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PubMed1970

The dynamics of life. II. The steady-state theory of mutation rates.

The statistical effect of internal irradiation on the survival of beagles is similar to that of aging, with the exception that death occurs earlier. Since biological processes are close to equilibrium most of the time, the above observation suggests that death ensues when the rate of insult has exceeded the rate of recovery to a sufficient extent that the reserves are depleted and the steady state can no longer be maintained. The steady-state theory of mutation rates is derived from first principles, and, through absolute rate theory, is completely general and is not limited to a specific kind of cellular alteration. However, the nature of the cellular alterations that lead to nonsurvival are considered. The young growing system is also considered in the context of this theory.

Aging↗
PubMed1988

Use of the averaged mutation rate in pieces of protein sequences to predict the location of antigenic determinants.

Antigenic determinants in proteins show properties, which can be used to their prediction: high degree of accessibility, mobility, polarity etc. Furthermore, there is a remarkable correlation between the location of antigenic determinants and regions with high frequency of accepted mutations during the evolution. Consequently, it is possible to predict successfully the location of antigenic epitopes in proteins using the averaged mutation rate of protein sequence pieces.

Amino Acid Sequence↗
PubMed1987

Spontaneous mutation rates in cloned murine tumors do not correlate with metastatic potential, whereas the prevalence of karyotypic abnormalities in the parental tumors does.

We tested the hypothesis that highly malignant cell lines are genomically more unstable than their less malignant counterparts, and that this instability is more pronounced in clones than in cell lines. We compared MDAY-D2 to its non-metastatic variant, D36W25, with regard to (1) the rate of development of ouabain resistance within parallel clones and (2) the prevalence of G-banded karyotypic abnormalities. We detected no significant difference between the spontaneous mutation rates for ouabain resistance. However, the MDAY-D2 cell line possessed both a higher prevalence and greater diversity of chromosomal abnormalities. One possible explanation for these seemingly inconsistent results is that genomic instability may remain essentially constant throughout tumor progression, whereas an accumulation of genetic changes may be responsible for the observed increased prevalence of abnormalities and the development of selective survival advantages during progression.

Animals↗
PubMed1994

A phylogenetic estimator of effective population size or mutation rate.

A new estimator of the essential parameter theta = 4Ne mu from DNA polymorphism data is developed under the neutral Wright-Fisher model without recombination and population subdivision, where Ne is the effective population size and mu is the mutation rate per locus per generation. The new estimator has a variance only slightly larger than the minimum variance of all possible unbiased estimators of the parameter and is substantially smaller than that of any existing estimator. The high efficiency of the new estimator is achieved by making full use of phylogenetic information in a sample of DNA sequences from a population. An example of estimating theta by the new method is presented using the mitochondrial sequences from an American Indian population.

DNA, Mitochondrial↗
PubMed1999

Some statistical improvements for estimating population size and mutation rate from segregating sites in DNA sequences.

In population genetics, under a neutral Wright-Fisher model, the scaling parameter straight theta=4Nmu represents twice the average number of new mutants per generation. The effective population size is N and mu is the mutation rate per sequence per generation. Watterson proposed a consistent estimator of this parameter based on the number of segregating sites in a sample of nucleotide sequences. We study the distribution of the Watterson estimator. Enlarging the size of the sample, we asymptotically set a Central Limit Theorem for the Watterson estimator. This exhibits asymptotic normality with a slow rate of convergence. We then prove the asymptotic efficiency of this estimator. In the second part, we illustrate the slow rate of convergence found in the Central Limit Theorem. To this end, by studying the confidence intervals, we show that the asymptotic Gaussian distribution is not a good approximation for the Watterson estimator.

Base Sequence↗
PubMed2006

Mitochondrial DNA sequence variation and mutation rate in patients with CADASIL.

Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is clinically characterised by recurrent ischemic strokes, migraine with aura, psychiatric symptoms, cognitive decline and dementia. We have previously described a patient with CADASIL caused by a R133C mutation in the NOTCH3 gene and with a concomitant myopathy caused by a 5650G>A mutation in the MTTA gene in mitochondrial DNA (mtDNA). We assume that the co-occurrence of the two mutations is not coincidental and that mutations in the NOTCH3 gene may predispose the mtDNA to mutations. We therefore examined the nucleotide variation in the mtDNA coding region sequences in 20 CADASIL pedigrees with 77 affected patients by conformation-sensitive gel electrophoresis and sequencing. The sequence variation in mtDNA was then compared with that among 192 healthy Finns. A total of 180 mtDNA coding region sequence differences were found relative to the revised Cambridge reference sequence, including five novel synonymous substitutions, two novel nonsynonymous substitutions and one novel tRNA substitution. We found that maternal relatives in two pedigrees differed from each other in their mtDNA. Furthermore, the average number of pairwise differences in sequences from the 41 unrelated maternal lineages with CADASIL was higher than that expected among haplogroup-matched controls. The numbers of polymorphic sites and polymorphisms that were present in only one sequence were also higher among the CADASIL sequences than among the control sequences. Our results show that mtDNA sequence variation is increased within CADASIL pedigrees. These findings suggest a relationship between NOTCH3 and mtDNA.

