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PubMed2002

Mutation rate at swine microsatellite loci.

During genotyping of 38 microsatellites for QTL (quantitative trait loci) mapping in three F2 swine populations, five mutant alleles were detected in a total of 66,436 parent-offspring transfers of microsatellite alleles, which gives an overall mutation rate of 7.52 x 10(-5) per locus per generation. No significant (P > 0.05) association between mutation rates and other factors (i.e., GC contents in the flanking regions, heterozygosity, and repeat number) was revealed. Detailed sequencing showed that four out of five mutant alleles were caused by insertions of one to five repeats, respectively. The other mutant allele was produced by either an insertion of three repeats or a change of 30 base pairs (a deletion of 16 CT repeats and an insertion of one CA repeat). An insertion of one base pair in the flanking region of a microsatellite was also detected. Together, these data indicate that expansions are more common than contractions among microsatellites and that the mutation processes are very complicated, do not fit with the strict stepwise mutation model and may vary from locus to locus.

Animals↗
PubMed1989

Potential DNA methods for measuring the human heritable mutation rate.

Potential methods are reviewed for estimating human heritable mutation rates by comparing the DNA of parents of offspring. In the 4 years since the Alta Workshop on this subject, information has accumulated on several of the six methods detailed in that meeting. Some of the methods now appear to be infeasible, and all continue to be too inefficient for practical implementation. Newer DNA approaches are discussed, including several that could become practical enough for implementation. Finally, DNA-oriented methods using human sperm are considered as possible alternatives to the heritable approaches.

Base Sequence↗
PubMed1993

How much do we know about spontaneous human mutation rates?

The much larger number of cell divisions between zygote and sperm than between zygote and egg, the increased age of fathers of children with new dominant mutations, and the greater evolution rate of pseudogenes of the Y chromosome than of those on autosomes all point to a much higher mutation rate in human males than in females, as first pointed out by Haldane [Ann Eugen 13:262-271, 1947] in his classical study of X-linked hemophilia. The age of the father is the main factor determining the human spontaneous mutation rate, and probably the total mutation rate. The total mutation rate in Drosophila males of genes causing minor reduction in viability is at least 0.4 per sperm, and may be considerably higher. The great mutation load implied by a rate of approximately 1 per zygote can be greatly ameliorated by quasi-truncation selection. Corresponding data are not available for the human population. The evolution rate of pseudogenes in primates suggests some 10(2) new mutations per zygote. Presumably the overwhelming majority of these are neutral, but even the approximate fraction is not known. Statistical evidence in Drosophila shows that mutations with minor effects cause about the same heterozygous impairment of fitness as those that are lethal when homozygous. The magnitude of heterozygous effect is such that almost all mutant genes are eliminated as heterozygotes before ever becoming homozygous. Although quantitative data in the human species are lacking, anecdotal information supports the conclusion that partial dominance is the rule here as well. This suggests that if the human mutation rate were increased or decreased, the effects would be spread over a period of 50-100 generations.

Age Factors↗
PubMed1999

Direct analysis by small-pool PCR of MS205 minisatellite mutation rates in sperm after mutagenic therapies.

We have used small-pool PCR to analyse mutation in samples of sperm taken from men after mutagenic therapy. Small-pool PCR uses direct analysis of germline DNA at a highly unstable tandem-repeated "minisatellite" locus to measure rates of length-change mutation in individual sperm samples. The advantages of this approach are that the normal mutation rate is extremely high (about 0.4% per gamete at the locus analysed here), so that relatively small increases in mutation rate can be detectable in individual samples. It is known from work on sperm from untreated individuals that different alleles at this locus have different mutation rates. For this reason, we have analysed the germline mutation rates in sperm samples from two men, in each case comparing a post-treatment sample with a pre-treatment sample from the same individual. We find no evidence for altered mutation in the post-treatment sample, suggesting that the repopulation of the germ-cell compartment after treatment may be subject to stringent mechanisms for the detection and elimination of germ-cell damage.

DNA↗
PubMed1999

Y-chromosome-specific microsatellite mutation rates re-examined using a minisatellite, MSY1.

