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PubMed1989

An apaH mutation causes AppppA to accumulate and affects motility and catabolite repression in Escherichia coli.

apaH- mutants lack the hydrolase responsible for degradation of AppppN dinucleotides in Escherichia coli and show a greater than or equal to 16-fold increase in AppppA under nonstress conditions. These mutants lack detectable activity of sigma F, a factor required for transcription of motility and chemotaxis genes. Expression of the flbB/flaI operon, thought to encode sigma F, is decreased in apaH- mutants, and there appears to be a general decrease in expression of genes regulated by cAMP-binding protein and cAMP as well.

Cell Movement↗
PubMed1997

Radiation damage accumulation over large time intervals: a descriptive model.

A simple model of DNA damage (mutation load) accumulation is considered. For time intervals exceeding average life duration, the kinetics of mutation load is determined. The major process determining these kinetics is shown to be natural selection (or any equivalent process of removal of the most affected lines). The characteristic time of this process (which is around three generations) is the approximate time of integration of the dose rate for determination of radiation damage. The conclusion is made that the maximum permissible dose should be established for this characteristic time, as it determines the remote effects of prolonged exposure to radiation. After this, the accumulated genetic damage presents "dose rate-effect" rather than "dose-effect" dependence. Dependence of mutation load on dose rate and parameters of selection processes is examined for different types of mutations. The cases of stable and exponentially decreasing dose rate are considered. The applicability of the model to human population is discussed.

DNA Damage↗
PubMed1988

The origin of MHC class II gene polymorphism within the genus Mus.

The I region of the major histocompatibility complex (MHC) of the mouse (H-2) contains a tightly-linked cluster of highly polymorphic genes (class II MHC genes) which control immune responsiveness. Speculation on the origin of this polymorphism, which is believed to be essential for the function of the class II proteins in immune responses to disease, has given rise to two hypotheses. The first is that hypermutational mechanisms (gene conversion or segmental exchange) promote the rapid generation of diversity in MHC genes. The alternative is that polymorphism has arisen from the steady accumulation of mutations over long evolutionary periods, and multiple specific alleles have survived speciation (trans-species evolution). We have looked for evidence of 'segmental exchange' and/or 'trans-species evolution' in the class II genes of the genus Mus by molecular genetic analysis of I-A beta alleles. The results indicate that greater than 90% (28 out of 31) of the alleles examined can be organized into two evolutionary groups both on the basis of restriction site polymorphisms and by the presence or absence of a short interspersed nucleotide element (SINE). Using this SINE sequence as an evolutionary tag, we demonstrate that I-A beta alleles in these two evolutionary groups diverged at least three million years ago and have survived the speciation events leading to several modern Mus species. Nucleotide sequence comparisons of eight Mus m. domesticus I-A beta alleles representing all three evolutionary groups indicate that most of the divergence in exon sequences is due to the steady accumulation of mutations that are maintained independently in the different alleles. But segmental exchanges between alleles from different evolutionary groups have also played a role in the diversification of beta 1 exons.

Alleles↗
PubMed2002

Mutations in the cardiac mitochondrial DNA control region associated with cardiomyopathy and aging.

BACKGROUND: An age-dependent accumulation of point mutations in the noncoding control region of human mitochondrial D-loop has been found in cultured fibroblasts and muscle cells. Damage in mitochondrial DNA (mtDNA) coding genes and decreased bioenergetic generation have also been found in human cardiac tissues with aging and in cardiac disease. METHODS AND RESULTS: We analyzed cardiac mtDNA for the incidence and distribution of point mutations in the D-loop control region involved in mtDNA replication (from nucleotides 110 to 570) in 47 patients with cardiomyopathy and 40 subjects with no history of cardiac disease. The nucleotide changes in the control region were compared with changes in a cytb fragment of roughly the same size in controls and patients. Frequency and distribution of mutations in relation to age and cardiac disease were assessed. No significant accumulation of point mutations in the D-loop control region or in cytb was found as a function of age. However, mutations in important sites within the D-loop control region were present in 8 patients (17%). CONCLUSIONS: We found specific mutations at critical sites in the D-loop in cardiomyopathy that may play a role in cardiac pathogenesis. Age does not appear to be a factor in mutation accumulation.

