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PubMed2000

Mutation induction by mechanical irritation caused by uracil-induced urolithiasis in Big Blue rats.

Some chronic mechanical irritations induce cancers, and it is speculated that mutations are induced by increased rate of cell proliferation caused by the irritation. In this study, it was investigated using chronic mechanical irritation to urothelium caused by urolithiasis, whether mutations are really induced by such cell proliferation or not. Male rats transgenic for lacI (Big Blue(R) rats), in which lacI mutations accumulated in tissue can be measured, were fed 3% uracil, a component of RNA, to induce urolithiasis associated with papillomatosis, and eventually with bladder cancers. The frequency of independent mutations in the bladders of the treated rats showed 3-5 fold increases at weeks 10, 20, and 51 (P=0.01 at week 51) while the frequency was not elevated at week 2. The mutation frequencies in the control bladders ranged from 3 to 9x10(-6). In both groups, G to A transitions at CpG sites, indicative of spontaneous mutations, constituted the most prevalent mutations. Mechanical irritation caused by uracil was shown to induce a 3-5 fold increase of mutations, possibly through an elevation of spontaneous mutations by vigorous cell proliferation.

Animals↗
PubMed2000

Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus.

The Duffy blood group locus, which encodes a chemokine receptor, is characterized by three alleles-FY*A, FY*B, and FY*O. The frequency of the FY*O allele, which corresponds to the absence of Fy antigen on red blood cells, is at or near fixation in most sub-Saharan African populations but is very rare outside Africa. The FST value for the FY*O allele is the highest observed for any allele in humans, providing strong evidence for the action of natural selection at this locus. Homozygosity for the FY*O allele confers complete resistance to vivax malaria, suggesting that this allele has been the target of selection by Plasmodium vivax or some other infectious agent. To characterize the signature of directional selection at this locus, we surveyed DNA sequence variation, both in a 1.9-kb region centered on the FY*O mutation site and in a 1-kb region 5-6 kb away from it, in 17 Italians and in a total of 24 individuals from five sub-Saharan African populations. The level of variation across both regions is two- to threefold lower in the Africans than in the Italians. As a result, the pooled African sample shows a significant departure from the neutral expectation for the number of segregating sites, whereas the Italian sample does not. The FY*O allele occurs on two major haplotypes in three of the five African populations. This finding could be due to recombination, recurrent mutation, population structure, and/or mutation accumulation and drift. Although we are unable to distinguish among these alternative hypotheses, it is likely that the two major haplotypes originated prior to selection on the FY*O mutation.

Africa South of the Sahara↗
PubMedDate not supplied

[The loss of dinucleotides CpG from DNA. IV. Methylation and divergence of genes and pseudogenes of small nuclear RNA].

The frequency of neighboring base pairs in nucleotide sequences of over 80 genes and pseudogenes of low molecular weight RNAs U1-U8, 4.5S and 7S in different eukaryotes was determined. The probable frequency of CpG----TpG + CpA substitutions, caused as a result of the deamination of 5-methylcytosine residues in DNA, was determined. It was found that the genes of small RNAs do not reveal a single level of CpG methylation for all the species studied. In most cases CpG in the genes of U1, 4.5S and 7S RNA are methylated, whereas in the genes of U2-U6-RNA these sites must have never been subjected to methylation. Nearly all the investigated pseudogenes of different small RNAs are strongly methylated due to a considerable lack of CpG. It was established that CpG----TpG + CpA transitions may amount to as much third of all the mutations accumulated in the genes of the same RNAs in different species. Such transitions in pseudogenes may account for 40% of all the nucleotide substitutions. This disproportionately high level of mutations in CpG dinucleotides (3-5-fold higher than in other DNA dupletes) must be the direct result of the methylation of these sites. Consequently, CpG methylation causes a dramatic acceleration of the divergence rate of DNA sequences. It has been concluded that protection of most vital genes against methylation is one of the essential conditions for sustaining the high level of stability of the macromolecular structure and for the reliability of macromolecular functioning in a cell.

Animals↗
PubMed2004

The accumulation of deleterious mutations within the frozen niche variation hypothesis.

The frozen niche variation hypothesis proposes that asexual clones exploit a fraction of a total resource niche available to the sexual population from which they arise. Differences in niche breadth may allow a period of coexistence between a sexual population and the faster reproducing asexual clones. Here, we model the longer term threat to the persistence of the sexual population from an accumulation of clonal diversity, balanced by the cost to the asexual population resulting from a faster rate of accumulation of deleterious mutations. We use Monte-Carlo simulations to quantify the interaction of niche breadth with accumulating deleterious mutations. These two mechanisms may act synergistically to prevent the extinction of the sexual population, given: (1) sufficient genetic variation, and consequently niche breadth, in the sexual population; (2) a relatively slow rate of accumulation of genetic diversity in the clonal population; (3) synergistic epistasis in the accumulation of deleterious mutations.

