Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Mutation Rate”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 451 records · Page 25Linked to original sources
PubMed1984

Modulation of mutation rates in bacteriophage T4 by a base-pair change a dozen nucleotides removed.

Neighboring base-pairs are known to affect site-specific mutability. A previous analysis had suggested that such effects might decrease rapidly with distance. Here, however, we demonstrate a longer-range (unneighborly) base-pair effect on site-specific mutabilities: a single base-pair substitution substantially alters transition mutation rates at sites more than ten base-pairs away. DNA sequencing carried out during this analysis extends the known sequence of the rIIA cistron by 333 residues.

Base Composition↗
PubMed1998

DNA hypomethylation leads to elevated mutation rates.

Genome-wide demethylation has been suggested to be a step in carcinogenesis. Evidence for this notion comes from the frequently observed global DNA hypomethylation in tumour cells, and from a recent study suggesting that defects in DNA methylation might contribute to the genomic instability of some colorectal tumour cell lines. DNA hypomethylation has also been associated with abnormal chromosomal structures, as observed in cells from patients with ICF (Immunodeficiency, Centromeric instability and Facial abnormalities) syndrome and in cells treated with the demethylating agent 5-azadeoxycytidine. Here we report that murine embryonic stem cells nullizygous for the major DNA methyltransferase (Dnmt1) gene exhibited significantly elevated mutation rates at both the endogenous hypoxanthine phosphoribosyltransferase (Hprt) gene and an integrated viral thymidine kinase (tk) transgene. Gene deletions were the predominant mutations at both loci. The major cause of the observed tk deletions was either mitotic recombination or chromosomal loss accompanied by duplication of the remaining chromosome. Our results imply an important role for mammalian DNA methylation in maintaining genome stability.

Animals↗
PubMed2005

A study of mutation rates and the characterisation of intermediate, null and duplicated alleles for 13 Y chromosome STRs.

Previously reported Y chromosome STR haplotype databases for three UK population groups, plus additionally analysed samples, have been scrutinised for the presence of non-standard (intermediate, null and duplicated) alleles. These alleles have been characterised by sequencing, some showing changes in the repeat structure, and the frequencies reported. Mutation rates for each of the 13 STRs have been calculated when analysis of father-son pairs has been possible. An example illustrating the use of non-standard alleles in a large family tree is outlined.

Chromosomes, Human, Y↗
PubMed1983

Retinoblastoma mutation rate in New Zealand and support for the two-hit model.

Age-specific incidence rates for 96 New Zealand patients with sporadic retinoblastoma peaked earlier for bilateral patients than for unilateral patients. The cumulative log survival until diagnosis for bilateral and unilateral patients followed linear and quadratic curves respectively, and supported the two-hit hypothesis for retinoblastoma. The germ cell mutation rate for retinoblastoma, assuming a single major gene, was calculated to be in the order of 9.3 X 10(-6) to 10.9 X 10(-6) for the New Zealand population.

Age Factors↗
PubMed2000

Meiosis and the evolution of recombination at low mutation rates.

The classical understanding of recombination is that in large asexual populations with multiplicative fitness, linkage disequilibrium is negligible, and thus there is no selective agent driving an allele for recombination. This has led researchers to recognize the importance of synergistic epistatic selection in generating negative linkage disequilibrium that thereby renders an advantage to recombination. Yet data on such selection is equivocal, and various works have shown that synergistic epistasis per se, when left unquantified in its magnitude or operation, is not sufficient to drive the evolution of recombination. Here we show that neither it, nor any mechanism generating negative linkage disequilibrium among fitness-related loci, is necessary. We demonstrate that a neutral gene for recombination can increase in frequency in a large population under a low mutation rate and strict multiplicative fitness. We work in a parameter range where individuals have, on average, less than one mutation each, yet recombination can still evolve. We demonstrate this in two ways: first, by examining the consequences of recombination correlated with misrepaired DNA damage and, second, by increasing the probability of recombination with declining fitness. Interestingly, the allele spreads without repairing even a single DNA mutation.

Alleles↗
PubMed2002

Chlorambucil-induced high mutation rate and suicidal gene downregulation in a base excision repair-deficient Escherichia coli strain.