Polymorphic Y-chromosome-specific microsatellites are becoming increasingly used in evolutionary and forensic studies and, in particular, in dating the origins of Y-chromosomal lineages. Previously, haplotyping of Y chromosomes from males belonging to a set of deep-rooting pedigrees was used to estimate a conservative average Y-chromosomal microsatellite mutation rate of 2.1 x 10(-3)per locus per generation. A number of males showed multiple differences in haplotypes compared with other males within their pedigrees, and these were excluded from the calculation of this estimate, on the grounds that non-paternity was a more probable explanation than multiple mutation within a lineage. Here we reanalyse the pedigrees using an independent highly polymorphic system, the Y-specific minisatellite, MSY1. This supports the hypothesis of non-paternity where more than one microsatellite difference was observed, provides further support for the previously deduced microsatellite mutation rate and throws light on the mutation dynamics of MSY1 itself, suggesting that single-step changes are not the only mode of mutation.

Genetic Markers↗
PubMed1987

Measurements of mutation rates in B lymphocytes.

It is established that somatic mutation is an important source of antibody diversity in vivo. It is also established that Igh-V gene segments are hypermutable in vitro. This is not a completely satisfactory situation. While there is no reason to believe that Igh-V genes are not hypermutable in vivo as well, direct experimental evidence is lacking. Perhaps experiments with transgenic mice will soon fill this gap. It is not so clear how much higher than normal the rate of hypermutation is. As far as we are aware, there are no direct measurements of mutation rates per base pair per cell generation in mammals, certainly not for lymphocyte cell lines. For a variety of reasons, it is difficult to measure very low mutation rates. The general consensus is that the normal rate should be somewhere between 10(-10) and 10(-12) mutations per base pair per cell generation. Therefore, an experiment designed to directly determine a rate using the compartmentalization test would involve hundreds of cultures, each containing at least 10(9) cells. It is not a trivial problem to find one or a few mutants among so many cells. It is simple to study mutation to resistance to a drug, for example, ouabain or azaguanine, but, as we discussed, there are technical and conceptual pitfalls. The vast excess of dead cells influences the growth of a few mutant cells, particularly in lymphocyte cell lines. Even if this problem could be solved, the mutation rate so obtained would be "per gene(s)" and not "per base pair". The problems associated with cytotoxic agents can be avoided by immunofluorescence methods in conjunction with selective cloning or cell sorting. Using these techniques, we have carried out extensive experiments to determine whether the immunoglobulin mutator system acts, at least partially, on genetic elements other than those in or near the heavy chain variable region gene segment. For an opal termination codon in a heavy chain constant region gene segment, the rate of reversion was less than 10(-7) per base pair per cell generation. This upper limit was fixed by the high rate of small deletions at the heavy chain locus. For an allotype mutation at B2m, the gene encoding beta 2 microglobulin, the rate of mutation was less than 10(-8). This upper limit could be lowered by at least two orders of magnitude by using a high-speed cell sorter.

Animals↗
PubMed1986

Sequence analysis of the E2 gene of a hyperglycosylated, host restricted mutant of Sindbis virus and estimation of mutation rate from frequency of revertants.

SVap15/21, a strain of Sindbis virus (SV) derived from our standard laboratory strain of SV (SVstd) after repeated passage on Aedes albopictus cells, grows normally in mosquito cells but is host restricted (hr) in vertebrate cells. It is also temperature sensitive (ts) and produces pinpoint plaques on vertebrate cells (sp). E2 glycoprotein of SVstd differs from that of the more widely used SVHR (from which SVstd was derived) by an additional (i.e., third) N-linked glycan. The E2 of SVap15/21, in turn, differs from that of SVstd by the addition of a fourth glycan. We have determined the nucleotide sequence of the E2 genes of SVap15/21 and of SVstd, as well as that of our isolate of SVHR. The nucleotide sequence of the SVstd E2 gene predicted the occurrence of an additional N-linked glycan attachment site, not present in the SVHR E2, at Asn232 (Asp in SVHR). The sequence of the SVap15/21 E2 gene demonstrated three mutations relative to the SVstd gene, including one that predicted the occurrence of another potential N-linked glycan attachment site at Asn275. Sequence analysis of 15 revertants of SVap15/21 which are no longer host-restricted revealed that all had lost the glycosylation site at Asn275, confirming the connection between the hyperglycosylation and the host dependent block in assembly. Most of these revertants had also lost the temperature sensitivity and small plaque traits (i.e., were ts+ and lp). Each revertant of this class was characterized by one of three different mutations in two separate codons (Asn275 and Thr277), resulting in the loss of the glycosylation site at Asn275. A fourth mutation, resulting in an Asn275----Tyr substitution, was associated with a hr+ ts phenotype in three isolates. Finally an additional mutation in a different part of the E2 gene was found in two hr+ ts sp isolates that had also lost the glycosylation site at Asn275 through a mutation resulting in a Thr277----Ile substitution. Knowledge of the nucleotide sequences associated with the ts defect in SVap15/21 and with its reversion permit an estimation of the mutation rate of this virus. This calculation indicates a mutation rate of less than 10(-6) errors per base incorporation.

