Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Mutation Accumulation”

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 289 records · Page 16Linked to original sources
PubMed2004

A common haplotype associated with the Basque 2362AG --> TCATCT mutation in the muscular calpain-3 gene.

Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by any of over 150 mutations in the calpain-3 (CAPN3) gene. Of those, 2362AG --> TCATCT is particularly prevalent in Basque patients, and this mutation was hypothesized to have arisen in the Basque Country. To explore the natural history of this mutation, we genotyped 65 Basque and non-Basque patients with LGMD2A who carry the 2362AG --> TCATCT mutation for four microsatellites within or flanking the gene. A particular haplotype was found in three-fourths of the patients and was assumed to be ancestral. From the average number of recombinations and mutations accumulated from this ancestral haplotype, the age of the 2362AG ----> TCATCT mutation was estimated to be 50 generations (i.e., 1,250 years), which is more recent than the Paleolithic Basque heritage. The subsequent spread of the 2362AG --> TCATCT mutation can be related to gene flow out of the Basque Country, even across a cultural border.

Calpain↗
PubMed2005

Genomic mutation in lines of Arabidopsis thaliana exposed to ultraviolet-B radiation.

Studies that have attempted to estimate the rate of deleterious mutation have typically been conducted under low levels of ultraviolet-B (UV-B) radiation, a naturally occurring mutagen. We conducted experiments to test whether the inclusion of natural levels of UV-B radiation in mutation-accumulation (MA) experiments influences the rate and effects of mildly deleterious mutation in the plant Arabidopsis thaliana. Ten generations of MA proved insufficient to observe significant changes in means or among-line variances in experimental lines maintained either with or without supplemental UV-B radiation. Maximum-likelihood estimates of mutation rate for total flower number revealed a small but significant rate of mutation for MA lines propagated under supplemental UV-B exposure, but not for those in which supplemental UV-B was omitted. A fraction of the flower number mutations under UV-B (approximately 25-30%) are estimated to increase flower number. Results from the application of transposon display to plant materials obtained after MA, in both the presence and absence of supplemental UV-B, suggest that the average rate of transposition for the class I and II transposable elements (TEs) surveyed was no more than 10(-4). Overall, the estimates of mutation parameters are qualitatively similar to what has been observed in other MA experiments with this species in which supplemental UV-B levels have not been used. As well, it appears that naturally occurring levels of UV-B do not lead to detectable increases in levels of transposable element activity.

Arabidopsis↗
PubMed1993

Low level of genetic drift in foreign sequences replicating in an RNA virus in plants.

The accumulation of mutations was measured in foreign sequences constituting a portion of a hybrid virus derived from the 6.4-kb (+) RNA virus, tobacco mosaic tobamovirus (TMV). Neither of the two foreign sequences tested (dihydrofolate reductase and neomycin phosphotransferase II) are functionally required by the virus, so they should be free of selective pressures and should be a true measure of viral sequence drift in whole plants. Four hybrid virus populations, two of each foreign sequence, were taken through 9-10 passages in whole plants of Nicotiana benthamiana. Sequences were sampled from these populations by conversion to cDNA, amplification by the polymerase chain reaction, and sequencing resulting bacterial clones. The background mutation rate contributed by the enzymes of this assay system allowed viral mutation rates greater than 10(-4) mutations per base per passage to be measured. Surprisingly, all native and foreign genes accumulated mutations at a very low rate, lower than could be detected by the assay procedure. This low mutation accumulation rate of < or = 10(-4) mutations per base per passage may be due to replicase fidelity or populational "bottlenecking." Sequence drift should not be a practical limitation to most uses of TMV as a vector, although deletion phenomena observed in this study may present difficulties.

Base Sequence↗
PubMed1993

p53 protein accumulation and gene mutation in the progression of human prostate carcinoma.

