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PubMedDate not supplied

Fluorescence in situ hybridization analysis with LIS1 specific probes reveals a high deletion mutation rate in isolated lissencephaly sequence.

PURPOSE: Recent revision of the lissencephaly critical region on chromosome 17p13.3 and confirmation of LIS1 as the causative gene for classical lissencephaly has allowed the development and application of fluorescence in situ hybridization (FISH) probes corresponding directly to this gene. METHOD: We have analyzed patients with isolated lissencephaly sequence (ILS) by FISH with probes at D17S379, an anonymous locus distal to LIS1, and with LIS1 specific probes. RESULTS: In 110 patients with ILS, a deletion at D17S379 was detected in 23.6%. Of those patients without a deletion, 32 were available for further study with LIS1 probes. Deletions were found in eight additional individuals. CONCLUSION: The overall deletion mutation rate detectable by FISH with LIS1 probes is approximately 40%. This rate is significantly higher than the deletion rate observed at D17S379. This indicates that FISH studies using probes specific to LIS1 should be undertaken as the initial diagnostic assay for the evaluation of patients with ILS, and the high frequency of deletions raises the possibility of "hotspots" for chromosome breakage in this region.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1991

Mammalian DNA replication: mutation biases and the mutation rate.

Experimental studies have shown that the fidelity of DNA replication can be affected by the concentrations of free deoxyribonucleotides present in the cell. Replication of mammalian chromosomes is achieved using pools of newly-synthesized deoxyribonucleotides which fluctuate during the cell cycle. Since regions of mammalian chromosomes are replicated sequentially, there is the potential for differences among mammalian loci in both the relative and absolute frequencies of the various transitional and transversional mutations which may occur. Where these mutations are effectively neutral, at silent sites in genes and in non-coding sequences, this may result in different rates of evolution and in different base compositions, as have been observed in data from mammalian genes. A simple model of the DNA replication process is developed to describe how the mutation rate could be affected by the G + C contents of the deoxyribonucleotide pools and of the replicating DNA. Mutation rates are predicted to vary from locus to locus; only in the particular case of identical G + C contents in the DNA locus and the deoxyribonucleotide pools, and no proofreading, will the mutation rate be uniform over all loci.

Animals↗
PubMed2001

Improved inference of mutation rates: II. Generalization of the Luria-Delbrück distribution for realistic cell-cycle time distributions.

In the first paper of this series (Kepler and Oprea, Theor. Popul. Biol. 2001) we found a continuum approximation of the Luria-Delbrück distribution in terms of a scaled variable related to the proportion of mutants in the culture. Here we show that the Luria-Delbrück distribution is inaccurate when realistic division processes are being considered due to the non-Markovian character of the cell cycle. We derive the expectation of the proportion of mutants in the culture for arbitrary cell-cycle time distributions. We then introduce a two-parameter generalization of the continuum Luria-Delbrück distribution for two of the more commonly used cell-cycle time distributions: gamma and shifted exponential. We obtain the generalized distribution by defining a map from the actual parameters to "effective" parameters. The effective mutation rate is obtained analytically, while the effective population size is obtained by fitting simulation data. Our simulations show that the second parameter depend mostly on the coefficient of variation of the cell-cycle time distribution.

Algorithms↗
PubMed1993

The experience of mutation rate quantitative evaluation in connection with environmental pollution (based on studies of congenital anomalies in human populations).

For 3 years genetic monitoring of congenital anomalies (CA) has been carried out in three Ukrainian towns essentially different in the level of air pollution: the most polluted, Mariupol (M.); medium polluted, Zaporozhye (Z.); and relatively clean, Simpheropol (S.). In this work we present the results of this study. Eighteen CAs being used in the International Clearinghouse program were registered during the first year of life. For each case of CA an individual questionnaire was filled in. It included practically all known causes of malformations. Similar questionnaires were filled in for cases of normal birth outcome. The estimation of newborns of control groups was made according to a score of 9-10 on the Apgar scale. The questionnaires were completed by physicians in all maternity hospitals and children's clinics and based on the information obtained from mothers. Multiple malformations, dominant and X-linked CA in M. were 2.6-3.1 times more frequent than in S. The frequency of new mutations was 0.45-0.95 and 0.17-0.47 per 10(3) births respectively. No differences in multifactorial and recessive CA were noted. The mathematical method (so-called statusmetrical analysis) was used to indirectly determine the part of CAs of unknown etiology (probably of mutation origin) in the total number of CAs. Their quota in Z. and M. was 1.2-1.5 times more than in S. The advantage of statusmetrical analysis lies in the absence of any restrictions connected with a large number of parameters which describe the object's status. It makes it possible to analyze tens, even hundreds of factors (along with the increased number of parameters the reliability of the conclusions increases) and range them in accordance with their validity. Genetic consequences of chemical pollution were estimated in biological equivalents Röntgen (BER). In M. they were equal to the effect of irradiation at doses of 180-300 BER (230 BER, central estimate) over 30 years. In the polluted towns (M. and Z.) the relation between average annual general emission of atmospheric pollutants (M./Z.) was 2.21, the frequency of dominant and X-linked CA 2.20 and of new skeleton mutations 2.24. The difference of mutation rate in the towns studied was due to the dynamics of demographic processes.