Adolescent↗
PubMed2002

Genes, telomeres and mammalian ageing.

Although there appear to be several influences, which contribute to the ageing of mammals, the role of DNA appears to be pivotal. There is increasing evidence that oxidative damage is an important factor in producing mutations in genes, shortening telomeres and damaging mitochondrial DNA. Accumulation of mutations in genomic DNA could result in the gradual decline in cellular function, which is exhibited in a variety of tissues. The random nature of these mutations, could also offer an explanation for differences in the degree and time of onset of age-related changes, exhibited by different individuals. Shortening of telomeres, caused by oxidative damage or the end-replication problem, could result in the accumulation of post-mitotic cells in-vivo during ageing. This might impair certain aspects of physiology, such as wound healing. Mutation of mitochondrial DNA may also be important in causing loss of cells in post-mitotic tissues such as muscle or brain. In addition changes in the redox state during the life of an animal may alter transcription factor activities, leading to consistent changes in the gene expression profiles of mammalian tissues. The latter could explain consistent age-related changes that have been observed in cell structure and physiology. Although all of these mechanisms may make a contribution to ageing, it is likely that it is the interplay between them that produces the most prominent effects.

Aging↗
PubMed2002

Base composition of mononucleotide runs affects DNA polymerase slippage and removal of frameshift intermediates by mismatch repair in Saccharomyces cerevisiae.

The postreplicative mismatch repair (MMR) system is important for removing mutational intermediates that are generated during DNA replication, especially those that arise as a result of DNA polymerase slippage in simple repeats. Here, we use a forward mutation assay to systematically examine the accumulation of frameshift mutations within mononucleotide runs of variable composition in wild-type and MMR-defective yeast strains. These studies demonstrate that (i) DNA polymerase slippage occurs more often in 10-cytosine/10-guanine (10C/10G) runs than in 10-adenine/10-thymine (10A/10T) runs, (ii) the MMR system removes frameshift intermediates in 10A/10T runs more efficiently than in 10C/10G runs, (iii) the MMR system removes -1 frameshift intermediates more efficiently than +1 intermediates in all 10-nucleotide runs, and (iv) the repair specificities of the Msh2p-Msh3p and Msh2p-Msh6p mismatch recognition complexes with respect to 1-nucleotide insertion/deletion loops vary dramatically as a function of run composition. These observations are relevant to issues of genome stability, with both the rates and types of mutations that accumulate in mononucleotide runs being influenced by the primary sequence of the run as well as by the status of the MMR system.

Base Composition↗
PubMed1973

Porphyrin-accumulating mutants of Escherichia coli.

Four mutants (pop-1, pop-6, pop-10, and pop-14) which accumulate a red water-insoluble pigment were obtained in Escherichia coli K-12 AB1621. For each mutant, the red pigment was shown to be protoporphyrin IX, a late precursor of heme. Mutagenic treatment of mutant pop-1 yielded a secondary mutant, pop-1 sec-20, which accumulated a brown water-soluble pigment. The brown pigment was shown to be coproporphyrin III. Mutant pop-1 resembled the parental strain in its cytochrome absorption spectrum, catalase activity, and ability to grow on nonfermentable carbon and energy sources; therefore, its ability to produce and utilize heme was unimpaired. Judged on the same criteria, the secondary mutant, pop-1 sec-20, was partially heme and respiratory deficient. Growth in anaerobic conditions decreased by 25% the accumulation of protoporphyrin by pop-1; under the same conditions, pop-1 sec-20 did not accumulate coproporphyrin or coproporphyrinogen. The mutations causing protoporphyrin accumulation in all four pop mutants were found to map in the lac to purE (10-13 min) region of the E. coli chromosome. In the case of mutant pop-1, the mutation was shown to be strongly linked to the tsx locus (12 min). In mutant pop-1 sec-20, the second mutation causing coproporphyrin accumulation was co-transducible with the gal locus at a frequency of 88 to 96%. The mechanism of porphyrin accumulation by the mutants is discussed.

