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PubMed2002

Insertional inactivation of mutS in Staphylococcus aureus reveals potential for elevated mutation frequencies, although the prevalence of mutators in clinical isolates is low.

Populations defective in mismatch repair that exhibit elevated mutation frequencies to antibiotic resistance have been reported amongst pathogenic Gram-negative bacteria. Whether such mutators occur widely in clinical isolates of Gram-positive species, and in important pathogens such as Staphylococcus aureus, is unknown. Insertional inactivation of the mutS gene of S. aureus RN4220 by targeted plasmid integration produced a strain with mutation frequencies for antibiotic resistance up to 78-fold greater than those exhibited by RN4220, thereby providing proof of the concept that staphylococcal mutators could arise. Subsequently, 493 clinical S. aureus isolates were examined for the presence of mutators. However, no strain exhibited a > or =10-fold increase in mutation frequency compared with laboratory strain 8325-4. Detailed phenotypic and genotypic analysis of vancomycin-intermediate S. aureus strain Mu50 was performed, since the published genome sequence of this organism suggests that mutS is inactive as a result of a frameshift. However, elevated mutation frequencies were not observed in Mu50, and re-sequencing of a portion of mutS from this strain indicated that this gene was intact. Transient increases in mutation frequency during the stationary phase of growth occur in other bacteria, although no such increases were observed in S. aureus. We conclude that neither permanent increases in the basal mutation frequency, nor transient increases in mutation frequency under starvation, are likely to play a significant role in the development of antibiotic resistance in S. aureus.

Adenosine Triphosphatases↗
PubMed1998

High mutation rate of a long microsatellite allele in Drosophila melanogaster provides evidence for allele-specific mutation rates.

Within recent years, microsatellite have become one of the most powerful genetic markers in biology. For several mammalian species, microsatellite mutation rates have been estimated on the order of 10(-3)-10(-5). A recent study, however, demonstrated mutation rates in Drosophila melanogaster of at least one order of magnitude lower than those in mammals. To further test this result, we examined mutation rates of different microsatellite loci using a larger sample size. We screened 24 microsatellite loci in 119 D. melanogaster lines maintained for approximately 250 generations and detected 9 microsatellite mutations. The average mutation rate of 6.3 x 10(-6) is identical to the mutation rate from a previous study. Most interestingly, all nine mutations occurred at the same allele of one locus (DROYANETSB). This hypermutable allele has 28 dinucleotide repeats and is among the longest microsatellite reported in D. melanogaster. The allele-specific mutation rate of 3.0 x 10(-4) per generation is within the range of mammalian mutation rates. Future microsatellite analyses will have to account for the dramatic differences in allele-specific mutation rates.

Alleles↗
PubMed1999

Recovery of mutations of different sizes from a population sample of DNA sequences under variable mutation rates across sites.

Mutations may be classified according to their positions of occurrence in the genealogy of the sampled DNA sequences from a population. A mutation is said to be of size i if it has i descendants in the sample. Such classifications for mutations may yield detailed insights into the evolutionary history and properties of the population. Statistical methods based on such classification have been developed and shown to be efficient and powerful. However, the utility of these statistical methods critically depends on reliable and robust recovery of mutations of different sizes. We investigated the distributional changes of mutations of different sizes due to genealogy reconstruction using the unweighted pair-group method with arithmetic mean (UPGMA) and the performance of maximum-parsimony method in inferring mutations of different sizes on a given topology. Genealogy reconstruction by UPGMA was found to change the distribution of mutations of different sizes on constructed topologies. Multiple hits at some nucleotide sites made it difficult to infer mutations of different sizes with the maximum-parsimony method, even when the true topology was designated. These results suggest that while the newly developed statistical methods employing information on mutations of different sites are powerful, they also impose significant new challenges for developing methods to accurately recover mutations of different sizes from population DNA sequence data.

Algorithms↗
PubMed1997

Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype.