Abnormalities, Drug-Induced↗
PubMed1975

On the mutation rate of neurofibromatosis.

A genetic study of 124 cases of neurofibromatosis was performed. The contingent of probands was mainly represented by a Russian population, most of the individuals being born in the European part of the RSFSR. Both parents of the probands were examined in only 58 cases, the proportion of sporadic cases in this group being 0.79, as compared to 0.77 for the whole group under study. The existing data evaluated by a direct method are not yet sufficient for a decisive estimation of the penetrance, which, however, cannot be under 80%. Segregation analysis of descendants from particular marriages showed a good correspondance to the hypothesis of Mendelian dominance (32 affected children out of 65). These results analyzed together with those obtained by other authors permit an inference on the full penetrance of neurofibromatosis. The genetic interpretation of sporadic cases as a result of new mutations is presented. The prevalence of neurofibromatosis among the 16-year-old youths was evaluated as 12.8 with 10-(5). This value is suggested to be an estimation of the incidence of the condition in the general population, the mutation rate evaluated by a direct method being equal to 4.4 with 10-(5) divided by 4.9 with 10-minus 5. The increased birth order of probands in sporadic cases (against the theoretical expectation) as well as increased paternal age (as compared with controls) were found to be statistically significant (P equals 0.004 and P equals 0.03, respectively) while the difference in maternal ages was statistically insignificant (P equals 0.008). No statistical relationship between sporadic cases and occupational exposure of parents to deleterious chemical and physical factors was found.

Adult↗
PubMed1994

Superoxide dismutase (sod-1) null mutants of Neurospora crassa: oxidative stress sensitivity, spontaneous mutation rate and response to mutagens.

Enzymatic superoxide-dismutase activity is believed to be important in defense against the toxic effects of superoxide. Although superoxide dismutases are among the best studied proteins, numerous questions remain concerning the specific biological roles of the various superoxide-dismutase types. In part, this is because the proposed damaging effects of superoxide are manifold, ranging from inactivation of certain metabolic enzymes to DNA damage. Studies with superoxide-deficient mutants have proven valuable, but surprisingly few such studies have been reported. We have constructed and characterized Neurospora crassa mutants that are null for sod-1, the gene that encodes copper-zinc superoxide dismutase. Mutant strains are sensitive to paraquat and elevated oxygen concentrations, and they exhibit an increased spontaneous mutation rate. They appear to have near wild-type sensitive to near- and far-UV, heat shock and gamma-irradiation. Unlike the equivalent Saccharomyces cerevisiae mutant and the sodA sodB double mutant of Escherichia coli, they do not exhibit aerobic auxotrophy. These results are discussed in the context of an attempt to identify consensus phenotypes among superoxide dismutase-deficient mutants. N. crassa sod-1 null mutant strains were also employed in genetic and subcellular fractionation studies. Results support the hypothesis that a single gene (sod-1), located between Fsr-12 and leu-3 on linkage group I, is responsible for most or all CuZn superoxide dismutase activity in this organism.

Fungal Proteins↗
PubMedDate not supplied

Rare allele heterozygosity and relative electromorph mutation rates in man.

Previous studies of human populations have failed to find a significant relationship between genetic variability, as measured by total heterozygosity, and cistron size, as measured by subunit molecular weight of proteins, but the number of different rare alleles in human populations has been shown to be correlated with subunit size. The present paper examines these relationships further, utilizing data on electrophoretic variants at 27 loci for 12 human populations with a total of 800 000 individual system observation. The results indicate that, if genetic variability is measured by rare allele heterozygosity instead of total heterozygosity, there is a significant correlation with subunit size. In addition, there are significant differences for rare allele heterozygosity between multimeric and monomeric proteins, the range of variability being less in the multimers (and in the total) than for monomers. Finally, rare allele heterozygosity has a much bigger range of variability than the range of subunit size. By contrast, the range of rare allele heterozygosity between populations is less than ten-fold, a factor not evident in effective population sizes. Both interlocus and interpopulational estimates of relative electromorph mutation rates (REMR) have been calculated, utilizing the distributions of the number of different rare alleles as well as rare allele heterozygosity. The range of these estimates are much lower than the estimates given by Zouros (1979) using total heterozygosity as input.