Aerobiosis↗
PubMedDate not supplied

Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations.

BACKGROUND AND OBJECTIVE: Patients with a clinical diagnosis of neurodegeneration with brain iron accumulation (NBIA, formerly called Hallervorden-Spatz syndrome) often have mutations in PANK2, the gene encoding pantothenate kinase 2. We investigated correlations between brain MR imaging changes, mutation status, and clinical disease features. METHODS: Brain MRIs from patients with NBIA were reviewed by 2 neuroradiologists for technical factors, including signal intensity abnormalities in specific brain regions, presence and location of atrophy, presence of white matter abnormality, contrast enhancement, and other comments. PANK2 genotyping was performed by polymerase chain reaction amplification of patient genomic DNA followed by automated nucleotide sequencing. RESULTS: Sixty-six MR imaging examinations from 49 NBIA patients were analyzed, including those from 29 patients with mutations in PANK2. All patients with mutations had the specific pattern of globus pallidus central hyperintensity with surrounding hypointensity on T2-weighted images, known as the eye-of-the-tiger sign. This sign was not seen in any studies from patients without mutations. Even before the globus pallidus hypointensity developed, patients with mutations could be distinguished by the presence of isolated globus pallidus hyperintensity on T2-weighted images. Radiographic evidence for iron deposition in the substantia nigra was absent early in disease associated with PANK2 mutations. MR imaging abnormalities outside the globus pallidus, including cerebral or cerebellar atrophy, were more common and more severe in mutation-negative patients. No specific MR imaging changes could be distinguished among the mutation-negative patients. CONCLUSION: MR imaging signal intensity abnormalities in the globus pallidus can distinguish patients with mutations in PANK2 from those lacking a mutation, even in the early stages of disease.

Adolescent↗
PubMed2002

The highest priority: what microbial genomes are telling us about immunity.

Study of microbial genomes has provided new insight into the functions that pathogens require for survival in the animal host. Small genome bacterial pathogens, defined as those < or = 1/3 the size of Escherichia coli, include chlamydiae, rickettsiae and ehrlichiae, mycoplasmas, and spirochetes. The small genome size is believed to result from reductive evolution, a process of initial mutation with loss of function followed by progressive accumulation of mutations and eventual gene deletion. This is most notable in the 1.1 Mb genome of Rickettsia prowazekki in which 24% of the genome is non-coding, as compared to approximately 10% in the 4.4 Mb E. coli. Consequently, these pathogens are thus presumed to retain only the most important functions for survival and propagation. There is consistent evidence from small genomes that the genetic deletion is primarily related to the loss of metabolic function and especially reduction of multiple overlapping pathways and duplicated genes. Thus, these pathogens undergo progressive reduction in their genomes yet maintain the ability to infect, survive within, and cause disease in animals. In the face of this reductive process, what genes and associated functions are maintained? Strikingly, these pathogens devote a high percentage of their genomes to paralogous families of polymorphic surface molecules. This retention suggests that evasion of the immune response is the highest priority of obligate microbial pathogens and provides a strategy for identifying protective antigens for vaccine development to control disease.

Adaptation, Physiological↗
PubMed2001

Mitochondrial DNA in human malignancy.

Alterations in expression of mitochondrial DNA (mtDNA)-encoded polypeptides required for oxidative phosphorylation and cellular ATP generation may be a general characteristic of cancer cells. Mitochondrial DNA has been proposed to be involved in carcinogenesis because of high susceptibility to mutations and limited repair mechanisms in comparison to nuclear DNA. Since mtDNA lacks introns, it has been suggested that most mutations will occur in coding sequences and subsequent accumulation of mutations may lead to tumor formation. The mitochondrial genome is dependent upon the nuclear genome for transcription, translation, replication and repair, but precise mechanisms for how the two genomes interact and integrate with each other are poorly understood. In solid tumors, elevated expression of mtDNA-encoded subunits of the mitochondrial electron respiratory chain may reflect mitochondrial adaptation to perturbations in cellular energy requirements. In this paper, we review mitochondrial genomic aberrations reported in solid tumors of the breast, colon, stomach, liver, kidney, bladder, head/neck and lung as well as for hematologic diseases such as leukemia, myelodysplastic syndrome and lymphoma. We include data for elevated expression of mtDNA-encoded electron respiratory chain subunits in breast, colon and liver cancers and also the mutations reported in cancers of the colon, stomach, bladder, head/neck and lung. Finally, we examine the role of reactive oxygen species (ROS) generated by mitochondria in the process of carcinogenesis.