BACKGROUND: Nuclear accumulation of p53 protein has been shown to be strongly associated with missense p53 mutations. Studies of nuclear accumulation of p53 protein in prostate carcinoma cells have to date been confined to material from primary tumors. PURPOSE: We studied the accumulation of p53 protein in specimens obtained from primary and metastatic sites of prostate carcinoma. By examining the accumulation of this protein as a function of stage, histologic grade, and androgen responsiveness of the tumor, we hoped to determine the role of p53 mutation in the progression of prostate carcinoma. METHODS: The accumulation of the p53 protein in the cell nuclei was determined by immunohistochemical methods using polyclonal antibody to human p53 CM-1. The material studied consisted of formalin-fixed, paraffin-embedded tissue obtained from primary tumors and metastases of 92 patients with prostate carcinoma. Twelve samples from 11 patients were analyzed for the presence of mutations within exons 5-8 of the p53 gene (also known as TP53) by polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) analysis. Sequence analysis was subsequently performed on DNA obtained by polymerase chain reaction amplification of PCR-SSCP reactions produced from six different specimens. The chi-square test, Fisher's exact test, and the Freeman Halton test were used for statistical analyses of the results. RESULTS: All tumors with p53 accumulation were metastatic (stage D), poorly differentiated, and androgen independent. Nuclear accumulation of p53 protein was strongly associated with stage (D2 versus D1 versus A-C, P < .0001), grade (Gleason score 8-10 versus 5-7, P < .003), and androgen sensitivity (androgen independent versus dependent, P < .0001). Logistic regression analysis demonstrated that androgen sensitivity predicted p53 outcome better than did stage (P < .0001) or grade alone (P < .006). There was a perfect concordance between the results obtained by PCR-SSCP analysis and the p53 protein accumulation determined by immunohistochemistry in the 12 samples studied. Mutation of the p53 gene was confirmed by sequencing DNA obtained from six specimens positive in the PCR-SSCP assay. CONCLUSIONS: p53 gene mutation is a late event in the progression of prostate cancer and is associated with advanced (metastatic) stage, loss of differentiation, and the transition from androgen-dependent to androgen-independent growth. IMPLICATION: Testing of prostate cancer biopsy specimens from metastatic sites for p53 protein accumulation and gene mutation may provide useful prognostic information and could influence the recommended course of treatment.

Adult↗
PubMed2000

Mutation frequency and specificity with age in liver, bladder and brain of lacI transgenic mice.

Mutation frequency and specificity were determined as a function of age in nuclear DNA from liver, bladder, and brain of Big Blue lacI transgenic mice aged 1.5-25 months. Mutations accumulated with age in liver and accumulated more rapidly in bladder. In the brain a small initial increase in mutation frequency was observed in young animals; however, no further increase was observed in adult mice. To investigate the origin of mutations, the mutational spectra for each tissue and age were determined. DNA sequence analysis of mutant lacI transgenes revealed no significant changes in mutational specificity in any tissue at any age. The spectra of mutations found in aging animals were identical to those in younger animals, suggesting that they originated from a common set of DNA lesions manifested during DNA replication. The data also indicated that there were no significant age-related mutational changes due to oxidative damage, or errors resulting from either changes in the fidelity of DNA polymerase or the efficiency of DNA repair. Hence, no evidence was found to support hypotheses that predict that oxidative damage or accumulation of errors in nuclear DNA contributes significantly to the aging process, at least in these three somatic tissues.

Aging↗
PubMed1997

Accumulation of transposable elements in laboratory lines of Drosophila melanogaster.

It is recognized that a stable number of transposable element (TE) copies per genome is maintained in natural populations of D. melanogaster as a result of the dynamic equilibrium between transposition to new sites and natural selection eliminating copies. The force of natural selection opposing TE multiplication is partly relaxed in inbred laboratory lines of flies. The average rate of TE transposition is from 2.6 x 10(-4) to 5.0 x 10(-4) per copy per generation, and the average rate of excision is at least two orders of magnitude lower; therefore inbred lines accumulate increasing numbers of copies with time. Correlations between the rate of transposition and TE copy number have been determined for copia, Doc, roo, and 412 and found to be either zero or positive. Because the rate of transposition is not a decreasing function of TE copy number, TE accumulation in inbred lines is self-accelerating. Transpositions cause a substantial fraction of mutations in D. melanogaster, therefore the mutation rate should increase with time in laboratory lines of this species. Inferences about the properties of spontaneous mutations from studies of mutation accumulation in laboratory lines should be reevaluated, because they are based on the assumption of a constant mutation rate.

Animals↗
PubMed1992

Decreased fidelity of DNA polymerases and decreased DNA excision repair in aging mice: effects of caloric restriction.

