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PubMed1998

Strong intrinsic biases towards mutation and conservation of bases in human IgVH genes during somatic hypermutation prevent statistical analysis of antigen selection.

Immunoglobulin V region genes acquire point mutations during affinity maturation of the T-cell-dependent B-cell response. It has been proposed that both selection by antigen and characteristics of the DNA sequence are involved in determining the distribution of mutations along the genes. There is a tendency for replacement mutations to occur in the complementarity-determining regions and for silent mutations to accumulate in the framework regions of used genes. By analysing a group of highly mutated human IgVH4-34 (VH4. 21) and family 5 genes derived from human gut-associated lymphoid tissues, which were out-of-frame between VH and JH (and therefore not used) we have investigated the distribution of mutations acquired in the absence of selection. We observed that these genes may show the statistical hallmarks of selected genes, suggesting that intrinsic biases alone may be enough to give the appearance of selection. These data suggest that analysis of the distribution of mutations in IgVH genes cannot be used reliably to state whether antigenic selection of the B-cell carrying the genes occurred. In-frame genes had more silent mutations than the out-of-frame genes and lacked stop codons. These characteristics were considered to be indicative of selection in the in-frame genes derived from human gut-associated lymphoid tissue.

Antibody Affinity↗
PubMed2001

Spontaneous mutation spectra in supF: comparative analysis of mammalian cell line base substitution spectra.

The last decade has seen a dramatic accumulation of mutation data from reporter genes utilized in mutagenesis experiments involving DNA reactive agents allowing comparisons for the mutagenic potential between many different mutagens. When analysing chemically induced mutation spectra it is important to establish the potential spontaneous background before drawing conclusions concerning specific chemically induced hotspots. A major mutation reporter system gene used in mammalian cells is the supF suppressor tRNA gene. The Mammalian Gene Mutation Database (MGMD) contains a considerable number of supF spontaneous mutations permitting a thorough analysis of spontaneous mutations in mammalian cell lines from different species and tissues. Analyses of spontaneous mutation spectra were performed using a range of statistical techniques. Spontaneous mutations were observed at 82.4% of the nucleotides in the supF suppressor tRNA sequence although the pattern of significant hotspots differed between cell lines. Our analyses of spontaneous mutation spectra show considerable variation both within and between cell lines for the distributions of spontaneous mutations occurring with no clear tissue or species-specific patterns emerging. In addition, spectra derived from supF recovered from liver and skin of transgenic mice, were similar to each other, but showed significant differences from many in vitro spectra. The most common base substitutions were G:C>TA transversions and G:C>A:T transitions, although levels of each type differed between cell lines. There was also variation between cell lines for the most mutable dinucleotides, however, significant hotspots were frequently observed at CpG sites and sequences containing GG/CC. We conclude that the number of varying distributions and potential hotspots for spontaneous mutations should thus be considered when comparing chemically induced mutation spectra in supF. The spectra presented here will be a useful reference for analysis and re-analysis of chemically induced spectra as well as for use in comparison with the spontaneous spectra of other gene systems.

Animals↗
PubMed2003

How are deleterious mutations purged? Drift versus nonrandom mating.

Accumulation of deleterious mutations has important consequences for the evolution of mating systems and the persistence of small populations. It is well established that consanguineous mating can purge a part of the mutation load and that lethal mutations can also be purged in small populations. However, the efficiency of purging in natural populations, due to either consanguineous mating or to reduced population size, has been questioned. Consequences of consanguineous mating systems and small population size are often equated under "inbreeding" because both increase homozygosity, and selection is though to be more efficient against homozygous deleterious alleles. I show that two processes of purging that I call "purging by drift" and "purging by nonrandom mating" have to be distinguished. Conditions under which the two ways of purging are effective are derived. Nonrandom mating can purge deleterious mutations regardless of their dominance level, whereas only highly recessive mutations can be purged by drift. Both types of purging are limited by population size, and sharp thresholds separate domains where purging is either effective or not. The limitations derived here on the efficiency of purging are compatible with some experimental studies. Implications of these results for conservation and evolution of mating systems are discussed.