Amino Acid Sequence↗
PubMed1999

Estimation of past demographic parameters from the distribution of pairwise differences when the mutation rates vary among sites: application to human mitochondrial DNA.

Distributions of pairwise differences often called "mismatch distributions" have been extensively used to estimate the demographic parameters of past population expansions. However, these estimations relied on the assumption that all mutations occurring in the ancestry of a pair of genes lead to observable differences (the infinite-sites model). This mutation model may not be very realistic, especially in the case of the control region of mitochondrial DNA, where this methodology has been mostly applied. In this article, we show how to infer past demographic parameters by explicitly taking into account a finite-sites model with heterogeneity of mutation rates. We also propose an alternative way to derive confidence intervals around the estimated parameters, based on a bootstrap approach. By checking the validity of these confidence intervals by simulations, we find that only those associated with the timing of the expansion are approximately correctly estimated, while those around the population sizes are overly large. We also propose a test of the validity of the estimated demographic expansion scenario, whose proper behavior is verified by simulation. We illustrate our method with human mitochondrial DNA, where estimates of expansion times are found to be 10-20% larger when taking into account heterogeneity of mutation rates than under the infinite-sites model.

DNA, Mitochondrial↗
PubMed2005

Mutation rates in the dystrophin gene: a hotspot of mutation at a CpG dinucleotide.

An analysis of mutations was performed in 141 Duchenne muscular dystrophy (DMD) patients previously found to be negative for large deletions by standard multiplex PCR assays. Comprehensive mutation scanning of all coding exons, adjacent intronic splice regions, and promoter sequences was performed by DOVAM-S, a robotically enhanced, high throughput method that detects essentially all point mutations. Samples negative for point mutations were further analyzed for duplications by multiplex amplifiable probe hybridization (MAPH). Presumptive causative mutations were detected in 90% of the patients (70% protein truncating point mutations, 13% duplications, and 7% deletions not detected by the standard multiplex screening method). A total of 40 of the mutations are putatively novel. Most duplications involve multiple exons with an average and median size of about 160 and 153 kb, respectively. This is the first analysis of the absolute and relative rates of point mutations in the dystrophin gene. Relative to microdeletions (0.68 x 10(-9) per bp per generation), transitions at CpG dinucleotides are enhanced 150-fold while complex indels, the least common mutation type, are less frequent than microdeletions by a factor of five. The frequency of microdeletions and microinsertions at mononucleotide repeats increases exponentially with length. When compared to the well-studied human factor IX gene (F9), the results are similar, with two exceptions: a hotspot of mutation in the dystrophin gene (c.8713C>T/p.R2905X) at a CpG dinucleotide and an altered size distribution of microdeletions. The hotspot reflects a difference in the underlying pattern of mutation, while the altered size distribution of microdeletions reflects certain abundant sequence motifs within the dystrophin coding sequence (relative to factor IX).

Adolescent↗
PubMed1988

Spontaneous mutation rates to new length alleles at tandem-repetitive hypervariable loci in human DNA.

Tandem-repetitive minisatellite regions in vertebrate DNA frequently show substantial allelic variation in the number of repeat units. This variation is thought to arise through processes such as unequal crossover or replication slippage. We show here that the spontaneous mutation rate to new length alleles at extremely variable human minisatellites is sufficiently high to be directly measurable in human pedigrees. The mutation rate at different loci increases with variability in accord with the neutral mutation/random drift hypothesis, and rises to 5% per gamete for the most unstable human minisatellite isolated. Mutations are sporadic, occur with similar frequencies in sperm and oocytes, and can involve the gain or loss of substantial numbers of repeat units, consistent with length changes arising primarily by unequal exchange at meiosis. Germline instability must therefore be taken into account when using hypervariable loci as genetic markers, particularly in pedigree analysis and parenthood testing.

Alleles↗
PubMed2003

Maternal and paternal lineages of the Samaritan isolate: mutation rates and time to most recent common male ancestor.