Hepatic DNA polymerases from calorie restricted and ad libitum 26 month old C57BL/6 mice showed a decline in fidelity of nucleotide incorporation compared with weanling animals. Both alpha and beta polymerases from calorie restricted aged mice exhibited a higher level of fidelity than polymerases from ad libitum aged mice. UV-initiated unscheduled DNA synthesis was significantly higher in hepatocytes from weanling and 18 month old calorie restricted animals compared with cells from 18 month old ad libitum animals, while MMS-initiated unscheduled DNA synthesis did not differ significantly between cells from young and old or ad libitum and calorie restricted animals. These data suggest that calorie restriction could play a significant role in decreasing the age-related decline of cellular mechanisms expected to reduce the rate at which mutations accumulate during aging, and could potentially prolong the onset age of mutation-associated diseases of the elderly.

Aging↗
PubMed2005

Evolutionary relationships between the former species Saccharomyces uvarum and the hybrids Saccharomyces bayanus and Saccharomyces pastorianus; reinstatement of Saccharomyces uvarum (Beijerinck) as a distinct species.

Analysis of the nucleotide sequence of the GDH1 homologues from Saccharomyces bayanus strain CBS 380T and S. pastorianus strains showed that they share an almost identical sequence, SuGDH1*, which is a diverged form of the SuGDH1 from the type strain of the former species S. uvarum, considered as synonym of S. bayanus. SuGDH1* is close to but differs from SuGDH1 by the accumulation of a high number of neutral substitutions designated as Multiple Neutral Mutations Accumulation (MNMA). Further analysis carried out with three other markers, BAP2, HO and MET2 showed that they have also diverged from their S. uvarum counterparts by MNMA. S. bayanus CBS 380T is placed between S. uvarum and S. pastorianus sharing MET2, CDC91 sequences with the former and BAP2, GDH1, HO sequences with the latter. S. bayanus CBS 380T has been proposed to be a S. uvarum/S. cerevisiae hybrid and this proposal is confirmed by the presence in its genome a S. cerevisiae SUC4 gene. Strain S. bayanus CBS 380T, with a composite genome, is genetically isolated from strains of the former S. uvarum species, thus justifying the reinstatement of S. uvarum as a distinct species.

Base Sequence↗
PubMed2004

Somatic mitochondrial DNA mutations in single neurons and glia.

Somatic mitochondrial DNA (mtDNA) point mutations reach high levels in the brain. However, the cell types that accumulate mutations and the patterns of mutations within individual cells are not known. We have quantified somatic mtDNA mutations in 28 single neurons and in 18 single glia from post-mortem human substantia nigra of six control subjects. Both neurons and glia contain mtDNA with somatic mutations. Single neurons harbor a geometric mean (95% CI) of 200.3 (152.9-262.4) somatic mtDNA point mutations per million base pairs, compared to 133.8 (97.5-184.9) for single glia (p=0.0251). If mutations detected multiple times in the same cell are counted only once, the mean mutation level per million base pairs remains elevated in single neurons (146.9; 124.0-174.2) compared to single glia (100.5; 81.5-126.5; p=0.009). Multiple distinct somatic point mutations are present in different cells from the same subject. Most of these mutations are individually present at low levels (less than 10-20% of mtDNA molecules), but with high aggregate mutation levels, particularly in neurons. These mutations may contribute to changes in brain function during normal aging and neurodegenerative disorders.

Adult↗
PubMed1998

On the three methods for estimating deleterious genomic mutation parameters.

Due to the tremendous cost of the traditional mutation-accumulation approach (the Bateman-Mukai technique), data are rare for deleterious mutation parameters such as genomic mutation rate, selection and dominance coefficients. Two alternative approaches have been developed (the Morton-Charlesworth and Deng-Lynch techniques). Except for the Deng-Lynch method, the statistical properties (bias and sampling variance) of these techniques are poorly understood; therefore we investigated them using computer simulation. With constant fitness effects of mutations, the Bateman-Mukai (assuming additive effects) and Deng-Lynch (assuming multiplicative effects) techniques are unbiased; the Morton-Charlesworth technique (assuming multiplicative effects) is very biased if fitness is used in the regression to estimate h, but slightly biased if the logarithm of fitness is used. With variable fitness effects, all techniques are biased. The Deng-Lynch technique is statistically better than the others except when fitness is used to estimate the average degree of dominance in selfing populations with the Morton-Charlesworth technique. If fitness effects are multiplicative but additivity is assumed, the Bateman-Mukai technique is biased under constant fitness effects, and less biased under variable fitness effects relative to when fitness effects are additive (as assumed by the technique). Our study not only quantifies the degree of bias under the biologically plausible situations investigated, thus forming a basis for correct inference of the true parameters by using these techniques, but also provides insights into the relative efficiencies of these techniques when the same number of genotypes are handled experimentally.