Biological Evolution↗
PubMed1992

Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy.

Four new missense mutations have been identified through restriction analysis and sequencing of the mitochondrial DNAs (mtDNA) from Leber's hereditary optic neuropathy (LHON) patients who lacked the previously identified 11778 mutation. Each altered a conserved amino acid and correlated with the LHON phenotype in population and phylogenetic analyses. The nucleotide pair (np) 13708 mutation (G to A, ND5 gene) changed an alanine to a threonine and was found in 6/25 (24%) of non-11778 LHON pedigrees and in 5.0% of controls, the np 15257 mutation (G to A, cytochrome b gene) changed an aspartate to an asparagine and was found in 4 of the 13708-positive pedigrees and 0.3% of controls, the np 15812 mutation (G to A, cytochrome b gene) changed a valine to a methionine and was detected in two of the 15257-positive pedigrees and 0.1% of controls and the np 5244 mutation (G to A, ND2 gene) changed a glycine to a serine and was found in one of the 15812-positive patients and none of 2103 controls. The 15257 mutation altered a highly conserved amino acid in an extramembrane domain of cytochrome b that is associated with the ligation of the low potential b566 heme and the 5244 mutation altered a strongly evolutionarily conserved region of the ND2 polypeptide. The 13708 and 15812 mutations changed moderately conserved amino acids. Haplotype and phylogenetic analysis of the four np 15257 mtDNAs revealed that all harbored the same rare Caucasian haplotype and that the np 13708, np 15257, np 15812 and np 5244 mutations were added sequentially along this mtDNA lineage. Since the percentage of sighted controls decreases as these mutations accumulate, it appears that they interact synergistically, each increasing the probability of blindness. The involvement of both mitochondrial complex I (np 5244, 11778, 13708) and complex III (np 15257, 15812) mutations in LHON indicates that the clinical manifestations of this disease are the product of an overall decrease in mitochondrial energy production rather than a defect in a specific mitochondrial enzyme.

Base Sequence↗
PubMed2002

A comprehensive model of mutations affecting fitness and inferences for Arabidopsis thaliana.

As the ultimate source of genetic variation, spontaneous mutation is essential to evolutionary change. Theoretical studies over several decades have revealed the dependence of evolutionary consequences of mutation on specific mutational properties, including genomic mutation rates, U, and the effects of newly arising mutations on individual fitness, s. The recent resurgence of empirical effort to infer these properties for diverse organisms has not achieved consensus. Estimates, which have been obtained by methods that assume mutations are unidirectional in their effects on fitness, are imprecise. Both because a general approach must allow for occurrence of fitness-enhancing mutations, even if these are rare, and because recent evidence demands it, we present a new method for inferring mutational parameters. For the distribution of mutational effects, we retain Keightley's assumption of the gamma distribution, to take advantage of the flexibility of its shape. Because the conventional gamma is one sided, restricting it to unidirectional effects, we include an additional parameter, rho, as an amount it is displaced from zero. Estimation is accomplished by Markov chain Monte Carlo maximum likelihood. Through a limited set of simulations, we verify the accuracy of this approach. We apply it to analyze data on two reproductive fitness components from a 17-generation mutation-accumulation study of a Columbia accession of Arabidopsis thaliana in which 40 lines sampled in three generations were assayed simultaneously. For these traits, U approximately/= 0.1-0.2, with distributions of mutational effects broadly spanning zero, such that roughly half the mutations reduce reproductive fitness. One evolutionary consequence of these results is lower extinction risks of small populations of A. thaliana than expected from the process of mutational meltdown. A comprehensive view of the evolutionary consequences of mutation will depend on quantitatively accounting for fitness-enhancing, as well as fitness-reducing, mutations.

Algorithms↗
PubMed1994

Naturally occurring genotypes of the human immunodeficiency virus type 1 long terminal repeat display a wide range of basal and Tat-induced transcriptional activities.