Biological Evolution↗
PubMed2006

Neuroserpin.

Neuroserpin is a member of the serpin family of serine protease inhibitors. Tissue distribution analysis reveals a predominantly neuronal expression during the late stages of neurogenesis and, in the adult brain, in areas where synaptic changes are associated with learning and memory (synaptic plasticity). In vitro studies revealed complex formation between neuroserpin and different serine proteases, i.e. tPA, uPA, and plasmin. The neuroserpin-target complex has so far not been characterized in vivo. However, some investigations help to understand the functional role of this serpin. Neuroserpin was shown to be involved in the regulation of the morphology of neuroendocrine cells in culture, possibly by modulating the degradation of the extracellular matrix by proteolytic enzymes such as tPA. Moreover, a role of neuroserpin in mood regulation has been deduced from the over- and underexpression of neuroserpin in genetically modified mice, which showed increased anxiety and novelty-induced hypo-locomotion. In pathological conditions of the central nervous system (i.e. stroke and seizures), neuroserpin plays a neuroprotective role, probably by blocking the deleterious effects of tPA. A familial form of a neurodegenerative disease, termed familial encephalopathy with neuroserpin inclusion bodies, is caused by point mutations in the neuroserpin gene. This condition is characterized by the intracellular polymerization and accumulation of mutated neuroserpin, leading to neuronal death and dementia.

Animals↗
PubMed1999

p53 mutation and allelic loss of chromosome 3p, 9p of preneoplastic lesions in patients with nonsmall cell lung carcinoma.

BACKGROUND: An accumulation of mutations can result in carcinogenesis. Comparing genetic alterations in preneoplastic lesions with those seen in cancer in the same patient may be helpful in the early diagnosis of lung carcinoma or preneoplastic lesions. METHODS: To identify genetic alterations that may play a role in the development of nonsmall cell lung carcinoma (NSCLC), the authors examined the p53 gene and microsatellite markers on chromosome 3p (D3S643, D3S1317), 9p (D9S171, IFNA) in 35 bronchial metaplastic lesions and 28 alveolar hyperplastic lesions from 61 patients. RESULTS: A total of 8 metaplastic lesions (1 squamous metaplasia and 7 dysplasias) and 3 alveolar hyperplastic lesions (with atypia) showed genetic alterations, including loss of heterozygosity (LOH) of 3p, 9p and mutations of the p53 gene. In an analysis of microsatellite markers, 5 of 35 cases of squamous cell carcinoma (SCC) and 3 of 26 cases of adenocarcinoma (Ad) showed LOH in both preneoplastic lesions and synchronous cancers. Nine patients (25.7%) with SCC and 6 patients (23.1%) with Ad were shown to have mutations of the p53 gene by single-strand conformation polymorphism. In 2 of these 9 patients with SCC, the same mutation was observed in both dysplasia and SCC. CONCLUSIONS: These findings suggest that several genetic alterations may occur in preneoplastic lesions or the early stage of SCC of the lung, whereas the genetic alterations examined appeared to occur relatively late in the pathogenesis of pulmonary adenocarcinoma.

Adult↗
PubMed2000

Mutated p53 in tumors, mutant p53 and p53-specific antibodies in the circulation in patients with gastric cancer.

The accumulation of mutated p53 in tumor cells results in the presence in the circulation of mutant p53 (p53m) and the production of p53-specific antibodies (p53Ab). We examined the relationships among these phenomena and analyzed their clinical implications in 62 patients with gastric cancer at various stages. Expression of p53 in tumors was studied by an immunohistochemical method and circulating p53m and p53Ab were quantitated with commercially available enzyme-linked immunosorbent assay kits. The detectable expression of p53 in tumors and circulating p53Ab was recognized in 28 (45.2%) and 7 (11.3%) of the 62 patients, respectively. The number of patients with higher levels of circulating p53m increased with the progression of the depth of cancer invasion. Patients with any positive findings for the three p53-related parameters had a poorer prognosis, and the difference was statistically significant in patients with p53Ab. When survival was analyzed in terms of the combination of the three p53-related parameters (detectable expression of p53 in tumor cells, high levels of p53m and p53Ab in the circulation), a significantly poorer prognosis was associated with an increase in the number of positive parameters. Analysis of p53 in tumor cells, together with analysis of circulating p53m and p53Ab, could improve the accuracy of prognosis in patients with gastric cancer.