Alleles↗
PubMed1997

Mutation rate of GB virus C/hepatitis G virus over the entire genome and in subgenomic regions.

A patient on maintenance hemodialysis was infected with a recently discovered putative non-A to -E hepatitis virus designated GB virus C (GBV-C) or hepatitis G virus (HGV) by transfusion. The viral isolate was recovered from the patient soon after she turned positive for GBV-C/HGV RNA in serum (GS185) and 8.4 years thereafter (GS193), and the entire nucleotide sequences were determined. They both had a genomic length of 9391 nucleotides with a defective C gene made of only 42 nucleotides. Between GS185 and GS193, 31 (0.33%) nucleotides were different, which changed 5 (0.18%) of the encoded 2842 amino acids. Thus, GBV-C/HGV was estimated to have a mutation rate of 3.9 x 10(-4) base substitutions per site per year. Nucleotide conversions were distributed over subgenomic regions, except in the 5' untranslated region of 552 nucleotides and a defective short C gene, which were conserved in sequence. The change in the putative envelope genes (E1 and E2) was no different from that in the entire genome with only 6 (0.35%) nucleotide substitutions among the 1730, just 1 of which induced an amino acid conversion. Taken along with the comparison of the two isolates with the reported five GBV-C or HGV isolates, these results indicate that GBV-C/HGV would not have hypervariable regions and would use a strategy for viral persistence that is different from immune escape.

Amino Acid Sequence↗
PubMed2000

Dynamic evolution of plant mitochondrial genomes: mobile genes and introns and highly variable mutation rates.

We summarize our recent studies showing that angiosperm mitochondrial (mt) genomes have experienced remarkably high rates of gene loss and concomitant transfer to the nucleus and of intron acquisition by horizontal transfer. Moreover, we find substantial lineage-specific variation in rates of these structural mutations and also point mutations. These findings mostly arise from a Southern blot survey of gene and intron distribution in 281 diverse angiosperms. These blots reveal numerous losses of mt ribosomal protein genes but, with one exception, only rare loss of respiratory genes. Some lineages of angiosperms have kept all of their mt ribosomal protein genes whereas others have lost most of them. These many losses appear to reflect remarkably high (and variable) rates of functional transfer of mt ribosomal protein genes to the nucleus in angiosperms. The recent transfer of cox2 to the nucleus in legumes provides both an example of interorganellar gene transfer in action and a starting point for discussion of the roles of mechanistic and selective forces in determining the distribution of genetic labor between organellar and nuclear genomes. Plant mt genomes also acquire sequences by horizontal transfer. A striking example of this is a homing group I intron in the mt cox1 gene. This extraordinarily invasive mobile element has probably been acquired over 1,000 times separately during angiosperm evolution via a recent wave of cross-species horizontal transfers. Finally, whereas all previously examined angiosperm mtDNAs have low rates of synonymous substitutions, mtDNAs of two distantly related angiosperms have highly accelerated substitution rates.

Biological Evolution↗
PubMed1994

International Commission for Protection Against Environmental Mutagens and Carcinogens. Working paper no. 5. Impact of the molecular spectrum of mutational lesions on estimates of germinal gene-mutation rates.

Review of the molecular characteristics of the variants identified at a series of disease loci suggests significant differences among loci in the relative frequency of nucleotide substitutions versus more complex events such as deletions. Some common features are repeatedly observed in each class of variant. For example, a high proportion of the nucleotide substitutions involve transitions of deoxycytidine and are suggested to result from deamination of cytosine at 5-methyl-CpG sites. Similarly, deletions of three or fewer nucleotides are relatively common in the non-nucleotide substitution class and these deletions are often associated with a seven-nucleotide core sequence. A significant fraction of the larger deletions and rearrangements may be associated with repetitive elements. Many of the deletion events do not appear to involve a chromosomal recombination mechanism. Mechanisms involving transcription slippage and chromatid exchange have been suggested as possible alternative mechanisms for generating deletion events. The spectrum of mutational events identified, e.g. nucleotide substitutions versus deletions, differs between loci and is probably a reflection of both the gene structure and the selective pressure to generate a disease phenotype. This locus specificity (at both the biological and molecular level) would appear to have significant potential to compromise estimates of increases in the gene germinal mutation rate following exposure to mutagenic agents.