Chlorambucil (CLB; N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid) is a bifunctional alkylating agent widely used as an anticancer drug and also as an immunosuppressant. Its chemical structure and clinical experience indicate that CLB is mutagenic and carcinogenic. We have investigated the ability of CLB to induce mutations and gene expression changes in the wild-type (WT) Escherichia coli strain AB1157 and in the base excision repair-deficient (alkA1, tag-1) E. coli strain MV1932 using a rifampicin (rif) forward mutation system and a cDNA array method. The results showed that CLB is a potent mutagen in MV1932 cells compared with the E. coli WT strain AB1157, emphasizing the role of 3-methyladenine DNA glycosylases I and II in protecting the cells from CLB-induced DNA damage and subsequent mutations. Global gene expression profiling revealed that nine genes in WT E. coli and 100 genes in MV1932, of a total of 4290 genes, responded at least 2.5-fold to CLB. Interestingly, all of these MV1932 genes were downregulated, while 22% were upregulated in WT cells. The downregulated genes in MV1932 represented most (19/23) functional categories, and unexpectedly, many of them code for proteins responsible for genomic integrity. These include: (i) RecF (SOS-response, adaptive mutation), (ii) RecC (resistance to cross-linking agents), (iii) HepA (DNA repair, a possible substitute of RecBCD), (iv) Ssb (DNA recombination repair, controls RecBCD), and (v) SbcC (genetic recombination). Our results strongly suggest that in addition to the DNA damage itself, the downregulation of central protecting genes is responsible for the decreased cell survival (demonstrated in a previous work) and the increased mutation rate (this work) of DNA repair-deficient cells, when exposed to CLB.

Alkylating Agents↗
PubMed1990

Neurofibromatosis-1: a maximum likelihood estimation of mutation rate.

Methods of classical segregation analysis were applied to a sample of 129 sibships with one or more individuals affected by neurofibromatosis-1 (NF-1). The sample consists only of subjects with NF-1; all the probands had been referred for genetic counselling because of café-au-lait spots, and a diagnostic protocol was invariably applied. No deviation from the segregation ratio expected for a fully penetrant Mendelian dominant gene was observed. A maximum likelihood estimate of the proportion of sporadic cases was obtained, and the mutation rate was estimated to be 6.5 x 10(-5) gametes per generation (95% CI 5.0-8.1).

Adult↗
PubMed2003

Recombination or mutation rate heterogeneity? Implications for Mitochondrial Eve.

The study of mitochondrial DNA (mtDNA) has helped to demonstrate the African origin of our species and the relationship between living humans and the Neanderthals. mtDNA data have also been used to establish the time and route of major events in human history, such as the expansion of Neolithic farmers into Europe, and the settlement of the Pacific and the New World. However, it is becoming apparent that mtDNA evolution is more complex than previously believed. Anomalous mutation patterns perturb phylogenetic assumptions based on mtDNA data. Although they are frequently dismissed as sequencing errors or mutation hotspots, some of the anomalies have no satisfactory explanation. The mechanisms behind apparent mutation rate heterogeneity, or even possible mtDNA recombination, remain unknown. These issues need to be addressed, as they have profound consequences for the interpretation of mtDNA data.

Base Sequence↗
PubMed2003

Impact of selection, mutation rate and genetic drift on human genetic variation.

The accumulation of genome-wide information on single nucleotide polymorphisms in humans provides an unprecedented opportunity to detect the evolutionary forces responsible for heterogeneity of the level of genetic variability across loci. Previous studies have shown that history of recombination events has produced long haplotype blocks in the human genome, which contribute to this heterogeneity. Other factors, however, such as natural selection or the heterogeneity of mutation rates across loci, may also lead to heterogeneity of genetic variability. We compared synonymous and non-synonymous variability within human genes with their divergence from murine orthologs. We separately analyzed the non-synonymous variants predicted to damage protein structure or function and the variants predicted to be functionally benign. The predictions were based on comparative sequence analysis and, in some cases, on the analysis of protein structure. A strong correlation between non-synonymous, benign variability and non-synonymous human-mouse divergence suggests that selection played an important role in shaping the pattern of variability in coding regions of human genes. However, the lack of correlation between deleterious variability and evolutionary divergence shows that a substantial proportion of the observed non-synonymous single-nucleotide polymorphisms reduces fitness and never reaches fixation. Evolutionary and medical implications of the impact of selection on human polymorphisms are discussed.