The primary body of information on the structure of human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)/gag leader genotypes has been determined from the analysis of cocultivated isolates. Functional studies of this regulatory portion of the provirus have been derived from the study of in vitro-generated mutations of laboratory-adapted molecular clones of HIV-1. We have performed a longitudinal analysis of molecular clones from the LTR/gag leader region amplified directly from the peripheral blood of four patients over three years. We have found a remarkable number of point mutations and length polymorphisms in cis- and trans-acting regulatory elements within this cohort. Most of the length polymorphisms were associated with duplications of Sp1 and TCF-1 alpha sequences. These mutations were associated with a wide range of transcriptional activities for these genotypes in a reporter gene assay. Mutations in conserved Sp1 sequences correlated with a diminished capacity of such genotypes to bind purified Sp1 protein. Although no generalized trend in transcriptional activity was seen, a single patient accumulated mutations in NF-kappa B, Sp1, and TAR elements over this period. The analysis of naturally occurring mutations of LTR genotypes provides a means to study the molecular genetic consequences of virus-host interactions and to assess the functional impact of HIV therapeutics.

Base Sequence↗
PubMed2006

Cell and animal models of mtDNA biology: progress and prospects.

The past two decades have witnessed an evolving understanding of the mitochondrial genome's (mtDNA) role in basic biology and disease. From the recognition that mutations in mtDNA can be responsible for human disease to recent efforts showing that mtDNA mutations accumulate over time and may be responsible for some phenotypes of aging, the field of mitochondrial genetics has greatly benefited from the creation of cell and animal models of mtDNA mutation. In this review, we critically discuss the past two decades of efforts and insights gained from cell and animal models of mtDNA mutation. We attempt to reconcile the varied and at times contradictory findings by highlighting the various methodologies employed and using human mtDNA disease as a guide to better understanding of cell and animal mtDNA models. We end with a discussion of scientific and therapeutic challenges and prospects for the future of mtDNA transfection and gene therapy.

Animals↗
PubMed2000

Large accumulation of mRNA and DNA point modifications in a plant senescent tissue.

Although nucleic acids are the paradigm of genetic information conservation, they are inherently unstable molecules that suffer intrinsic and environmental damage. Oxidative stress has been related to senescence and aging and, recently, it has been shown that mutations accumulate at high frequency in mitochondrial DNA with age. We investigated RNA and DNA modifications in cork, a senescent plant tissue under high endogenous oxidative stress conditions. When compared to normally growing young tissue, cork revealed an unexpected high frequency of point modifications in both cDNA (Pn = 1/1784) and nuclear DNA (Pn = 1/1520). Cork should be viewed as a mosaic of genetically heterogeneous cells. This has biological implications: it supports somatic mutation models for aging and challenges 'single cDNA clone' as descriptor for the molecular genetics of senescent tissues.

DNA, Plant↗
PubMed2002

Molecular basis of 2',3'-dideoxycytidine-induced drug resistance in human cells.

Human monoblastoid cells (U937) grown in the presence of therapeutically relevant dideoxycytidine concentrations (0.1 microM) become resistant to the drug thanks to an altered deoxycytidine kinase. In this paper we show that deoxycytidine kinase mRNA is significantly reduced in drug-resistant U937 cells (U937-R) although the deoxycytidine kinase promoter is normal. Anumber of nucleotide deletions, insertions and substitutions was found in the coding region of deoxycytidine kinase gene. Several identified mutations result in truncated forms of the enzyme or in the introduction of stop codons: in one case a complete lack of exon 4 was found. Thus, the deoxycytidine kinase gene accumulates mutations at a very high rate, as already reported for other cytidine analogues (i.e. Ara C) suggesting that the design of new antiviral or anticancer drugs of the cytidine family should take into account the potential development of cell resistance as a critical factor in drug failure.

Amino Acid Sequence↗
PubMed2025

Characterization of a PRKCE::ETV6 fusion as a potential oncogenic driver in T-cell acute lymphoblastic leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy caused by mutation accumulation during hematopoiesis. The characterization of chromosomal abnormalities may provide significant insights into genetic mechanisms of malignant transformation in hematopoietic cells. However, T-ALL is genetically very heterogenous and driving mutations as well as clonal markers for the assessment of minimal residual disease are not always identifiable. Hence, there is a clinical need to further refine the genetic landscape of T-ALL including previously unrecognized fusion partners of commonly translocated genes in T-ALL of childhood. RESULTS: In this study, we screened n = 229 T-ALL cases by our targeted genomic capture high-throughput sequencing (gc-HTS) approach. In total, we identified n = 60 gene–gene fusions, present in n = 57 (25%) of the patients. Nine rare or even unrecognized translocations were identified and validated. Furthermore, owing to its interesting chromosomal structure, we studied the oncogenic potential of the complex rearrangement of chromosome 2 and 12, found in a near-early T-cell progenitor (ETP) ALL that leads to the fusion events PRKCE::ETV6 and ETV6::INO80D. Exogenous expression of PRKCE::ETV6 in Ba/F3 pro-B and D1 T-cells caused interleukin-independent proliferation and enhanced survival upon interleukin withdrawal, respectively. CONCLUSION: Our study underlines the heterogenous mutational landscape in T-ALL. The previously unrecognized PRKCE::ETV6 resulting from a complex rearrangement involving chromosome 2 and 12 demonstrated transforming potential in cytokine-dependent cellular models support the notion of a driver mutation in near ETP-ALL. Our data reconfirm the relevance of ETV6-fusion proteins in the pathogenesis of undifferentiated T-ALL. Importantly, genomic breakpoints at the ETV6 locus represent potentially robust MRD markers for (near) ETP-ALL that lack IG/TR rearrangements.