The Samaritan community is a small, isolated, and highly endogamous group numbering some 650 members who have maintained extensive genealogical records for the past 13-15 generations. We performed mutation detection experiments on mitochondrial DNAs and Y chromosomes from confirmed maternal and paternal lineages to estimate mutation rates in these two haploid compartments of the genome. One hundred and twenty four DNA samples from different pedigrees (representing 200 generation links) were analyzed for the mtDNA hypervariable I and II regions, and 74 male samples (comprising 139 links) were typed for 12 Y-STRs mapping to the non-recombining portion of the Y chromosome (NRY). Excluding two somatic heteroplasmic substitutions and several length variants in the homopolymeric C run in the HVII region, no mutations were found in the Samaritans' maternal lineages. Based on mutations found in Samaritan paternal lineages, an estimate of a mutation rate of 0.42% (95% confidence interval of 0.22%-0.71%) across 12 Y-STRs was obtained. This estimate is slightly higher than those obtained in previous pedigree studies in other populations. The haplotypes identified in Samaritan paternal lineages that belong to the same haplogroup were used to estimate the number of generations elapsed since their most recent common ancestor (MRCA). The estimate of 80 generations corresponds with accepted traditions of the origin of this sect.

Biological Evolution↗
PubMed1981

Unbalanced Robertsonian translocations associated with Down's syndrome or Patau's syndrome: chromosome subtype, proportion inherited, mutation rates, and sex ratio.

Summary data are presented on 168 D/21 and 131 G/21 translocation trisomies reported to the New York State Chromosome Registry. By combining these data with others from the literature it is estimated that about 59% of D/21 cases are the result of mutation in hte parental generation; the rest are translocations inherited from parental carriers (39% maternal, 3% paternal). The proportion of mutants is about 10% greater for 14/21 cases and significant lower for 13/21 cases. Of G/21 cases 93% are mutant, about 6% of maternal origin, and 1% of paternal origin. All the mutant cases involve 21/21 rearrangements. Estimated mutation rates per 10(5) gametes for translocation trisomies in affected livebirths are 0.1 for 21/13, 0.5 to 0.9 for 21/14, and 1.1 to 1.4 for 21/21. The rates for 21/15 and 21/22 translocation trisomies are probably all conservatively less than 0.1 per 10(5) gametes. Of interchange trisomy Patau's syndrome, about 60% of cases are mutant; the rest are translocations inherited from a parental carrier (about 25% maternal, 15% paternal). The mutant proportion is about 90% for 13/13 cases and about 45% for 13/14 cases. The estimated mutation rates for 13/13 and 13/14 interchange trisomies are each about 0.5 per 10(5) gametes; te rate for 13/15 interchange trisomies is less than 0.1 per 10(5) gametes. A male excess is observed for D/21 (sex ratio = 1.70) and G/21 (sex ratio = 1.38) interchange Down's syndrome, and a female excess for D/13 interchange Patau's syndrome (sex ration = 0.77), trends similar to those seen in the respective 47, trisomies associated with these phenotypes.

Chromosomes, Human, 13-15↗
PubMed2000

Differential influence of nucleoside analog-resistance mutations K65R and L74V on the overall mutation rate and error specificity of human immunodeficiency virus type 1 reverse transcriptase.

Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) variants with the K65R or L74V substitution display resistance to several nucleoside analogs. An in vitro dNTP exclusion assay revealed an increased fidelity for K65R RT compared with wild-type RT, but little change for L74V RT. When the forward mutation rates were measured via a gap-filling assay, the K65R variant displayed an 8-fold decrease in the overall mutation rate (1.0 x 10(-3) versus 8.6 x 10(-3) for wild-type HIV-1 RT), whereas the rate for the L74V variant was closer to that for wild-type RT (5.0 x 10(-3)). The increase in overall fidelity observed for K65R RT is the largest reported for any drug-resistant HIV-1 RT variant. Nucleotide sequence analysis of lacZalpha mutants generated by variant RTs indicated that K65R RT displays uniform reduction in most types of errors, whereas L74V RT does not. Modeling the substitutions into the x-ray structure of the ternary complex revealed that the major influence of Leu(74) in stabilizing the templating base is unaffected by Val substitution, whereas the K65R substitution appears to increase the stringency of dNTP binding. It is speculated that the increased fidelity of K65R RT is due to an altered interaction with the dNTP substrate.

Anti-HIV Agents↗
PubMed1996

The estimation of in vivo mutation rate and frequency from samples of human lymphocytes.

