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PubMed1998

Microsatellite mutation rates in cancer cell lines deficient or proficient in mismatch repair.

A selectable system has been used to determine mutation rates within a microsatellite sequence in human cancer cell lines with or without defects in mismatch repair. A sequence consisting of 17 repeats of poly (dC-dA).poly(dT-dG) [abbreviated as (Ca)17] was inserted near the 5' end of the bacterial neomycin-resistance gene in a plasmid vector, such that the reading frame of the neo gene is disrupted. This plasmid was introduced into cancer cell lines, where it became integrated into the cellular genome. Clones with insertions or deletions of CA-repeats that restored the normal reading frame of the neo gene were selected in G418, and mutation rates were determined by fluctuation analysis. The rates of reversion in LoVo cells, which are deficient for hMSH2, were about one in a thousand per generation, which is approximately two orders of magnitude higher than in the repair-proficient HT-1080 human fibrosarcoma cell line. The mutation rates in H6 cells, which are derived from the hMLH1-deficient HCT116 line, were more heterogeneous than in LoVo, but all were considerably higher than in the repair-proficient line. Nearly all of the revertants of the repair-deficient lines had deletions of a single CA-repeat from the microsatellite sequence, whereas repair-proficient cells had a broader spectrum of mutations.

Carcinoma↗

PubMed1989

Mutation rates differ among regions of the mammalian genome.

In the traditional view of molecular evolution, the rate of point mutation is uniform over the genome of an organism and variation in the rate of nucleotide substitution among DNA regions reflects differential selective constraints. Here we provide evidence for significant variation in mutation rate among regions in the mammalian genome. We show first that substitutions at silent (degenerate) sites in protein-coding genes in mammals seem to be effectively neutral (or nearly so) as they do not occur significantly less frequently than substitutions in pseudogenes. We then show that the rate of silent substitution varies among genes and is correlated with the base composition of genes and their flanking DNA. This implies that the variation in both silent substitution rate and base composition can be attributed to systematic differences in the rate and pattern of mutation over regions of the genome. We propose that the differences arise because mutation patterns vary with the timing of replication of different chromosomal regions in the germline. This hypothesis can account for both the origin of isochores in mammalian genomes and the observation that silent nucleotide substitutions in different mammalian genes do not have the same molecular clock.

Animals↗

PubMed1999

High genome-wide mutation rates in vegetatively propagated bermudagrass.

A cascade DNA amplification strategy that generates arbitrary signatures from amplification profiles (ASAP) was used to measure genome-wide mutation rates in bermudagrass (Cynodon). ASAP quantified nucleotide changes that were induced by irradiation, genetic instabilities and normal vegetative growth of cultivars and accessions of sterile interspecific hybrids. DNA sequence divergence between cultivar 'Tifway' and its gamma radiation-induced mutant 'Tifway II' (0.70 +/- 0.66%) was comparable to estimates in radiation-induced mutants and spontaneous sports of chrysanthemum (Chrysanthemum morifolium Ramat.). A similar divergence in sequence (0.95 +/- 0.20%) was observed in the pairwise comparison of 17 nondisjunctive 'Tifgreen' and 'Tifdwarf' accessions. Mutation during normal Tifdwarf vegetative growth was evaluated by planting sprigs and sampling their offspring. Somatic sequence divergence levels (0.004 +/- 0.007%) resulted in a mutation rate of 1.05 x 10-8 per nucleotide per generation, assuming that a bermudagrass sprig constitutes a generation of growth. These rates were comparable to those found in germinal cells and individuals of either human or Drosophila melanogaster, supporting the notion that eukaryotic evolution is generation rather than time dependent. The high accumulation of somatic mutations (10 per triploid genome) is consistent with a model whereby mutation load in a population exhibiting obligate vegetative reproduction is substantially higher than in a population under sexual or asexual reproduction. These constraints could be the cause of reported genetic instabilities in the Tifgreen-Tifdwarf complex. Finally, a long-term rate measured across accessions and indicative of the accumulation of mutations in 17 Tifgreen-Tifdwarf populations (µ = 1.02 x 10-8 per nucleotide per generation) was strikingly congruent with the bermudagrass vegetative mutation rate, suggesting absence of evolutionary constraints in the sampled genomic regions. Mutation rates calculated from across-accesions divergence estimates (5.18 +/- 0.53%) indicated that plant material was evolving 100 times faster (3.8 x 10-7 changes per nucleotide per year) than a molecular clock rate estimate for grasses, probably resulting from the compound effect of clonal growth and life span of the hybrid plant material.