ETV6::INO80D↗
PubMed2005

Evolution of mutational robustness in an RNA virus.

Mutational (genetic) robustness is phenotypic constancy in the face of mutational changes to the genome. Robustness is critical to the understanding of evolution because phenotypically expressed genetic variation is the fuel of natural selection. Nonetheless, the evidence for adaptive evolution of mutational robustness in biological populations is controversial. Robustness should be selectively favored when mutation rates are high, a common feature of RNA viruses. However, selection for robustness may be relaxed under virus co-infection because complementation between virus genotypes can buffer mutational effects. We therefore hypothesized that selection for genetic robustness in viruses will be weakened with increasing frequency of co-infection. To test this idea, we used populations of RNA phage phi6 that were experimentally evolved at low and high levels of co-infection and subjected lineages of these viruses to mutation accumulation through population bottlenecking. The data demonstrate that viruses evolved under high co-infection show relatively greater mean magnitude and variance in the fitness changes generated by addition of random mutations, confirming our hypothesis that they experience weakened selection for robustness. Our study further suggests that co-infection of host cells may be advantageous to RNA viruses only in the short term. In addition, we observed higher mutation frequencies in the more robust viruses, indicating that evolution of robustness might foster less-accurate genome replication in RNA viruses.

Bacteriophage phi 6↗
PubMed1994

Microevolution of Sabin 1 strain in vitro and genetic stability of oral poliovirus vaccine.

Mutants consistently accumulating in Sabin 1 poliovirus during serial passaging in vitro were identified by sequence heterogeneity assay and quantitated using mutant analysis by PCR and restriction enzyme cleavage (MAPREC). Only four unstable genomic sites were identified in virus passaged 10 times in African green monkey kidney (AGMK) cells, and eight sites in virus passaged in Vero cells. Mutations accumulated both in untranslated regions of RNA (nucleotides 480, 525 and 7441) and in coding sequences, as missense (nucleotides 1449, 4944, and 6203) or silent (nucleotides 1123 and 1141) mutations. The most prominent selectable mutations were found at complementary nucleotides 480 and 525 of the 5'-untranslated region (5'-UTR) of the Sabin strain, changing the G:U pair in F-domain to either A:U or G:C variants. These two variants have been shown previously to have an increased neurovirulence in monkeys. The G:C variant accumulated during passage in Vero cells, while A:U variant accumulated in CV-1 cells. Virus passaged in AGMK cells accumulated both variants. Higher temperature (37 instead of 34 degrees) strongly favored selection of mutants in Vero cells, had a smaller effect on mutant accumulation in AGMK cells, and had no effect in CV-1 cells. Monopools of type 1 oral poliovirus vaccine (OPV) made by seven manufacturers were found to contain both 480-A and 525-C revertants at a combined level of 1.1-2.7%. Viral samples with increased amounts of these revertants had higher neurovirulence in monkeys. Our results suggest that quantitation of these reversions by MAPREC may be prognostic for results of the monkey neurovirulence test (MNVT) and can be used for monitoring type 1 OPV consistency.

Animals↗
PubMed1996

Age-specific patterns of genetic variance in Drosophila melanogaster. I. Mortality.

PETER MEDAWAR proposed that senescence arises from an age-related decline in the force of selection, which allows late-acting deleterious mutations to accumulate. Subsequent workers have suggested that mutation accumulation could produce an age-related increase in additive genetic variance (VA) for fitness traits, as recently found in Drosophila melanogaster. Here we report results from a genetic analysis of mortality in 65,134 D. melanogaster. Additive genetic variance for female mortality rates increases from 0.007 in the first week of life to 0.325 by the third week, and then declines to 0.002 by the seventh week. Males show a similar pattern, though total variance is lower than in females. In contrast to a predicted divergence in mortality curves, mortality curves of different genotypes are roughly parallel. Using a three-parameter model, we find significant VA for the slope and constant term of the curve describing age-specific mortality rates, and also for the rate at which mortality decelerates late in life. These results fail to support a prediction derived from MEDAWAR's "mutation accumulation" theory for the evolution of senescence. However, our results could be consistent with alternative interpretations of evolutionary models of aging.