Computer Simulation↗
PubMed2002

High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain.

The mitochondrial theory of aging proposes that mitochondrial DNA (mtDNA) accumulates mutations with age, and that these mutations contribute to physiological decline in aging and degenerative diseases. Although a great deal of indirect evidence supports this hypothesis, the aggregate burden of mtDNA mutations, particularly point mutations, has not been systematically quantified in aging or neurodegenerative disorders. Therefore, we directly assessed the aggregate burden of brain mtDNA point mutations in 17 subjects with Alzheimer's disease (AD), 10 elderly control subjects and 14 younger control subjects, using a PCR-cloning-sequencing strategy. We found that brain mtDNA from elderly subjects had a higher aggregate burden of mutations than brain mtDNA from younger subjects. The average aggregate mutational burden in elderly subjects was 2 x 10(-4) mutations/bp. The bulk of these mutations were individually rare point mutations, 60% of which changed an amino acid. Control experiments ensure that these results were not due to artifacts arising from PCR error, mistaken identification of nuclear pseudogenes or ex vivo oxidation. Cytochrome oxidase activity correlated negatively with increasing mutational burden. These findings significantly bolster the mitochondrial theory of aging.

Adult↗
PubMed2006

Comprehensive mutation identification in an evolved bacterial cooperator and its cheating ancestor.

Precise characterization of the mutation histories of evolutionary lineages is crucial for understanding the evolutionary process, yet mutation identification has been constrained by traditional techniques. We sought to identify all accumulated mutations in an experimentally evolved lineage of the cooperative bacterium Myxococcus xanthus, which constructs fruiting bodies by a process of social multicellular development in response to starvation. This lineage had undergone two major transitions in social phenotype: from an ancestral cooperator to a socially defective cheater, and from the cheater to a competitively dominant cooperator that re-evolved social and developmental proficiency. The 9.14-Mb genome of the evolved, dominant cooperator (strain "PX") was sequenced to approximately 19-fold coverage by using recent "sequencing-by-synthesis" technology and partially sequenced (approximately 45%) by using capillary technology. The resulting data revealed 15 single-nucleotide mutations relative to the laboratory ancestor of PX after the two phases of experimental evolution but no evidence of duplications, transpositions, or multiple-base deletions. No mutations were identified by capillary sequencing beyond those found by pyrosequencing, resulting in a high probability that all mutations were discovered. Seven errors in the reference strain previously sequenced by the Sanger approach were revealed, as were five mutational differences between two distinct laboratory stocks of the reference strain. A single mutation responsible for the restoration of development in strain PX was identified, whereas 14 mutations occurred during the prior phase of experimental evolution. These results provide insight into the genetic basis of two large adaptive transitions in a social bacterium.

Adaptation, Biological↗
PubMed1997

The lack of mutational variance for fluctuating and directional asymmetry in Drosophila melanogaster.

Starting from a completely homozygous population of Drosophila melanogaster, lines were derived and independently maintained by a single brother-sister mating in each generation. Two bilateral traits--sternopleural bristle number and wing length--were individually scored on the right-(R) and left-hand (L) sides. Directional (DA) and fluctuating (FA) asymmetries were represented by the signed (R-L) and unsigned magnitude of R-L difference, respectively. Mutational variances (the mutational rate of input of genetic variation) and heritabilities (the mutational variance scaled by the environmental variance) of R, L, (R-L) and magnitude of R-L were calculated from the between-line divergence after a number of generations of mutation accumulation (bristle number: 171 lines, 122 generations; wing length: 148 lines, 170 generations). Mutational heritabilities of R and L were all significant, ranging from 0.73 x 10(-3)-2.10 x 10(-3). Those of (R-L) and magnitude of R-L were two orders of magnitude smaller and nonsignificant, ranging from -1.95 x 10(-5)-5.49 x 10(-5). These results imply that mutations affecting the DA or FA of bristle number and wing length have not been fixed in the lines or alternatively, that their effects were too small to be detected. In the population under study, the data strongly suggest that FA reflects only developmental noise due to non-genetic processes.

Animals↗
PubMed2003

High deleterious genomic mutation rate in stationary phase of Escherichia coli.