Adult↗
PubMed1985

Exceptionally high and diverse mutation rates in insects small rRNA.

The nucleotide sequence of 5S rRNA from the posterior silk gland of the silk worm Philosamia cynthia ricini has been determined. The comparison with other insect 5S rRNAs revealed an exceptionally conserved secondary structure, in spite of an extremely high mutation rate: Thirteen nucleotides are different in Philosamia and Drosophila 5S rRNA, but all substitutions are either compensatory or occur in loops or introduce G:U base pairs. The rates of base substitution per site per year of several insect species (diptera and lepidoptera) 5S and 5.8S rRNAs are compared with those occurring in vertebrate rRNAs. In the latter cases the rates are remarkably constant, whereas their value is not only about twofold higher in insect rRNAs, but is found to be extremely large in the 5S rRNA of the silkworm Bombyx mori. These data demonstrate that phylogenetic conclusions derived from small rRNA sequence comparisons are only of limited value.

Animals↗
PubMed1997

De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling.

Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder. We have identified de novo rearrangements in 7 (approximately 2%) index patients from 340 informative SMA families. In each, the rearrangements resulted in the absence of the telomeric copy of the survival motor neuron (SMN) gene (telSMN), in two cases accompanied by the loss of the neuronal apoptosis-inhibitory protein gene . Haplotype analysis revealed unequal recombination in four cases, with loss of markers Ag1-CA and C212, which are near the 5' ends of the SMN genes. In one case, an interchromosomal rearrangement involving both the SMN genes and a regrouping of Ag1-CA and C212 alleles must have occurred, suggesting either interchromosomal gene conversion or double recombination. In two cases, no such rearrangement was observed, but loss of telSMN plus Ag1-CA and C212 alleles in one case suggested intrachromosomal deletion or gene conversion. In six of the seven cases, the de novo rearrangement had occurred during paternal meiosis. Direct detection of de novo SMA mutations by molecular genetic means has allowed us to estimate for the first time the mutation rate for a recessive disorder in humans. The sex-averaged rate of 1.1 x 10(-4), arrived at in a proband-based approach, compares well with the rate of 0.9 x 10(-4) expected under a mutation-selection equilibrium for SMA. These findings have important implications for genetic counseling and prenatal diagnosis in that they emphasize the relevance of indirect genotype analysis in combination with direct SMN-gene deletion testing in SMA families.

Alleles↗
PubMed1992

Genetics of neurofibromatosis 1 in Japan: mutation rate and paternal age effect.

We have performed formal genetic studies on 26 patients (14 males, 12 females) with neurofibromatosis 1 (von Recklinghausen's disease, NF1) in Japan. Family studies of 74 members of 18 kindreds revealed that 50% of the cases were caused by a new mutation; the mutation rate was assumed to be 7.3-10.5 x 10(-5). A tendency of paternal age effect, which was not accounted for by the maternal age effect, was observed, but live-birth order had no significant effect. Genetic linkage of neurofibromatosis 1 to the NF1 gene or the genetic marker in the pericentric region of chromosome 17 was established in 3 informative families.

Age Factors↗
PubMed2002

Moderate G6PD deficiency increases mutation rates in the brain of mice.

Mice that harbored the x-ray-induced low efficiency allele of the major X-linked isozyme of glucose-6-phospate dehydrogenase (G6PD), Gpdx(a-m2Neu), and, in addition, harbored the transgenic shuttle vector for the determination of mutagenesis in vivo, pUR288, were employed to further our understanding of the interdependence of general metabolism, oxidative stress control, and somatic mutagenesis. The Gpdx(a-m2Neu) mutation conferred moderate G6PD deficiency in hemizygous males (Gpdx(a-m2Neu/y)) displaying residual enzyme activities of 27% in red blood cells and 13% in brain (compared to wild-type controls, Gpdx(a/y) males). In spite of this mild phenotype, the brains of G6PD-deficient males exhibited a significant distortion of redox control ( approximately 3-fold decrease in the ratio of reduced glutathione to oxidized glutathione), a considerable accumulation of promutagenic etheno DNA adducts ( approximately 13-fold increase in ethenodeoxyadenosine and approximately 5-fold increase in ethenodeoxycytidine), and a substantial elevation of somatic mutation rates ( approximately 3-fold increase in mutant frequencies in lacZ, the target and reporter gene of mutagenesis in the shuttle vector, pUR288). The mutation pattern in the brain was dominated by illegitimate genetic recombinations, a presumed hallmark of oxidative mutagenesis. These findings suggested a critical function for G6PD in limiting oxidative mutagenesis in the mouse brain.

Anemia, Hemolytic↗
PubMed2002

Synonymous-non-synonymous mutation rates between sequences containing ambiguous nucleotides (Syn-SCAN).