Eleven early-onset dementia families, all with affected individuals who have either presented clinical symptoms of early onset familial Alzheimer's disease (EOFAD) or have been confirmed to have EOFAD by autopsy, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of presenilin-1 (PS-1) and -2 (PS-2) genes. Missense mutations were detected by direct sequence analysis of PCR products amplified from genomic DNA templates of affected individuals. Three pedigrees were attributable to known mutations in the PS-1 gene: P264L, E280A and the splice acceptor site (G to T) mutation, which results in the deletion of residues 290-319 of PS-1 (PS-1 delta 290-319). In a fourth pedigree, a novel PS-1 mutation was identified in exon 7 (M233T), which is homologous to a pathogenic PS-2 mutation (M239V), and is characterized by a very early average age of onset (before the age of 35). In one early onset case, another novel PS-1 mutation was identified in exon 8 (R278T). Of the five remaining families and the other early onset case, none have missense mutations in the PS-1 or PS-2 genes, or in exon 16 and 17 of the APP gene. Moreover, two of the PS-1 mutations, PS-1 delta 290-319 and R278T, are associated with the co-presentation of familial spastic paraparesis (FSP) in some of the affected family members. Our data raise the possibility that the phenotypic spectrum associated with PS-1 mutations may extend beyond typical FAD to include FSP, a disease heretofore unsuspected to bear any relationship to FAD. In addition, our data suggest that other novel EOFAD loci, in addition to APP and the presenilin genes, are involved in the aetiology of up to 50% of EOFAD cases.

Adult↗
PubMed2004

Biological consequences of 8-methoxypsoralen-photoinduced lesions: sequence-specificity of mutations and preponderance of T to C and T to a mutations.

Psoriatic patients undergoing psoralen plus ultraviolet radiation (PUVA) therapy are susceptible for squamous cell carcinoma and melanoma of the skin. To investigate the etiological relevance of PUVA for these diseases, we performed mutation spectrometry on the cII transgene in mouse embryonic fibroblasts treated with a single or split PUVA dose (PUVA-I or PUVA-II, respectively). Both treatments were significantly mutagenic as they increased the cII mutant frequency up to 3.7-fold over background, and produced different mutational spectra from that derived spontaneously (p<0.01), but not from one another. The signature of induced mutations, i.e., T to C transitions and T to A transversions with significant site-specificities, i.e., adjacent to T bases at the 3'-neighboring side and to pyrimidines at the 5'-neighboring side, was more pronounced after PUVA-II treatment. Also, the overall mutations occurring at T bases with the same site-specificities were more prevalent after PUVA-II treatment. The characteristic PUVA-induced mutations predominate in the p53 mutational spectrum in controlled in vivo test systems or in high-dose PUVA-treated patients, and also are easily recognizable in the overall PUVA-treated patients. We conclude that PUVA-induced mutagenesis is initiated by PUVA-I treatment and subsequently, augmented by PUVA-II treatment, leaving a unique mutational signature on the cII transgene. The signature mutations of PUVA are discernible in the p53 mutational spectrum in PUVA-treated patients but complex exposure to other therapeutic/environmental carcinogens also leads to the frequent occurrence of other types of mutations in this population.

Animals↗
PubMed2003

Mechanisms of cold sensitivity of paramyotonia congenita mutation R1448H and overlap syndrome mutation M1360V.

Missense mutations of the human skeletal muscle voltage-gated Na+ channel (hSkM1) cause a variety of neuromuscular disorders. The mutation R1448H results in paramyotonia congenita and causes cold-induced myotonia with subsequent paralysis. The mutation M1360V causes an overlapping syndrome with both K+-induced muscle weakness and cold-induced myotonia. The molecular mechanisms of the temperature dependence of these disorders are not well understood. Therefore we investigated physiological parameters of these Na+ channel mutations at different temperatures. Channel proteins were recombinantly expressed in human embryonic kidney cells and studied electrophysiologically, using the whole-cell patch-clamp technique. We compared the wild-type (WT) channel with both mutants at different temperatures. Both mutations had slower inactivation and faster recovery from inactivation compared to WT channels. This effect was more pronounced at the R1448H mutation, leading to a larger depolarization of the cell membrane causing myotonia and paralysis. The voltage dependence of activation of R1448H was shifted to more negative membrane potentials at lower temperature but not at the M1360V mutation or in the WT. The window current by mutation R1448H was increased at lower temperatures. The results of this study may explain the stronger cold-induced clinical symptoms resulting from the R1448H mutation in contrast to the M1360V mutation.

Cell Line↗
PubMed2006

Deterministic, compensatory mutational events in the capsid of foot-and-mouth disease virus in response to the introduction of mutations found in viruses from persistent infections.