Journal Article↗

PubMed1992

Similarity of spontaneous germinal and in vitro somatic cell mutation rates in humans: implications for carcinogenesis and for the role of exogenous factors in "spontaneous" germinal mutagenesis.

The rate of spontaneous mutation resulting in electrophoretic variants per cell generation in a human lymphoblastoid cell line, on the basis of experiments described in this paper, is found to be 7.2 x 10(-8) per locus. A review of similar data on electrophoretic variants resulting from spontaneous mutation in the human germ line leads to an estimate of 3.3 x 10(-8) per locus per cell generation. It is argued that the similarity of these two estimates, despite an average cell generation time of 18.5 hr for the cultured somatic cells but about 26 days in the germ line, suggests that spontaneous mutation involving nucleotide substitutions is much more dependent on cell generation than on time. This finding permits the inference that environmental (exogenous) variables make a relatively small contribution to the rate of this type of human germinal spontaneous mutation. While in vitro somatic-cell mutation rates, such as derived in this study, provide a basis for modeling the contribution of nucleotide substitutions in multihit/clonal theories of carcinogenesis, it is also argued that the complex of events involved in carcinogenesis, including chromosomal rearrangements and mitotic recombination, could have very different individual probabilities. Estimates for the rates of these other types of mutation are needed to provide a better understanding of the manner in which multiple mutations accumulate in malignant cells.

Alleles↗

PubMed1987

The spontaneous mutation rate in Drosophila simulans.

The purpose of this investigation was to determine whether there exists a correlation in Drosophila between the spontaneous mutation rate and the amount of dispersed middle repetitive (mobile) DNA sequences. The amount of these sequences is 7 times less in Drosophila simulans as compared to Drosophila melanogaster. Therefore, if a correlation exists, the spontaneous mutation rate in Drosophila simulans should be 7 times lower than that in Drosophila melanogaster. We isolated an X-chromosome inversion after X-irradiation of wild-type Drosophila simulans males, that reduced crossing-over between white and forked, two X-linked visible markers, to less than 1%. This inversion was subsequently used to determine the sex-linked recessive lethal mutation rate in Drosophila simulans males of a laboratory strain marked with white. The frequency of these lethal mutations found is not different from that observed in Drosophila melanogaster males of laboratory strains.

Animals↗

PubMed1995

Extensive loss of heterozygosity accounts for differential mutation rate on chromosome 17q in human lymphoblasts.

In order to investigate the influence of loss of heterozygosity (LOH) events on mutation rate, we studied two closely related human lymphoblastoid cell lines, AHH-1 (h2E1.v2) and MCL-5, which are heterozygous at the tk locus (chromosome 17q23-25). Although they have similar mutant fractions at the hprt locus, the mutant fraction and rate at tk is four to five times higher in AHH-1. Analysis of 58 spontaneous TK- mutants from AHH-1 and MCL-5 showed that the occurrence of LOH events was more frequent (23/24) in AHH-1 than MCL-5 (16/34). A set of five microsatellite polymorphism loci was used to map the extent of LOH along chromosome 17q. In AHH-1 cells, 15/23 of the LOH events encompassed at least 35% of the sex-averaged genetic length of chromosome 17q (98 cM). Additionally, the next most extensive category of LOH accounted for 5/23 TK- mutants, and encompassed at least 17 cM. In contrast, LOH events observed in MCL-5 are very restricted in extent; only one LOH tract extended as far as 4 cM from tk. The higher mutation rate at tk in AHH-1 can, therefore, be entirely attributed to the recovery of chromosomal scale LOH in viable, normal growth TK- mutants. Furthermore, these data demonstrate that the regional potential for LOH is likely to be an important determinant of mutation rate for loci within that chromosomal segment.