Breast Neoplasms↗
PubMed1994

Mitochondrial DNA sequence variation in human evolution and disease.

Germ-line and somatic mtDNA mutations are hypothesized to act together to shape our history and our health. Germ-line mtDNA mutations, both ancient and recent, have been associated with a variety of degenerative diseases. Mildly to moderately deleterious germ-line mutations, like neutral polymorphisms, have become established in the distant past through genetic drift but now may predispose certain individuals to late-onset degenerative diseases. As an example, a homoplasmic, Caucasian, tRNA(Gln) mutation at nucleotide pair (np) 4336 has been observed in 5% of Alzheimer disease and Parkinson disease patients and may contribute to the multifactorial etiology of these diseases. Moderately to severely deleterious germ-line mutations, on the other hand, appear repeatedly but are eliminated by selection. Hence, all extant mutations of this class are recent and associated with more devastating diseases of young adults and children. Representative of these mutations is a heteroplasmic mutation in MTND6 at np 14459 whose clinical presentations range from adult-onset blindness to pediatric dystonia and basal ganglial degeneration. To the inherited mutations are added somatic mtDNA mutations which accumulate in random arrays within stable tissues. These mutations provide a molecular clock that measures our age and may cause a progressive decline in tissue energy output that could precipitate the onset of degenerative diseases in individuals harboring inherited deleterious mutations.

Amino Acid Sequence↗
PubMed1993

Somatic hypermutation of an immunoglobulin mu heavy chain transgene.

We have analyzed somatic hypermutation of an immunoglobulin (Ig) heavy chain transgene. Hybridomas expressing the transgene were produced from immunized transgenic mice and transgene copies were sequenced to assay for mutation. In two IgM-producing hybridomas, as well as in several IgG-producing hybridomas, mutations were found in the VDJ region of the transgene. In the IgM-producing hybridomas, both mutated and unmutated transgene copies were present and expressed as mRNA. Several mutated transgene copies were present in a single cell and these showed different patterns of mutation. Two IgG-producing hybridomas isolated from a single animal also showed a hierarchical pattern of mutation indicating that transgene mutations can accumulate during B cell proliferation, similar to the mutational process for endogenous antibody genes. Among hybridomas that expressed both IgG and IgM molecules derived from the transgene, the isotype-switched gamma transgene copy exhibited a higher level of mutation than the mu transgene copies. Our results indicate that the 15-kb ARSmu transgene contains all the sequence information required to target the Ig-specific hypermutational machinery, and raise the possibility that sequences associated with the endogenous CH locus might enhance somatic mutation.

Amino Acid Sequence↗
PubMed2003

Accumulation of mitochondrial DNA mutations in human immunodeficiency virus-infected patients treated with nucleoside-analogue reverse-transcriptase inhibitors.