The evolution of foot-and-mouth disease virus (FMDV) (biological clone C-S8c1) in persistently infected cells led to the emergence of a variant (R100) that displayed increased virulence, reduced stability, and other modified phenotypic traits. Some mutations fixed in the R100 genome involved a cluster of highly conserved residues around the capsid pores that participate in interactions with each other and/or between capsid protomers. We have investigated phenotypic and genotypic changes that occurred when these replacements were introduced into the C-S8c1 capsid. The C3007V and M3014L mutations exerted no effect on plaque size or viral yield during lytic infections, or on virion stability, but led to a reduction in biological fitness; the D3009A mutation caused drastic reductions in plaque size and viability. Remarkably, competition of the C3007V mutant with the nonmutated virus invariably resulted in the fixation of the D3009A mutation in the C3007V capsid. In turn, the presence of the D3009A mutation invariably led to the fixation of the M3014L mutation. In both cases, two individually disadvantageous mutations led, together, to an increase in fitness, as the double mutants outcompeted the nonmutated genotype. The higher fitness of C3007V/D3009A was related to a faster multiplication rate. These observations provide evidence for a chain of linked, compensatory mutational events in a defined region of the FMDV capsid. Furthermore, they indicate that the clustering of unique amino acid replacements in viruses from persistent infections may also occur in cytolytic infections in response to changes caused by previous mutations without an involvement of the new mutations in the adaptation to a different environment.

Adaptation, Physiological↗
PubMed1990

Analysis of lethal mutations induced in a mutator strain that activates transposable elements in Caenorhabditis elegans.

A screen was conducted for lethal mutations in the nematode Caenorhabditis elegans in a strain containing the mutator mut-4 (st700)I to examine the nature of mutator-induced lethal mutations within two large chromosomal regions comprising a total of 49 map units (linkage group IV (right) and linkage group V (left)). The genetic analysis of 28 lethal mutations has revealed that the mutator locus mut-4(st700)I causes both putative single-gene mutations and deficiencies. We have identified lethal mutations in three different genes, in addition to seven deficiencies. There is a mutational hot spot on linkage group V (left) around the lin-40 locus. Six mutations appear to be alleles of lin-40. In addition, 5 of 7 deficiencies have breakpoints at or very near lin-40. All seven deficiencies delete the left-most known gene on linkage group V (left) and thus appear to delete the tip of the chromosome. This is in contrast to gamma ray and formaldehyde induced deficiencies, which infrequently delete the closest known gene to the tip of a chromosome.

Animals↗
PubMed2004

Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium.

PURPOSE: The aim of the study was the analysis of the involvement and phenotypic manifestations of MSH6 germline mutations in families suspected of hereditary nonpolyposis colorectal cancer (HNPCC). PATIENTS AND METHODS: Patients were preselected among 706 families by microsatellite instability, immunohistochemistry, and/or exclusion of MLH1 or MSH2 mutations and were subjected to MSH6 mutation analysis. Clinical and molecular data of MSH6 mutation families were compared with data from families with MLH1 and MSH2 mutations. RESULTS: We identified 27 families with 24 different pathogenic MSH6 germline mutations, representing 3.8% of the total of the families, and 14.7% of all families with DNA mismatch repair (MMR) gene mutations (n = 183). The median age of onset of colorectal cancer in putative mutation carriers was 10 years higher for MSH6 (54 years; 95% CI, 51 to 56) compared with MLH1 and MSH2 (44 years; 95% CI, 43 to 45; log-rank test, P = .0038). Relative to other malignant tumors, colorectal cancer was less frequent in MSH6 families compared with MLH1 and MSH2 families (Fisher's exact test, P < .001). In contrast, the frequency of non-HNPCC-associated tumors was increased (Fisher's exact test, P < .001). CONCLUSION: Later age of disease onset and lower incidence of colorectal cancer may contribute to a lower proportion of identified MSH6 mutations in families suspected of HNPCC. However, in approximately half of these families, at least one patient developed colorectal or endometrial cancer in the fourth decade of life. Therefore, a surveillance program as stringent as that for families with MLH1 or MSH2 mutations is recommended.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Gonadotropin-independent precocious puberty due to luteinizing hormone receptor mutations in Brazilian boys: a novel constitutively activating mutation in the first transmembrane helix.