Aminacrine↗

PubMed2003

Mutation rate and evolution of fluoroquinolone resistance in Escherichia coli isolates from patients with urinary tract infections.

Escherichia coli strains from patients with uncomplicated urinary tract infections were examined by DNA sequencing for fluoroquinolone resistance-associated mutations in six genes: gyrA, gyrB, parC, parE, marOR, and acrR. The 54 strains analyzed had a susceptibility range distributed across 15 dilutions of the fluoroquinolone MICs. There was a correlation between the fluoroquinolone MIC and the number of resistance mutations that a strain carried, with resistant strains having mutations in two to five of these genes. Most resistant strains carried two mutations in gyrA and one mutation in parC. In addition, many resistant strains had mutations in parE, marOR, and/or acrR. No (resistance) mutation was found in gyrB. Thus, the evolution of fluoroquinolone resistance involves the accumulation of multiple mutations in several genes. The spontaneous mutation rate in these clinical strains varied by 2 orders of magnitude. A high mutation rate correlated strongly with a clinical resistance phenotype. This correlation suggests that an increased general mutation rate may play a significant role in the development of high-level resistance to fluoroquinolones by increasing the rate of accumulation of rare new mutations.

Anti-Bacterial Agents↗

PubMed2005

p53 deficiency does not affect mutation rate in the mouse germline.

Although the influence of p53 deficiency on somatic genetic stability is well established, its effect in the germline is poorly understood. Mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the germline of nonexposed and irradiated p53-deficient mice. Spontaneous mutation rates in the homozygous and heterozygous p53-deficient males did not significantly differ from that in the isogenic wild-type mice. Acute exposure to 1 Gy of X rays resulted in a similar increase in mutation rates across males with different p53 genotypes. ESTR mutation spectra did not significantly differ across males with different p53 genotypes. Taken together, these results suggest that p53-deficiency does not affect spontaneous and radiation-induced mutation in the mouse germline.

Animals↗

PubMed1996

Human minisatellite mutation rate after the Chernobyl accident.

Germline mutation at human minisatellite loci has been studied among children born in heavily polluted areas of the Mogilev district of Belarus after the Chernobyl accident and in a control population. The frequency of mutation was found to be twice as high in the exposed families as in the control group. Mutation rate in the Mogilev families was correlated with the level of caesium-137 surface contamination, consistent with radiation induction of germline mutation.

Adult↗

PubMed2006

Higher intensity of purifying selection on >90% of the human genes revealed by the intrinsic replacement mutation rates.

For over 3 decades, the rate of replacement mutations has been assumed to be equal to, and estimated from, the rate of "strictly" neutral sequence divergence in noncoding regions and in silent-codon positions where mutations do not alter the amino acid encoded. This assumption is fundamental to estimating the fraction of harmful protein mutations and to identifying adaptive evolution at individual codons and proteins. We show that the assumption is not justifiable because a much larger fraction of codon positions is involved in hypermutable CpG dinucleotides as compared with the introns, leading to a higher expected replacement mutation rate per site in a vast majority of the genes. Consideration of this difference reveals a higher intensity of purifying natural selection than previously inferred in human genes. We also show that a much smaller number of genes are expected to be evolving with positive selection than that predicted using sequence divergence at intron and silent positions in the human genome. These patterns indicate the need for using new approaches for estimating rates of amino acid-altering mutations in order to find positively selected genes and codons in genomes that contain hypermutable CpG's.

Animals↗

PubMed1998

Increased transcription decreases the spontaneous mutation rate at the thymidine kinase locus in human cells.

Transcription increases DNA repair efficiency and modulates the distribution of certain types of DNA damage. Furthermore, increased transcription level stimulates spontaneous mutation rate in yeast. We explored whether transcription level affects spontaneous mutation rate in human cells. We first developed two thymidine kinase (tk) inducible human cell lines using the Gal4-Estrogen receptor system. In our TK6i-G3 and G9 tk heterozygous cell lines, the active tk allele is linked to an inducible promoter element. Tk mRNA is induced following treatment with estrogen. Spontaneous mutation rate was significantly decreased in human cell lines after induction in contrast to the report in yeast. Thus, humans may have evolved different or additional mechanisms to deal with transcription related spontaneous mutagenesis.