Deoxyribonucleotides↗
PubMed2006

Expression of feline immunodeficiency virus Vif is associated with reduced viral mutation rates without restoration of replication of vif mutant viruses.

The vif gene of lentiviruses has been demonstrated to be essential for efficient viral replication in many cell types. Although the Vif protein of feline immunodeficiency virus (FIV) displays limited homology to HIV-1 Vif, the role of vif in FIV replication is not known. We have examined the requirements of vif for replication of a FIV strain isolated from a non-domestic felid, Otocolobus manul (FIV-Oma). In agreement with others, we find that replication of FIV vif mutant molecular clones in CrFK cells is highly attenuated. Initial attempts to rescue vif mutant viruses in trans were limited by lack of detectable wild-type Vif expression from DNA constructs. We demonstrate that FIV-Oma Vif expression can be increased by re-synthesis of the gene to remove splice donor and acceptor sites as well as improving codon usage to a mammalian codon optimized model. Cellular localization of resynthesized Vif (Vif-RS) is cytoplasmic. Clonal stable transfectants expressing HA-tagged Vif-RS do not restore replication levels of vif mutant virus. However, in such cell lines, G-to-A mutation rates in replicating wild-type viruses are reduced.

Amino Acid Sequence↗
PubMed2005

The integrated development of network complexity modulates the diverse evolutionary mutation rates of individual proteins.

The rate of evolution-related mutation varies widely among proteins while the unity of the organism implies an integrated evolution of its protein network. Focusing on the yeast interactome, we monitored the structural impact of amino acid substitution on yeast proteins with reported structure. The impact of mutation in creating or deleting structural markers for interactivity varies across proteins and modulates the evolutionary rates, yielding a unified kinetic law of accumulation of connectivities consistent with an integrated evolution of the interactome.

Amino Acid Substitution↗
PubMed1993

The relationship between mutation rates for the (C-G)-->(T-A) transition and features of T-G mispair structures in different neighbor environments, determined by free energy molecular mechanics.

The results of this theoretical study combining sequence analysis and minimization with integral equation liquid structural methods indicate that the local sequence context of a T-G wobble mismatch influences the local conformation of the helix, and that conformational alterations are correlated with mutational activity. Studies on the mismatch in four different 5' and 3' neighbor contexts indicate that the nature of the 5' base to the thymine of the mispair is probably the single most critical factor in determining the structural features that facilitate or discourage mutations. When cytosine is the 5' neighbor, the helix adopts a mostly BII conformation, whereas a 5' guanine preserves the canonical BI. Structures that vary little from the BI structure on the incorporation of the mismatch have sequences that correspond to lower rates of transition, whereas those with mostly BII conformations, have sequences with high mutation rates. Subtle variations in stacking patterns around the mismatch precipitate a structural Domino-effect, with a variety of changes in conformation. The helix opens at the mismatch with increased roll angle and propeller twist, causing the thymine to migrate into the major groove and the guanine into the minor groove, exposing the heteroatomic groups to the solvent in the major and minor grooves, respectively, and allowing for some unusual hydrogen bonds. These alterations show a tentative correlation with mutation rates, implying that stacking and structure around the mismatch are important features in the discrimination by proofreading activities of canonical W-C and wobble mismatch base pairs during replication-repair. Variations in the C1'-C1' distances, high propeller twists, changes in the electrostatic complementarity leading to unusual hydrogen bonding patterns probably all correlate with detectability.

Base Composition↗
PubMed2002

Acceleration of genomic evolution caused by enhanced mutation rate in endocellular symbionts.

Endosymbionts, which are widely observed in nature, have undergone reductive genome evolution because of their long-term intracellular lifestyle. Here we compared the complete genome sequences of two different endosymbionts, Buchnera and a protist mitochondrion, with their close relatives to study the evolutionary rates of functional genes in endosymbionts. The results indicate that the rate of amino acid substitution is two times higher in symbionts than in their relatives. This rate increase was observed uniformly among different functional classes of genes, although strong purifying selection may have counterbalanced the rate increase in a few cases. Our data suggest that, contrary to current views, neither the Muller's ratchet effect nor the slightly deleterious mutation theory sufficiently accounts for the elevated evolutionary rate. Rather, the elevated evolutionary rate appears to be mainly due to enhanced mutation rate, although the possibility of relaxation of purifying selection cannot be ruled out.

Buchnera↗