Animals↗
PubMed1988

Nonsense and missense mutations in hemophilia A: estimate of the relative mutation rate at CG dinucleotides.

Hemophilia A is an X-linked disease of coagulation caused by deficiency of factor VIII. Using cloned cDNA and synthetic oligonucleotide probes, we have now screened 240 patients and found CG-to-TG transitions in an exon in nine. We have previously reported four of these patients; and here we report the remaining five, all of whom were severely affected. In one patient a TaqI site was lost in exon 23, and in the other four it was lost in exon 24. The novel exon 23 mutation is a CG-to-TG substitution at the codon for amino acid residue 2166, producing a nonsense codon in place of the normal codon for arginine. Similarly, the exon 24 mutations are also generated by CG-to-TG transitions, either on the sense strand producing nonsense mutations or on the antisense strand producing missense mutations (Arg to Gln) at position 2228. The novel missense mutations are the first such mutations observed in association with severe hemophilia A. These results provide further evidence that recurrent mutations are not uncommon in hemophilia A, and they also allow us to estimate that the extent of hypermutability of CG dinucleotides is 10-20 times greater than the average mutation rate for hemophilia A.

Adolescent↗
PubMed1992

[Genetic differentiation of the inhabitants of Mongolia. Geographic distribution of mitochondrial DNA RFLPs and mitotypes in the inhabitants of Mongolia and a population assessment of the mutation rate in the mitochondrial genome].

The geographical distribution of the Asian specific deletion--insertion polymorphisms and or the RFLP's in the V noncoding region and the D-loop and of the mitotypes was analysed in Mongolia. The frequencies of the mtDNA markers demonstrated homogeneity of 18 local groups in Mongolia. The geographical distribution of the mitotypes showed the existence of two ancestral maternal lineages in mongols. There was no significant difference in the average FST values between mitochondrial gene flow and the nuclear gene flow of the Mongolian population. The equality of FST values permit to calculate the mutation rate for the human mtDNA--6.10(-9) per nucleotide per year. The data reveals the Mongolian population is in the equilibrium.

DNA, Mitochondrial↗
PubMed2006

Evidence of altered gene flow, mutation rate, and genetic diversity in redbreast sunfish from a pulp-mill-contaminated river.

To determine effects of pulp mill effluent on population genetic structure, redbreast sunfish (Lepomis auritus) were collected from several sites along the Pigeon River, NC, as well as from reference sites. Previous studies found effects on molecular, biochemical, physiological, population, and community level endpoints in these populations. The population genetic structure of these fish was determined using the randomly amplified polymorphic DNA (RAPD) technique. The level of genetic diversity was higher in the Pigeon River populations than in the reference populations. Genetic distances among populations could not be explained by drainage patterns and may have been altered by contaminant exposure. Phylogeographic analysis, maximum likelihood analysis, and assignment tests suggested that there were fewer emigrants and more immigrants in the contaminated sites than in the reference sites, suggesting that the contaminated sites may harbor "sinklike" populations. Finally, a "terminal branch amplitype" analysis (neighbor-joining and minimum-spanning trees) and maximum likelihood analysis indicated that there may be an elevated mutation rate in the polluted sites. Thus, the genetic diversity (within and among populations) in the Pigeon River populations may have been affected by altered gene flow and mutational processes as a result of pulp mill effluent discharge.

Animals↗
PubMed2000

[Expansion and mutation rate in CTG repeats in the myotonic dystrophy gene].

The CTG repeat of the myotonic dystrophy (MD) gene was analyzed in 62 MD patients and 54 healthy members of their families. A CTG repeat expansion was revealed in 57 (92%) patients and in 12 relatives who did not express clinical signs of MD. Family analysis showed that the CTG repeat number increased, which was associated with anticipation, decreased, or remained the same (17.6%) in alleles transmitted from parents to their children. The spontaneous mutation rate of the CTG repeat was estimated at 4 x 10(-2). Instability was characteristic of alleles with more than 19 repeated units.

Adolescent↗
PubMed2002

Human SNP variability and mutation rate are higher in regions of high recombination.

Understanding the co-variation of nucleotide diversity and local recombination rates is important both for the mapping of disease-associated loci and in understanding the causes of sequence evolution. It is known that single nucleotide polymorphisms (SNPs) around protein coding genes show higher diversity in regions of high recombination. Here, we find that this correlation holds for SNPs across the entire human genome, the great majority of which are not near exons or control elements. Contrasting with results from coding regions, we provide evidence that the higher nucleotide diversity in regions of high recombination is most likely due, at least in part, to a higher mutation rate. One possible explanation for this is that recombination is mutagenic.