Aged↗
PubMed1998

[Is hereditary predisposition to breast cancer linked to BRCA1 a disease of response to genotoxic lesions?].

Germline mutations in either the BRCA1 or the BRCA2 gene are responsible for the majority of hereditary breast cancers. The proposition that BRCA1 may play a role as a caretaker of the genome, was first put forward by the demonstration that, in mitotic and meiotic cells, BRCA1 can interact with Rad51, a major actor in repair and/or recombination processes. From there, a fair body of observations have converged to support the concept that BRCA1 and BRCA2 play a role in monitoring and/or repairing DNA lesions. The relaxation in this monitoring, due to mutations of either of these two genes, leaves unrepaired events and leads to the accumulation of mutations and ultimately to cancer. Understanding the precise biochemical function of BRCA1 and BRCA2 should provide basis for early diagnosis and prevention in women carrying a predisposition to breast cancer.

Animals↗
PubMed1993

Somatic diversification and affinity maturation of IgM and IgG anti-DNA antibodies in murine lupus.

Molecular events occurring during the process of generation of pathogenic immunoglobulin (Ig)G anti-DNA antibodies in systemic lupus erythematosus (SLE) were studied using a newly established method. We analyzed the Ig variable (V) region gene sequence and DNA-binding activity of IgM and IgG anti-DNA monoclonal antibodies (mAb) from individual SLE-prone (NZB x NZW) F1 mice. The first event appeared to be clonal selection and expansion of IgM anti-DNA clones, in which several clones had intraclonal V gene mutations. Although the number of mutations was small, the mutated IgM clones were associated with an increase in DNA-binding activity. The somatic mutations located in complementarity-determining regions (CDR) and in framework regions (FR) of V genes were apparently related to changes in DNA-binding activity. IgG anti-DNA clones that progressively increased in number with aging had numerous somatic mutations in the V region genes and there was a pair of clones which showed an intraclonal accumulation of mutations, in association with increase in the DNA-binding activity. All these findings show that somatic mutations associated with affinity maturation of the V region begin immediately before isotype-switching from IgM to IgG of the clones that have been selected and expanded, in an antigen-driven manner and/or by other forces. We propose that further accumulations of intraclonal somatic hypermutation, in association with selection and expansion of high affinity IgG clones, may lead to formation of highly pathogenic anti-DNA antibodies.

Age Factors↗
PubMed1997

Rapid evolution of translational control mechanisms in RNA genomes.

We have introduced 13 base substitutions into the coat protein gene of RNA bacteriophage MS2. The mutations, which are clustered ahead of the overlapping lysis cistron, do not change the amino acid sequence of the coat protein, but they disrupt a local hairpin, which is needed to control translation of the lysis gene. The mutations decreased the phage titer by four orders of magnitude but, upon passaging, the virus accumulated suppressor mutations that raised the fitness to almost wild-type level. Analysis of the pseudorevertants showed that the disruption of the local hairpin, controlling expression of the lysis gene, had apparently been so complete that its restoration by chance mutations could not be achieved. Instead, alternative foldings initiated by the starting mutations were further stabilized and optimized. Strikingly, in the pseudorevertants analyzed, translational control of the lysis gene had been restored. This feat was accomplished by, on average, four suppressor mutations that generally occurred at codon wobble positions. We also introduced 11 mutations in a hairpin more upstream in the coat protein gene and not implicated in lysis control. Here the titer dropped by three logs, but pseudorevertants with a fitness close to wild-type were soon generated. These pseudorevertants again were the result of the optimization of alternative foldings induced by the mutations. The transition of the secondary structure from wild-type to pseudorevertant could be visualized by structure probing. Our study shows that the folding of the RNA is an important phenotypic property of RNA viruses. However, its distortion can easily be overcome by optimizing alternative base-pairings. These new structures are not qualitatively equivalent to the original one, since they do not successfully compete with the wild-type.