SUMMARY: Direct PCR sequencing on genetic material containing allelic mixtures results in sequences containing ambiguous nucleotides. Because codons exhibiting allelic mixtures present evidence of evolutionary pressure, it is important to include this information in the assessment of codon synonymy. We developed a program, 'Synonymous-Nonsynonymous Mutation Rates between Sequences Containing Ambiguous Nucleotides' (Syn-SCAN), that calculates synonymous and non-synonymous substitution rates using a model that includes allelic mixtures. AVAILABILITY: Syn-SCAN is implemented on the web and can be downloaded from http://hivdb.stanford.edu.

Alleles↗
PubMed1977

HLA variants of cultured human lymphoid cells: evidence for mutational origin and estimation of mutation rate.

Variants of a diploid lymphoid cell line that show a loss of HLA-B27 antigen occur randomly in time and independently of exposure to the alloantiserum used for their isolation. From these and previous findings of variant stability, inducibility by mutagens, and the absence of linked variation, we colclude that most HLA variants arise by mutation. The mutation rate for HLA-B27 loss is 8 x 10(-7) per cell per generation.

B-Lymphocytes↗
PubMed1979

Increased mutation rates in doubly viral transformed Chinese hamster cells.

An untransformed parental Chinese hamster cell line, one polyoma transformed clone, and two clones containing both SV40 and polyoma DNA were tested for the appearance of variants resistant to 6-thioguanine or oubain. The frequency of such variants was found to be highest in doubly transformed cells. The mutation rate at these loci was correlated with the level of transformation. The mutants observed were stable and had low reversion frequencies with no gross cytogenetic changes. These results establish a quantitative basis for the evaluation of phenotypic variability observed in transformed cell populations.

Animals↗
PubMed2004

Updated Brazilian genetic data, together with mutation rates, on 19 STR loci, including D10S1237.

Allelic frequencies for 19 STR loci (F13B, TPOX, D3S1358, FGA, CSF1PO, D5S818, F13A01, D7S820, D8S1179, D10S1237, TH01, VWA, D13S317, FESFPS, Penta E, D16S539, D18S51, D19S253, and D21S11) were obtained from an average of 13,000 unrelated Brazilian adults undergoing parentage testing. D10S1237 is a tetranucleotide repeat locus shown to be useful for forensic and paternity studies. Null allele frequencies and mutation rates were ascertained from this population sample.

Brazil↗
PubMed1989

A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity.

A population based study of von Recklinghausen neurofibromatosis in south east Wales (population 668,100) identified 69 families with 135 affected members (prevalence 1/4950 of the population). In these families penetrance of the NF-1 gene was 100% by the age of five years. The genetic fitness of NF-1 sufferers was found to be reduced to 0.47, the effect being more marked in males than females (f = 0.31 and 0.60, respectively). Forty-one of 135 cases were judged to represent new disease mutations and the mutation rate was estimated to lie between 3.1 x 10(-5) and 10.4 x 10(-5). A parental age effect for new mutations was not found, nor was a maternal effect on disease severity.

Adolescent↗
PubMed2005

Overproduction of DNA polymerase eta does not raise the spontaneous mutation rate in diploid human fibroblasts.

Telomerase-immortalized lines of diploid xeroderma pigmentosum variant (XP-V) fibroblasts (XP115LO and XP4BE) were complemented for constitutive or regulated expression of wild-type human DNA polymerase eta (hpol eta). The ectopic gene was expressed from a retroviral LTR at a population average of 34- to 59-fold above the endogenous (mutated) mRNA and high levels of hpol eta were detected by immunoblotting. The POLH cDNA was also cloned downstream from an ecdysone-regulated promoter and transduced into the same recipient cells. Abundance of the wild-type mRNA increased approximately 10-fold by addition of ponasterone to the culture medium. Complemented cell lines acquired normal resistance to the cytotoxic effects of UVC, even in the presence of 1mM caffeine. They also tolerated higher levels of UVC-induced template lesions during nascent DNA elongation when compared to normal fibroblasts (NHF). UVC-induced mutation frequencies at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus were measured in the XP115LO+XPV cell line overproducing hpol eta constitutively (E. Bassett, N.M. King, M.F. Bryant, S. Hector, L. Pendyala, S.G. Chaney, M. Cordeiro-Stone, The role of DNA polymerase eta in translesion synthesis past platinum-DNA adducts in human fibroblasts, Cancer Res. 64 (2004) 6469-6475). Induced mutation frequencies were significantly reduced, even below those observed in NHF; however, the average mutation frequency in untreated cultures was about three-fold higher than in the isogenic vector-control cell line. In this study, spontaneous HPRT mutation frequencies were measured at regular intervals, as isogenic fibroblasts either lacking or overproducing hpol eta were expanded for 100 population doublings. The mutation rates estimated from these results were not significantly increased in XP115LO cells expressing abnormal levels of hpol eta, relative to the cells lacking this specialized polymerase. These findings suggest that diploid human fibroblasts with normal DNA repair capacities and intact checkpoints are well protected against the potential mutagenic outcome of overproducing hpol eta, while still benefiting from accurate translesion synthesis of UV-induced pyrimidine dimers.

Blotting, Western↗