In vivo mutation assays usually involve enumeration of mutant cells in samples drawn from individuals or populations, and inferences concerning quantitative aspects of mutation are made from the results. Individual cells within the samples may show clonal relationships with each other. For populations of constant size, which do not obey Luria-Delbruck kinetics, mutation frequency should be calculated from the number of mutant cells and not from the number of mutant clones. The change in mutation frequency/unit time provides the best estimate of the mutation rate, which for human T lymphocytes is approx. 2.0 x 10(-9) mutations/cell/day, a rate higher than that explicable by proliferation alone. Since lymphocyte populations in vivo contain uncommon large clones, the statistics of rare events results in all measured mutant frequencies for individuals being affected by discontinuous variation. The presence or absence of a large mutant clone in an individual results in the measured MF being either a large overestimate of the population MF in a minority of individuals or a small underestimate in the majority of individuals. An adjusted mutation frequency can be calculated to eliminate this source of variation but this is rarely necessary.

Cell Division↗
PubMedDate not supplied

Inequality in mutation rates of the two strands of DNA.

As the mechanisms for replicating the two strands of duplex DNA differ it is, in principle, possible for the mutation rates to differ depending on which strand is being copied. In the absence of selection this would lead to a difference in the measured rate of a particular base substitution, such as T to C, depending on which DNA strand was analysed to determine the rate. Thus a change such as T to C on one DNA strand results from either a direct T-to-C mutation on that strand or an A-to-G mutation on the complementary strand; for the other strand the situation is reversed, and it can be seen that different processes are responsible for the two cases, allowing for asymmetry in substitution rate. We have tested whether such asymmetry indeed occurs by studying equivalent sequences from the beta-globin complexes of six species of primate. Our results reveal an asymmetry in substitution rates consistent with predictions based on strand-inequalities in mutation rates. Our sequence comparisons also allow us to make predictions about the positions of replication origins and the replication error rates of one strand relative to the other.

Animals↗
PubMed1996

Purine deoxynucleoside metabolism in human melanoma cells with a high spontaneous mutation rate.

A human melanoma cell line (MM96L) had a spontaneous mutation rate at the HGPRT locus of approx. 7 times normal. The cells had elevated dATP and dGTP pools, lacked purine nucleoside phosphorylase (PNP) and were sensitive to killing by deoxyadenosine, deoxyinosine and related purines but not to inosine or hypoxanthine. Four other melanoma cell lines exhibited a range of nucleoside sensitivities and dNTP pool sizes. Failure of intact MM96L cells to degrade exogenous deoxyadenosine and deoxyinosine to hypoxanthine was confirmed by NMR of culture medium. Normal melanocytes were PNP+ and were insensitive to deoxyinosine. Comparison of the metabolites of [14C]deoxyinosine from MM96L and a PNP+ cell line of similar doubling time (HeLa) showed that both cell types produced 14C-labelled guanine and adenine nucleotides, with [14C]dATP and [14C]dADP being found in MM96L. This indicates that human sAMP synthetase or a similar enzyme catalyses the conversion of dIMP to dAMP, the resultant elevation of dATP causing base misincorporation and a mutator phenotype.

Alanine↗
PubMed1966

Increased mutation rate of E. coli K12 lambda cultures maintained in continuous logarithmic growth.

Continuous logarithmic growth of E. coli K12 lambda in an automatic culture cell resulted in marked increases in the proportion of several mutants. The P1 phage-resistant cells increased 10 to 3000 times, the T2 phage-resistant cells 1 to 1000 times, the neomycin-resistant cells 1 to 10 times, and the virus-producing cells 30 to 70 times. No change occurred in the penicillin-resistant cells. Calculation of the growth curves and direct determination of the mutation rates by the null fraction method showed that the increases in the proportion of mutants were due to increases in the mutation rates.

Escherichia coli↗
PubMed1996

Bayesian procedures for the estimation of mutation rates from fluctuation experiments.

Bayesian procedures are developed for estimating mutation rates from fluctuation experiments. Three Bayesian point estimators are compared with four traditional ones using the results of 10,000 simulated experiments. The Bayesian estimators were found to be at least as efficient as the best of the previously known estimators. The best Bayesian estimator is one that uses (1/m2) as the prior probability density function and a quadratic loss function. The advantage of using these estimators is most pronounced when the number of fluctuation test tubes is small. Bayesian estimation allows the incorporation of prior knowledge about the estimated parameter, in which case the resulting estimators are the most efficient. It enables the straightforward construction of confidence intervals for the estimated parameter. The increase of efficiency with prior information and the narrowing of the confidence intervals with additional experimental results are investigated. The results of the simulations show that any potential inaccuracy of estimation arising from lumping together all cultures with more than n mutants (the jackpots) almost disappears at n = 70 (provided that the number of mutations in a culture is low). These methods are applied to a set of experimental data to illustrate their use.

Bacteria↗