Animals↗
PubMed2005

Independent methods for evolutionary genetic dating provide insights into Y-chromosomal STR mutation rates confirming data from direct father-son transmissions.

Five datasets consisting of samples jointly typed for Y-chromosomal Unique Event Polymorphism (UEP) and simple tandem repeat (STR) markers were re-examined with independent methods for dating the different UEP-defined lineages. We report on the results obtained with an original program which performs comparative dating (BARCODE) in comparison with coalescent analyses performed with BATWING under various prior conditions. For the first time these are equalized across datasets. We also report on the results concerning STR mutability as obtained with both methods. The dating results for the entire series of sub-haplogroups are highly correlated. Within coalescent analyses, dating-estimates under a wide range of priors tend to converge. As to STR mutation rates the main findings are: (1) large variations among loci within the same dataset with both methods, also when the same prior was used for all loci; (2) figures in most cases above 1x10(-3) and often above 2x10(-3); (3) a few loci that mutate differently across studies. These results closely match those obtained from direct observation of father-son transmissions. Overall, this work supports the use of genetic dating procedures that take into account the complexity of the phenomenon, with a repertoire of priors tailored on the particular dataset.

Chromosomes, Human, Y↗
PubMed1992

A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity.

A clinical and genetic study of type 2 neurofibromatosis (NF2) has been carried out in the United Kingdom. Virtually complete ascertainment of cases in the north-west of England was achieved and suggests a population incidence of 1 in 33,000 to 40,000. In the UK as a whole, 150 cases have been identified and been used to study the clinical and genetic features of NF2. The autosomal dominant inheritance of NF2 was confirmed, 49% of cases were assessed as representing new mutations, and the mutation rate was estimated to be 6.5 x 10(-6). Evidence to support a maternal gene effect was found in that age at onset was 18.17 years in 36 maternally inherited cases and 24.5 in 20 paternally inherited cases (p = 0.027). The preponderance of maternally inherited cases was also significant (p = 0.03). Data are presented which suggest that there are two types of NF2, one with later onset and bilateral vestibular schwannomas as the only usual feature, and the other with earlier onset and multiple other tumours. A considerable number of cases did not fall easily into one or other group and other factors such as maternal effect on severity and anticipation need to be considered.

Adolescent↗
PubMed1997

Austrian Caucasian population data for the quadruplex plus amelogenin: refined mutation rate for HumvWFA31/A.

Human identification of biological specimens has undergone immense change since the development of PCR typing systems for forensic casework. In contrast to RFLP and VNTRs, STRs are the method of choice when the investigated genomic DNA is present in low quantity or in degraded shape. In the current study, the X-Y homologous gene Amelogenin has been added to a widely used multiplex PCR amplification system consisting of four tetrameric STR loci (Quadruplex-HumTH01, HumvWFA31/A, HumFES/FPS, and HumF13A1). The modified Quadruplex was used to type 382 unrelated Caucasians from Western Austria. The population data meet Hardy-Weinberg and linkage equilibrium expectations, and do not show significant deviations from either US, German, and Turkish Caucasian databases. In an investigation of 382 meioses, two mutations were revealed at the HumvWFA31/A locus. Consequently, the data in this paper provide the conditions for adding Amelogenin to the Quadruplex, and suggest that when doing paternity testing, the mutation rate for the HumvWFA31/A locus must be considered.

Alleles↗
PubMed1993

High mutation rate loci in a subdivided population.

Analytic and simulation studies were carried out in order to predict the average geographic area occupied by alleles in a continuously distributed population. The properties of three statistics were investigated: the sum of the squared distances between members of allelic classes, the sum of the root mean squared distances, and the sum of the squares of the numbers of alleles. The expectations of these quantities can be obtained analytically from both stepping-stone and branching diffusion models. The predictions of these two models are similar for wide ranges of parameter values and are consistent with the simulation results from a stepping-stone model. These results suggest that measures of the geographic distribution of alleles can be useful for estimating average dispersal distances at loci, such as minisatellite and microsatellite loci, at which mutation rates are high enough that they can be estimated with confidence.

Alleles↗