Nucleoside reverse-transcriptase inhibitor (NRTI) therapy for human immunodeficiency virus (HIV) infection has been associated with mitochondrial DNA (mtDNA) polymerase-gamma inhibition and subsequent mtDNA depletion. Effects on mtDNA mutation, although suggested by critical involvement of polymerase-gamma in DNA-repair reactions, are unknown. In the present study, we assessed the nature and frequency of mitochondrial genome sequence differences in peripheral-blood samples taken prior to NRTI therapy and after 6-77 mo of treatment in 16 NRTI-treated patients. Samples from 10 HIV-infected, treatment-naive control individuals were taken at similar time intervals. Single-stranded conformation polymorphism (SSCP) and DNA-sequencing analysis techniques were used to detect mitochondrial genome sequence variants between paired longitudinal samples, and heteroplasmic populations were quantified after cloning and repeat SSCP/sequencing. Of 16 individuals treated with NRTIs, 5 exhibited altered SSCP profiles associated with the development of novel heteroplasmic DNA sequence changes, whereas no SSCP pattern change within these regions was observed in the control individuals. Heteroplasmic sequence changes were distributed across four regions of the genome: the noncoding region to 12S ribosomal RNA, reduced-nicotinamide-adenine-dinucleotide dehydrogenase 1, and cytochrome oxidase subunits I and III. Of the total of 26 patients who were examined in the present study, 4 of 5 patients with detectable mtDNA sequence changes since commencement of therapy developed evidence of peripheral fat wasting (lipoatrophy) between sample intervals (P=.031). One patient, without detectable sequence changes on NRTI therapy, also developed lipoatrophy. Levels of mtDNA copies/cell in blood samples were determined by quantitative PCR for 11 of the 16 NRTI-exposed patients; 7 of these 11 patients showed reduced levels of mtDNA in blood after therapy, including all 3 patients tested with evidence of mtDNA sequence changes on therapy. These data indicate that NRTI therapy provides conditions permissive for the development of peripheral-blood mtDNA mutations in vivo.

Base Sequence↗
PubMed2005

Risk of selecting de novo drug-resistance mutations during structured treatment interruptions in patients with chronic HIV infection.

BACKGROUND: Structured treatment interruption (STI) may allow viral replication in the presence of decreased plasma drug levels, with risk of selection of resistance mutations. METHODS: For patients recruited for an STI study, genotypic resistance testing was performed at baseline (before receipt of any treatment), immediately before the STI, and 2 weeks after each interuption of therapy. RESULTS: During 20 (18%) of 112 STI cycles (95% CI, 11%-26%), resistance mutations were selected; 6% of the mutations were de novo (i.e., not detected before the start of STI), and 12% were archived mutations (i.e., mutations already detected before the STI). Overall, resistance mutations during STI were selected in 9 (26%) of 35 patients; 5 (14%) of the mutations were de novo, and 4 (12%) were archived mutations. Mutations conferring resistance to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) were selected in 3 (23%) of 13 patients receiving NNRTI-based regimens (all mutations were de novo). Mutations conferring resistance to lamivudine were selected in 9 (50%) of 18 patients receiving lamivudine-containing regimens (4 [22%] were de novo, and 5 [28%] were archived mutations). Mutations conferring resistance to nucleoside reverse-transcriptase inhibitors (NRTIs), excluding the M184V mutation, were selected in 2 (6%) of 35 recipients of NRTIs (1 [3%] of these mutations was de novo, and 1 [3%] was an archived mutation. Finally, mutations conferring resistance to protease inhibitors were selected in none of the 22 patients receiving protease inhibitors. In most cases, de novo and archived mutations were selected during the first STI cycle, and their number did not increase during successive cycles. Plasma viral load decreased to undetectable levels in all the patients when the earlier drug regimen was reintroduced. CONCLUSIONS: Genotypic mutations are selected during STI in a high proportion of patients (especially in patients receiving NNRTIs or lamivudine). Approximately one-half of selected mutations were archived mutations. Patients who had archived mutations did not have a higher risk of accumulating new mutations than did patients who were infected with wild-type virus before the STI.

Adult↗
PubMed2006

Stem cell aging and cancer.

Stem cells are capable of self-renewal, differentiation into various lineages, and proliferation; thus, they play critical roles in the functioning and maintenance of many biological systems. However, these unique qualities of stem cells also make them more vulnerable to mutations as the organism ages. The biggest risk factor in cancer development is age, and most scientists believe that cancers partly result from a buildup of mutations in different cell types over time. This accumulation of mutations takes place over the course of a person's lifetime, during which repeated rounds of cell division result in editing errors in the DNA. Genetic alterations can cause changes in the signaling pathways controlling proliferation, differentiation, and apoptosis. In the case of stem cells, such mutations would be passed on to all of the stem cell's progeny, ultimately resulting in a pool of stem cells that feeds neoplastic formation. Studies aiming to identify and characterize these putative cancer stem cells and to understand how they arise will shed light on the process of stem cell aging and its role in cancer.

