fidelity of purified HIV-1 reverse transcriptase may not accurately reflect the level of genetic variation in a natural infection.

Animals↗
PubMed1999

The dynamics of infinitesimally rare alleles, applied to the evolution of mutation rates and the expression of deleterious mutations.

A new method is presented for analysing the dynamics of a classical model where infinitesimally rare alleles segregate at an infinite number of unlinked loci, and where the alleles at different loci have equivalent effects. The dynamics of the distribution of the number of rare alleles per individual (the "phenotypic distribution") can be followed without knowing the frequencies of individual genotypes. Meiosis and random union of gametes have a very simple effect on the factorial cumulants of the phenotypic distribution which are consequently the natural set of variables to follow. An exact solution is presented for the dynamics of rare alleles under mutation and multiplicative selection. This solution has a simple representation in terms of the factorial cumulants. Unlike the QLE (quasi-linkage equilibrium) solution, this solution applies even when the population is far from linkage equilibrium. This approach is extended to analyse the joint dynamics of infinitesimally rare alleles at an infinite number of unlinked loci, together with a locus (with arbitrary allele frequencies) with which they interact. This more general method is used to investigate (1) the joint dynamics of a modifier of the mutation rate, together with deleterious alleles under mutation and multiplicative selection, and (2) the fate of an allele that ameliorates or exacerbates the fitness effects of deleterious alleles. When a new modifier allele causes a large change in the mutation rate, strong linkage disequilibrium is generated during its progress. However, using this new approach based on factorial cumulants, it is found that a remarkably simple invasion condition applies to alleles at the modifier locus, even when strong linkage disequilibrium is generated.

Alleles↗
PubMed2000

Estimate of the mutation rate per nucleotide in humans.

Many previous estimates of the mutation rate in humans have relied on screens of visible mutants. We investigated the rate and pattern of mutations at the nucleotide level by comparing pseudogenes in humans and chimpanzees to (i) provide an estimate of the average mutation rate per nucleotide, (ii) assess heterogeneity of mutation rate at different sites and for different types of mutations, (iii) test the hypothesis that the X chromosome has a lower mutation rate than autosomes, and (iv) estimate the deleterious mutation rate. Eighteen processed pseudogenes were sequenced, including 12 on autosomes and 6 on the X chromosome. The average mutation rate was estimated to be approximately 2.5 x 10(-8) mutations per nucleotide site or 175 mutations per diploid genome per generation. Rates of mutation for both transitions and transversions at CpG dinucleotides are one order of magnitude higher than mutation rates at other sites. Single nucleotide substitutions are 10 times more frequent than length mutations. Comparison of rates of evolution for X-linked and autosomal pseudogenes suggests that the male mutation rate is 4 times the female mutation rate, but provides no evidence for a reduction in mutation rate that is specific to the X chromosome. Using conservative calculations of the proportion of the genome subject to purifying selection, we estimate that the genomic deleterious mutation rate (U) is at least 3. This high rate is difficult to reconcile with multiplicative fitness effects of individual mutations and suggests that synergistic epistasis among harmful mutations may be common.

Animals↗
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↗
PubMed2005

Mutation rate variation at human dinucleotide microsatellites.

Mutation is the ultimate source of genetic variation, and mutation rate is thus an important parameter governing the extent of genetic variation. Microsatellites are highly informative genetic markers that have been widely used in genetic studies. While previous studies showed that the mutation rate differs in di-, tri-, and tetranucleotide repeats, how mutation rate distributes within each class of repeat is poorly understood. This study first revealed the pattern of the mutation rate variation within the dinucleotide repeats. Two data sets were used. The first is the allele frequency data from 115 microsatellites with dinucleotide repeats distributed along the human genome in 10 worldwide populations. The second data set is much larger, consisting of the allele frequency of 5252 dinucleotide repeats from the Genome Database. Mutation rate for each locus is estimated through a new homozygosity-based estimator, which has been shown to be unbiased and highly efficient and is reasonably robust against deviations from the single-step model. The mutation rates among loci can be approximated well by a gamma distribution and its shape parameter can be accurately estimated with this approach. This result provides the basic guidelines for analyzing the large-scale genomic data from microsatellite loci.

Alleles↗
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↗
PubMed2003

Mutation rate variation in the mammalian genome.

Recent advances in the large-scale sequencing of mammalian genomes have provided a means to study divergence in not only genic sequences but also in the non-coding bulk of DNA. There is evidence of significant variation in the levels of divergence between presumably neutral regions, pointing at an underlying variation in the rate of mutation across the genome. Apparently, such variation occurs on different scales, including sequence context effects (the influence of neighboring nucleotides on the rate of mutation at individual sites), variation within chromosomes (on the scales of kilobases as well as megabases), and between chromosomes (among autosomes as well as between autosomes and sex chromosomes). An important aspect for further research in this area is to study whether there is an ultimate evolutionary explanation for mutation rate variation within mammalian genomes.

Animals↗
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↗