Base Sequence↗
PubMed1992

Alteration of enzyme specificity and catalysis.

In the past year, site-directed mutagenesis and other forms of protein engineering have been used to reverse the substrate specificity of several pairs of enzymes, including disulphide oxidoreductases, proteases, sugar-processing enzymes, and nucleases, as well as the specificity of hormones and their receptors. Mutations have been found that affect rate-determining steps, allowing normally transient intermediates to accumulate. Other mutations endow enzymes with totally new chemical reactions, and even novel biological functions. A combination of molecular genetics and chemical modification has been used for protein engineering.

Animals↗
PubMed2005

Targeted somatic mutation of the BCL6 proto-oncogene and its impact on lymphomagenesis.

Cloning translocation breakpoints which cluster suspiciously to specific chromosomal loci has proved fruitful, leading to the identification of genes implicated in the onset of hematological malignancy. One of the most notable is BCL6, located on chromosome 3q27. The BCL6 is now known to encode a nuclear transcriptional repressor, with pivotal roles in germinal center (GC) formation and regulation of lymphocyte function, differentiation and survival. Unusually, the BCL6 gene locus is also actively targeted by the somatic mutation (SM) mechanism, at a rate indicative of specific, regulated events in both normal and malignant B-cells. These mutations occur in approximately 30% of normal centrocytes and centroblasts, but not in naive or pre-GC B-cells. They are also observed in approximately 70% of diffuse large B-cells lymphomas, approximately 30% of follicular lymphomas (FL) and at various frequencies in many lymphoma subtypes. Mutations are generated in the 5' proximity of the BCL6 promoter, including the first intron and are mainly single nucleotide substitutions, but with insertions and deletions also observed. Mutations in BCL6 occur independently of translocations, although mutational levels can be dramatically influenced by aberrantly translocated chromosomal elements, which map in the vicinity of the gene. Indeed, SMs are directly implicated in the generation of chromosomal translocations, as suggested by the overlap of the breakpoint cluster region and the mutational cluster domain. The prognostic value of the overall level of BCL6 mutations in specific lymphoma populations is, in the main, not as yet fully resolved. The accumulation of mutations in BCL6 during high grade transformation of FL, a mutational clustering and specific recurrent mutations suggest that some mutations may be selected for by their effect on the survival of the tumoral clone. In fact, it is now clear that SM can target and disrupt regulatory motifs in BCL6 to result in upregulated gene expression. Exogenous factors can also perturbate SM in BCL6. Viral infection elevates BCL6 mutational activity, suggesting a potential link with onset of virus-associated lymphoma. These findings to date reveal several mechanisms which can influence specific mutations targeting BCL6, and which may contribute to lymphomagenesis by dysregulating control of BCL6 expression.

Animals↗
PubMed2001

Reversion of a live porcine reproductive and respiratory syndrome virus vaccine investigated by parallel mutations.

A live attenuated porcine reproductive and respiratory syndrome (PRRS) vaccine virus has been shown to revert to virulence under field conditions. In order to identify genetic virulence determinants, ORF1 from the attenuated vaccine virus and three Danish vaccine-derived field isolates was sequenced and compared with the parental strain of the vaccine virus (VR2332). This revealed five mutations that had occurred independently in all three vaccine-derived field isolates, indicating strong parallel selective pressure on these positions in the vaccine virus when used in swine herds. Two of these parallel mutations were direct reversions to the parental VR2332 sequence and were situated in a papain-like cysteine protease domain and in the helicase domain. The remaining parallel mutations might be seen as second-site compensatory mutations for one or more of the mutations that accumulated in the vaccine virus sequence during cell-culture adaptation. Evaluation of the remaining mutations in the ORF1 sequence revealed stronger selective pressure for amino acid conservation during spread in pigs than during vaccine production. Furthermore, it was found that the selective pressure did not change during the time period studied. The implications of these findings for PRRS vaccine attenuation and reversion are discussed.