Aging↗
PubMed1988

Why the rate of silent codon substitutions is variable within a vertebrate's genome.

Different genes within the murine genome are diverging at different rates. The rate of synonymous codon substitutions in these genes is related to their base composition. It is proposed that the variabilities of rate of mutation accumulation, of codon choice and of average GC content within vertebrate genomes are caused by differences between DNA synthesis in repair and replication, as far as the frequency and compositional bias of mutations introduced by these systems are concerned. DNA repair contributes substantially to the evolution of the DNA domains, which are actively repaired in germline cells and which correspond to regions available for transcription in these cells and to Giemsa-negative bands in stained chromosomes.

Animals↗
PubMed2001

Computational method to reduce the search space for directed protein evolution.

We introduce a computational method to optimize the in vitro evolution of proteins. Simulating evolution with a simple model that statistically describes the fitness landscape, we find that beneficial mutations tend to occur at amino acid positions that are tolerant to substitutions, in the limit of small libraries and low mutation rates. We transform this observation into a design strategy by applying mean-field theory to a structure-based computational model to calculate each residue's structural tolerance. Thermostabilizing and activity-increasing mutations accumulated during the experimental directed evolution of subtilisin E and T4 lysozyme are strongly directed to sites identified by using this computational approach. This method can be used to predict positions where mutations are likely to lead to improvement of specific protein properties.

Bacteriophage T4↗
PubMed2005

Polygenic mutation in Drosophila melanogaster: Mapping spontaneous mutations affecting sensory bristle number.

Our ability to predict long-term responses to artificial and natural selection, and understand the mechanisms by which naturally occurring variation for quantitative traits is maintained, depends on detailed knowledge of the properties of spontaneous polygenic mutations, including the quantitative trait loci (QTL) at which mutations occur, mutation rates, and mutational effects. These parameters can be estimated by mapping QTL that cause divergence between mutation-accumulation lines that have been established from an inbred base population and selected for high and low trait values. Here, we have utilized quantitative complementation to deficiencies to map QTL at which spontaneous mutations affecting Drosophila abdominal and sternopleural bristle number have occurred in 11 replicate lines during 206 generations of divergent selection. Estimates of the numbers of mutations were consistent with diploid per-character mutation rates for bristle traits of 0.03. The ratio of the per-character mutation rate to total mutation rate (0.023) implies that >2% of the genome could affect just one bristle trait and that there must be extensive pleiotropy for quantitative phenotypes. The estimated mutational effects were not, however, additive and exhibited dependency on genetic background consistent with diminishing epistasis. However, these inferences must be tempered by the potential for epistatic interactions between spontaneous mutations and QTL affecting bristle number on the deficiency-bearing chromosomes, which could lead to overestimates in numbers of QTL and inaccurate inference of gene action.

Animals↗
PubMed1995

Probing the evolution of senescence in Drosophila melanogaster with P-element tagging.

Natural populations host a wealth of genetic variation in longevity and age-specific schedules of reproduction. This variation provides critical information for inferring the evolutionary origin of senescence. Patterns of mutational effects on age-specific fecundity and survival provide additional insight to distinguish alternative models of senescence. In this study, P-elements bearing the white minigene were inserted at random into a common genetic background, generating lines of D. melanogaster with single, stable transposon inserts. A series of 48 single-P-element lines revealed statistically significant heterogeneity in both longevity and fecundity. Longevity and early fecundity were only weakly positively correlated (r = 0.286, P = 0.0398). Both the pooled sample and 30 of the individual lines exhibited a leveling of age-specific mortality at advanced ages, in opposition to the classical demographic models. To the extent that these mutational effects are representative of naturally-occurring mutations in heterogeneous populations, this result presents a problem for the evolutionary theory of senescence. Natural selection is inefficient at removing deleterious mutations that are expressed only at late ages, and selection may not differentiate between mutations whose effects on longevity are post-reproductive. A leveling of the mortality rate would also be seen if mutations whose expression is delayed until very late simply do not occur. A simulation of mutation-selection balance among the 48 P-element tagged lines shows that the mean longevity declines monotonically with increasing mutation rate, consistent with the mutation-accumulation model.

Aging↗