B-Lymphocytes↗

PubMed2006

En bloc duplications, mutation rates, and densities of amino acid changes clarify the evolution of vertebrate alpha-1,3/4-fucosyltransferases.

Numerous vertebrates have four alpha-1,3/4-fucosyltransferase genes (FUT9, FUT7, FUT4, and FUT Lewis) belonging to the same family. Until now, studies on the evolution of this family have mainly focused on Lewis genes but how the other alpha-1,3/4-fucosyltransferases have emerged from a common ancestor is not well known. In order to define the respective roles of duplications and mutations, we have compared amino acid sequences representative of bony fish (Takifugu rubripes), amphibians (Xenopus laevis), birds (Gallus gallus), and mammals (Bos taurus). The FUT tree has two fundamental branches, each split into two subfamilies. We found evidence for two duplication events, dated around 710-760 Myr and 590-640 Myr, respectively, compatible with the hypothesis of two rounds of whole genome duplications in chordate genomes, before the emergence of bony vertebrates. Based on the Homo sapiens (human) physical map, we identified blocks of paralogues belonging to regions of FUT9 (6q16), FUT4 (11q21), FUT7 (9q34), and FUT Lewis (19p13) and to a region on HSA1p that is devoid of any FUT. In zebrafish (Danio rerio), an orthologue region of HSA1 harbors an FUT9 specific to bony fish, showing that duplications are not restricted to a single FUT gene but involve blocks of paralogues. In addition, sets of genes within each block clarify the order of duplication events and, as a result, the order of alpha-1,3/4-fucosyltransferase gene emergence. We have also determined the mutation rates and the density of amino acid changes along protein sequences in each alpha-1,3/4-fucosyltransferase subfamily during the main vertebrate transitions. After the emergence of tetrapods, the mutation rate of FUT9 decreased dramatically, suggesting the early acquisition of a crucial fucosyltransferase activity in the first stages of development. The FUT7 mutation rate, which in tetrapod ancestors is about half that in amniote ancestors, may be related to the role of this gene in immune systems. In contrast to other subfamilies, we found a constant mutation rate in FUT Lewis and a rather homogeneous amino acid density change, independently of the vertebrate transition, suggesting that hitherto Lewis epitopes have dispensable functions.

Ambystoma↗

PubMed2004

A statistical treatment of biases affecting the estimation of mutation rates.

We consider the estimation of mutation rates, using family data obtained from disputed paternity cases. It is shown how to take appropriate account of a number of complicating features-in particular, hidden mutation, differential mutation, and uncertain paternity-which can necessitate large corrections to simple estimates.

Alleles↗

PubMed2006

High mutation rates have driven extensive structural polymorphism among human Y chromosomes.

Although much structural polymorphism in the human genome has been catalogued, the kinetics of underlying change remain largely unexplored. Because human Y chromosomes are clonally inherited, it has been possible to capture their detailed relationships in a robust, worldwide genealogical tree. Examination of structural variation across this tree opens avenues for investigating rates of underlying mutations. We selected one Y chromosome from each of 47 branches of this tree and searched for large-scale variation. Four chromosomal regions showed extensive variation resulting from numerous large-scale mutations. Within the tree encompassed by the studied chromosomes, the distal-Yq heterochromatin changed length > or = 12 times, the TSPY gene array changed length > or = 23 times, the 3.6-Mb IR3/IR3 region changed orientation > or = 12 times and the AZFc region was rearranged > or = 20 times. After determining the total time spanned by all branches of this tree (approximately 1.3 million years or 52,000 generations), we converted these mutation counts to lower bounds on rates: > or = 2.3 x 10(-4), > or = 4.4 x 10(-4), > or = 2.3 x 10(-4) and > or = 3.8 x 10(-4) large-scale mutations per father-to-son Y transmission, respectively. Thus, high mutation rates have driven extensive structural polymorphism among human Y chromosomes. At the same time, we found limited variation in the copy number of Y-linked genes, which raises the possibility of selective constraints.