Amino Acid Sequence↗
PubMed2003

[Study on DNA polymerase beta gene mutation in human cervical cancer].

OBJECTIVE: To investigate whether DNA polymerase beta (POLB) gene mutations occur in human cervical cancer (CC). METHODS: To collect fresh specimens from 34 cervical cancer and examine the mutation of POLB gene using reverse transcription polymerase chain reaction (RT-PCR), single strand conformation polymorphism (SSCP) analysis and sequence analysis. According to their histological grading, the 34 cases of CC were divided into three groups: 9 cases of grade I (G(1)), 14 cases of grade II (G(2)), 11 cases of grade III (G(3)). RESULTS: POLB mutations were detected in the tissues of CC. The mutation of POLB is related with the histological differentiated of the CC. The mutated rates in low differentiated cancer were significantly higher than those in moderate and high ones, and the difference was significant (P < 0.05). The sequencing of the PCR product showed an A to G chang at nucleotide 660, which resulted in a substitution of the amino acid from arginine to glycin at codon 182. CONCLUSIONS: There were POLB mutations in the tissues of CC, and this may be related with the development of the CC. The mutations impaired the catalytic activity of POLB. As a result, this may lead to observed accumulation of mutations in tumor cells.

DNA Polymerase beta↗
PubMedDate not supplied

Hereditary cancer and its clinical implications: a view.

In hereditary cancers the responsible inherited cancer genes are defective (mutated) anti-oncogenes (tumour suppressor genes). This inherited mutation is present in all cells of the organism, and only leads to cancer if in a somatic cell a complete set of specific cancer mutations is accumulated. Since one defective anti-oncogene has been inherited, only three additional somatic cancer mutations are required, according to our previously published view (Anticancer Res 10:1990). The number of de novo arising tumour cells in such a person is thus multiplied by a factor equal to the reverse of the mutant frequency, that is about 10(4)-10(5). This can be observed e.g. in retinoblastoma. Mutations occur in proliferating cells only. Consequently cancer mutations also depend on cell proliferation. If an inherited cancer mutation predisposes to cancer formation in certain organs, then the cancer risk in these organs is enhanced by 10(4)-10(5) times. Tumours in these organs will appear simultaneously if the number of cells and the growth kinetics are similar. This is of course observed in paired organs, like the retina and the female breast. In cancer family syndromes different organs may be affected at the same time. Examples are type I and type II cancer family syndrome and multiple endocrine neoplasia type 1 2a, and 2b. The secondly diagnosed tumours are not caused by metastatic spread. Tumours in two organs will arise at difference times if the number of end cells per organ and the growth kinetics differ. In this case the second tumour is called a second primary malignancy and is not caused by metastatic spread. A good example are the second primary malignancies in hereditary retinoblastoma. The inherited defective anti-oncogene is a recessive gene. This defective inherited gene causes a 10(4)-10(5) fold increase of the normal tumour incidence. This means that nearly always one or more tumours will arise. Evidently, this pattern of inheritance has led to the erroneous conclusion that the genetic abnormality is dominant at the level of the chromosome. The 10(4)-10(5) times enhanced tumour incidence in hereditary cancer is helpful for the clinical recognition of hereditary cancer. That is, hereditary cancer can be recognized not only by family history, but also by early occurrence, the multifocal and bilateral localisation, its occurrence as cancer family syndrome or by second primary malignancies. It is thus recommended to screen patients and families with hereditary cancer for first and second primary tumours. Treatment of patients with hereditary tumours requires extra care to avoid additional cancer mutations.(ABSTRACT TRUNCATED AT 400 WORDS)

Genes, Dominant↗
PubMed2004

Leukemic transformation.