Cell Transformation, Neoplastic↗
PubMed2006

Accumulation of recessive lethal mutations in Saccharomyces cerevisiae mlh1 mismatch repair mutants is not associated with gross chromosomal rearrangements.

We examined mismatch repair (MMR)-defective diploid strains of budding yeast grown for approximately 160 generations to determine whether decreases in spore viability due to the uncovering of recessive lethal mutations correlated with an increase in gross chromosomal rearrangements (GCRs). No GCRs were detected despite dramatic decreases in spore viability, suggesting that frameshift and/or other unrepaired DNA replication lesions play a greater role than chromosomal instability in decreasing viability in MMR-defective strains.

Adaptor Proteins, Signal Transducing↗
PubMed1993

Accumulated helix-destabilizing mutations in the leucine zipper of c-Fos leads to attenuation and temperature sensitivity of function.

Fos protein heterodimerizes through one surface of an alpha-helical domain called the leucine zipper. We have investigated the effect of destabilizing this domain by multiply substituting small residues of its non-interacting surface with glycine. Ternary complex formation between mutated Fos, Jun and DNA was determined in vitro in the presence of denaturant. We also tested the ability of constitutively expressed, mutated Fos proteins to support anchorage independent growth of the cell line Rat1A. Combinations of two substitutions are tolerated in both assays of Fos function, while four substitutions resulted in attenuation in both functions. Rat1A expressing one of the quadruple mutants also showed temperature sensitivity in anchorage independent growth. In dense monolayers of these cells, stromelysin (a Fos-responsive gene product) decreased in abundance as a function of temperature and was less abundant even at 34 degrees C than in cells that overexpressed the wild-type c-fos mRNA. However the mutant transgene itself appeared to show temperature sensitive expression. We suggest that creating a range of glycine substitutions for small residues in the non-interacting face of a leucine zipper might be of general use as a strategy to produce attenuated mutants of other transcription factors.

Animals↗
PubMed1999

Sequential accumulation of K-ras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy.

OBJECTIVE: Pancreatic mucinous cystic neoplasms (MCNs) provide a spectrum of neoplastic changes ranging from benign to malignant. The authors have correlated K-ras mutations and p53 overexpression with the evolution of these tumors. METHODS: Areas of mild, moderate, or severe dysplasia were microdissected from paraffin-embedded tissue sections of 28 different MCNs (10 benign, 9 borderline, 9 malignant). Nonneoplastic pancreatic ducts were also microdissected from tissues adjacent to the tumors. Ten serous cystadenomas served as negative controls. K-ras codon 12 mutations were identified by a mutant-enriched nested polymerase chain reaction-restriction fragment length polymorphism assay and confirmed by sequencing. p53 overexpression was demonstrated by immunohistochemistry. RESULTS: K-ras mutations were detected in 20% of benign, 33% of borderline, and 89% of malignant MCNs. Histologically, mutations were found in 26% (7/27) of MCN epithelia with mild dysplasia, 38% (5/13) of MCN epithelia with moderate dysplasia, and 89% (8/9) of MCN epithelia with severe dysplasia or carcinoma. Ten percent (4/39) of nonneoplastic pancreatic ducts at the margins of MCN harbored mutations, all associated with borderline or malignant tumors. Overexpression of p53 occurred in none of the benign or borderline MCNs but in 44% (4/9) of the malignant tumors (p = 0.006 benign/borderline vs. malignant). p53 immunoreactivity was concentrated in areas of severe dysplasia/carcinoma or invasion, where K-ras mutation had been detected. CONCLUSION: These findings demonstrate a sequential accumulation of genetic changes in the carcinogenesis of MCN. K-ras mutations appear early and increase in proportion with increasing dysplasia. Overexpression of p53 is a late finding observed only in carcinomas, and in combination with mutated K-ras genes. The presence of K-ras mutations in nonneoplastic ducts supports formal pancreatic resection over enucleation for treatment. Mucinous cystic neoplasms may be a useful model to study the evolution of pancreatic ductal adenocarcinomas, in which precursor lesions remain unknown.

DNA Mutational Analysis↗