Chromosomes, Human, Y↗

PubMed2006

Environmental tuning of mutation rates.

Through their life cycles, bacteria experience many different environments in which the relationship between available energy resources and the frequency and the nature of various stresses is highly variable. In order to survive in such changeable environments, bacteria must balance the need for nutritional competence with stress resistance. In Escherichia coli natural populations, this is most frequently achieved by changing the regulation of the RpoS sigma factor-dependent general stress response. One important secondary consequence of altered regulation of the RpoS regulon is the modification of mutation rates. For example, under nutrient limitation during stationary phase, the high intracellular concentration of RpoS diminishes nutritional competence, increases stress resistance, and, by downregulating the mismatch repair system and upregulating [corrected] the expression of the dinB gene (coding for PolIV translesion synthesis polymerase) increases mutation rates. The reduction of the intracellular concentration of RpoS has exactly opposite effects on nutritional competence, stress resistance and mutation rates. Therefore, the natural selection that favours variants having the highest fitness under different environmental conditions results in high variability of stress-associated mutation rates in those variants.

Bacterial Proteins↗

PubMed1975

Specific locus mutation rates after repeated small radiation doses to mouse oocytes.

When female mice were given a dose of 20 X 20 rad X-rays, the specific locus mutation rate among offspring conceived up to 7 weeks after the end of treatment was 1/39887 or 0.18-10(-7)/rad/locus, whereas when the same total dose of 200 rad was given in a single exposure the mutation rate was 9/34813 or 1.85-10(-7)/rad/locus. The lower mutation rate after the 20 X 10 rad dose was obtained whether the total or 200 rad was given over a period of 5 days or 4 weeks, and if only young conceived in the first 20 days, rather than 7 weeks, were considered. It is suggested that each 10 rad fraction had the same small effect, and hence that these results confirm and extend RUSSELL's previous finding that the dose-response relationship for specific locus muations in females is curved.

Animals↗

PubMedDate not supplied

Male-biased mutation rates and the overestimation of extrapair paternity: problem, solution, and illustration using thick-billed murres (Uria lomvia, Alcidae).

The widespread utility of hypervariable loci in genetic studies derives from the high mutation rate, and thus the high polymorphism, of these loci. Recent evidence suggests that mutation rates can be extremely high and may be male biased (occurring in the male germ-line). These two factors combined may result in erroneous overestimates of extrapair paternity, since legitimate offspring with novel alleles will have more mismatches with respect to the biological father than the biological mother. As mutations are male driven, increasing the number of hypervariable loci screened may simply increase the number of mismatches between fathers and their legitimate offspring. Here we describe a simple statistic, the probability of resemblance (PR), to distinguish between mismatches due to parental misassignment versus mutation in either sex or null alleles. We apply this method to parentage data on thick-billed murres (Uria lomvia), and demonstrate that, without considering either mutations or male-biased mutation rates, cases of extrapair paternity (7% in this study) would be grossly overestimated (14.5%-22%). The probability of resemblance can be utilized in parentage studies of any sexually reproducing species when allele or haplotype frequency data are available for putative parents and offspring. We suggest calculating this probability to correctly categorize legitimate offspring when mutations and null alleles may cause mismatches.

Animals↗

PubMed2005

Mutation rates at Y chromosome specific microsatellites.

A collaborative work was carried out by the Spanish and Portuguese ISFG Working Group (GEP-ISFG) to estimate Y-STR mutation rates. Seventeen Y chromosome STR loci (DYS19, DYS385, DYS389I and II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS460, DYS461, DYS635 [GATA C4], GATA H4, and GATA A10) were analyzed in a sample of 3,026 father/son pairs. Among 27,029 allele transfers, 54 mutations were observed, with an overall mutation rate across the 17 loci of 1.998 x 10(-3) (95% CI, 1.501 x 10(-3) to 2.606 x 10(-3)). With just one exception, all of the mutations were single-step, and they were observed only once per gametogenesis. Repeat gains were more frequent than losses, longer alleles were found to be more mutable, and the mutation rate seemed to increase with the father's age. Hum Mutat 26(6), 520-528, 2005. (c) 2005 Wiley-Liss, Inc.

Age Factors↗