Leukemia results from the uncontrolled accumulation of primitive, poorly differentiated blood cells, and is a consequence of the accumulation of mutations in hematopoietic precursor cells. These mutations include point mutations (single base pair insertions, deletions, or substitutions), gross chromosomal rearrangements such as deletions, insertions, amplifications, and translocations, and epigenetic changes. It seems likely that mutations affecting at least two pathways are required for the development of leukemia. One of these pathways regulates cell accumulation; the second regulates hematopoietic differentiation. Molecularly targeted therapy, which interrupts functions of the leukemogenic proteins generated by mutations, has been developed and shown to be effective for several forms of malignancy. Therefore, it is our hope and belief that a clearer understanding of the mechanism(s) that underlie leukemic transformation will lead to effective new therapies for this dreaded disease.

Cell Transformation, Neoplastic↗
PubMed2006

From bad to good: Fitness reversals and the ascent of deleterious mutations.

Deleterious mutations are considered a major impediment to adaptation, and there are straightforward expectations for the rate at which they accumulate as a function of population size and mutation rate. In a simulation model of an evolving population of asexually replicating RNA molecules, initially deleterious mutations accumulated at rates nearly equal to that of initially beneficial mutations, without impeding evolutionary progress. As the mutation rate was increased within a moderate range, deleterious mutation accumulation and mean fitness improvement both increased. The fixation rates were higher than predicted by many population-genetic models. This seemingly paradoxical result was resolved in part by the observation that, during the time to fixation, the selection coefficient (s) of initially deleterious mutations reversed to confer a selective advantage. Significantly, more than half of the fixations of initially deleterious mutations involved fitness reversals. These fitness reversals had a substantial effect on the total fitness of the genome and thus contributed to its success in the population. Despite the relative importance of fitness reversals, however, the probabilities of fixation for both initially beneficial and initially deleterious mutations were exceedingly small (on the order of 10(-5) of all mutations).

Adaptation, Biological↗
PubMed1996

p53 gene mutation in relation to p53 protein accumulation in male and female breast cancer.

The aim of this investigation was to study the prevalence of p53 gene mutations in male and female breast cancers and to find out the relationship between this event and p53 protein expression. Genomic p53 was amplified by polymerase chain reaction (PCR). Exons 5-8 were screened for mutations using single stranded conformation polymorphism (SSCP) analysis. P53 protein expression was detected by immunohistochemistry (IHC) with the monoclonal antibody DO-1. In female breast cancer, p53 gene mutation was detected in 33% cases in either exon 5 or 6. However, in male, mutation was detected only in exon 6 in 90% cases. On the other hand, p53 protein expression was observed in all of these cases. Moreover, p53 protein immunostaining was observed in some of those cancer tissues, where no mutation was detected in exons 5-8. P53 dysfunction, as indicated by mutation or increased protein expression, common in both male and female breast cancer, but rate of occurrence or site of mutation differ from each other. Our results in male breast tumors indicate a positive correlation between p53 mutation and p53 protein overexpression, whereas the results in female breast tumors indicate an overexpression of p53 protein even without p53 gene mutation. Therefore, it may be presumed that p53 protein accumulation can result primarily from mutation. In addition, stabilization of p53 through binding to other proteins is another possible reason of p53 overexpression.

Breast Neoplasms↗
PubMed1989

A frameshift mutation prevents Kunitz trypsin inhibitor mRNA accumulation in soybean embryos.

We investigated the molecular basis of a soybean Kunitz trypsin inhibitor (KTi) gene mutation that prevents the accumulation of Kunitz trypsin inhibitor protein during seed development. We found that mRNA encoding the major Kunitz trypsin inhibitor protein (KTi3 mRNA) is reduced at least 100-fold in null (KTi-) embryos but that KTi3 gene transcriptional activity is similar in Kunitz trypsin inhibitor producing embryos (KTi+) and in KTi- embryos. We sequenced the Kunitz trypsin inhibitor KTi3 gene from both KTi3+ and KTi3- lines and found that these genes differ by only three nucleotides (+481, +486, and +487) within the KTi3 coding region. Alteration of these nucleotides results in a frameshift within the KTi3- gene that causes premature termination during translation. Our results suggest that the KTi3- frameshift mutation results in KTi3- mRNA destabilization and leads to a drastic reduction in KTi3 mRNA prevalence.

Amino Acid Sequence↗