In natural habitats, bacteria spend most of their time in some form of growth arrest. Little is known about deleterious mutations in such stages, and consequently there is limited understanding of what evolutionary events occur. In a deleterious mutation accumulation experiment in prolonged stationary phase of Escherichia coli, about 0.03 slightly deleterious mutations were observed per genome per day. This is over an order of magnitude higher than extrapolations from fast-growing cells, but in line with inferences from observations in adaptive stationary phase mutation experiments. These findings may affect understanding of bacterial evolution and the emergence of bacterial pathogenicity.

Biological Evolution↗
PubMed1996

Accumulation of mitochondrial DNA deletions in human retina during aging.

PURPOSE: The authors investigated the presence of mitochondrial DNA (mtDNA) mutations in aging human retina. METHODS: A quantitative polymerase chain reaction technique for studying the common mtDNA 4977-deletion (delta mtDNA4977) in retinal pigment epithelium (RPE) and neural retinal (NR) was developed. RESULTS: Although no deletion was detected in the fetus, every adult RPE and NR had this common deletion. The ratio of the deleted delta mtDNA4977 to the total mtDNA increased significantly in elderly persons 60 to 110 years of age and was greater in peripheral than in central RPE. CONCLUSIONS: These results suggest that at least one type of mutation accumulates in the mtDNA in the retina during aging, reflecting a general phenomenon of genomic instability that could influence its function.

Aged↗
PubMed2003

Protein p53--structure, function, and possible therapeutic implications.

Cell cycle is driven by a number of positive and negative regulatory phosphorylation and dephosphorylation events that ultimately influence the activity of transcription factors. Normal skin architecture depends on the regulation mechanisms of cell proliferation and differentiation and on apoptosis. Complex interaction of different factors in the regulation of these mechanisms, aimed at maintaining constant desquamation, is often changed in skin diseases. The main difference between normal cells and tumor cells results from discrete changes in specific genes important for cell proliferation control mechanisms and tissue homeostasis. These genes are mainly proto-oncogenes or tumor-suppressor genes, and their mutation could play a role in cell hyperproliferation and carcinogenesis. Tumor-suppressor genes normally function as a physiological barrier against clonal expansion or mutation accumulation in the genome. They also control and arrest growth of the cells that hyperproliferate due to oncogene activity. Alteration or DNA damage in tumor-suppressor genes and oncogenes are considered key events in human carcinogenesis. Tumor-suppressor protein p53 is an important transcription factor, which plays a central role in the cell cycle regulation mechanisms and cell proliferation control, and its inactivation is considered a key event in human carcinogenesis. The role of p53 protein in the cell cycle, high proportion of tumors with mutated p53 gene, and accumulation of significant amount of knowledge on molecular biology of this protein make this molecule especially attractive for development of new therapeutic approaches. Main strategies for development of new antineoplastic therapies are based on "wild-type" p53 protein acting as a tumor suppressor, selective apoptosis inductor, and a protein able to arrest cell cycle.

Genes, p53↗
PubMed2005

In vivo spectrofluorimetry reveals endogenous biomarkers that report healthspan and dietary restriction in Caenorhabditis elegans.

Autofluorescent lipofuscin and advanced glycation end-products (age pigments) accumulate with age across phyla, yet little is understood about their formation under physiological conditions and their specific contributions to the aging process. We used in vivo spectrofluorimetry to quantitate autofluorescence in wild-type Caenorhabditis elegans and longevity mutants disrupted for distinct aspects of the aging process. In wild-type animals, age pigments increase into adulthood, accumulating slowly during the reproductive phase and more rapidly during the post-reproductive period. As in humans, insulin signaling influences age pigment accumulation - mutations that lower efficacy of insulin signaling and extend lifespan [daf-2(e1370) insulin receptor and age-1(hx546) PI3-kinase] dramatically lower age pigment accumulation; conversely, elimination of the insulin-inhibited DAF-16/FOXO transcription factor causes a huge increase in age pigment accumulation, supporting that the short-lived daf-16 null mutant is truly progeric. By contrast, mutations that increase mitochondrial reactive oxygen species production do not affect age pigment accumulation, challenging assumptions about the role of oxidative stress in generating these species in vivo. Dietary restriction reduces age pigment levels significantly and is associated with a unique spectral shift that might serve as a rapidly scored reporter of the dietary restricted state. Unexpectedly, genetically identical siblings that age poorly (as judged by decrepit locomotory capacity) have dramatically higher levels of age pigments than their same-aged siblings that appear to have aged more gracefully and move youthfully. Thus, high age pigment levels indicate a physiologically aged state rather than simply marking chronological time, and age pigments are valid reporters of nematode healthspan.

Aging↗