Naturally occurring activating mutations in the human LH receptor (hLHR) gene are the cause of sporadic or familial male gonadotropin-independent precocious puberty. We have previously reported three different activating mutations of the hLHR gene in four unrelated Brazilian boys with male-limited precocious puberty. In the current study, we examined three other Brazilian boys, two brothers and one unrelated boy, with gonadotropin-independent precocious puberty. Direct sequencing of the entire exon 11 of the hLHR gene in the two brothers revealed a heterozygous substitution of T for C at nucleotide 1103, resulting in the substitution of leucine at position 368 by proline in the first transmembrane helix. Their mother carried the same mutation, establishing the familial nature of this mutation. Human embryonic 293 cells expressing hLHR(L368P) bound hCG with the same high affinity as cells expressing the wild-type hLHR. Cells expressing the novel L368P mutation displayed up to a 12-fold increase in basal cAMP production compared with cells expressing the same number of cell surface wild-type hLHR, indicating constitutive activation of the mutant receptor. In addition, the cAMP levels in cells expressing the hLHR mutant were further augmented by hCG. Molecular dynamics simulations suggest that substitution of L368 of the hLHR by proline results in lack of a salt bridge interaction between D405 and R464 (distance 9. 0 A vs. 4.7 A in wild-type hLHR) as well as by the opening of a crevice between the second and third intracellular loops, which may allow G proteins greater accessibility. These structural features were shared by other activating mutants of the hLHR. Sequencing of exon 11 of the hLHR gene of the unrelated boy revealed that he carried a homozygous nucleotide substitution causing an A568V mutation in the third cytoplasmic loop of the receptor. This mutation was previously found in two unrelated Brazilian boys, but in heterozygous state. Clinical and hormonal data of the patient with the homozygous A568V were not different from those individuals with the Ala568Val mutation in a heterozygous state. Furthermore, the phenotype caused by dominant activating mutations of the hLHR gene are not altered when both alleles carry a mutant sequence. Our studies show that the A568V is the most frequent cause of male-limited precocious puberty in Brazilian boys. Lastly, the identification of a novel activating L368P mutation in the first transmembrane helix of two Brazilian boys with familial male-limited precocious puberty provides further insights into the mechanism of activation of the hLHR.

Amino Acid Substitution↗
PubMed1995

Somatic mutations causing constitutive activity of the thyrotropin receptor are the major cause of hyperfunctioning thyroid adenomas: identification of additional mutations activating both the cyclic adenosine 3',5'-monophosphate and inositol phosphate-Ca2+ cascades.

A series of somatic mutations of the TSH receptor gene have been demonstrated in hyperfunctioning thyroid adenomas. The mutations studied up to now cause constitutive (i.e. TSH-independent) activation of the cAMP-regulatory cascade only. As a follow-up to our original study, we have now completely sequenced exon number 10 of the TSH receptor gene in the same series of toxic adenomas. An activating mutation was found in nine of 11 tumors. In addition to the mutations already described, two isoleucine residues belonging to the first and second extracellular loops of the receptor (Ile486 and Ile568) were found mutated. Two different adenomas were found to harbor a different amino acid substitution at residue 486 (Ile486Phe, Ile486Met). Ile568 was mutated to threonine in one. When studied by transfection in COS-7 cells, all three mutations caused very strong activation of the cAMP-regulatory cascade. In addition, the Ile486Phe and, to a lesser extent, the Ile486Met and Ile568Thr mutants stimulated constitutively the inositol phosphate-diacylglycerol cascade. Our results demonstrate that 1) the first and second extracellular loops contribute to the silencing of the unliganded TSH receptor; 2) the two regulatory cascades normally under TSH control can be constitutively activated by somatic mutations of the receptor; 3) the TSH receptor can be activated by mutation of a large number of residues distributed over the first and second extracellular loops, the third intracellular loop, and the third, sixth, and seventh transmembrane segments; 4) activating mutations of the TSH receptor constitute the major cause of toxic adenomas, accounting for about 80% of the cases.

Adenoma↗
PubMed2001

Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations.

BACKGROUND: Mutations in the presenilin-1 gene (PS1) account for a majority of patients with early-onset familial AD. However, the clinical indications and algorithms for genetic testing in dementia are still evolving. METHODS: The entire open reading frame of the PS1 gene was sequenced in a series of 414 consecutive patients referred for diagnostic testing, including 372 patients with AD and 42 asymptomatic persons with a strong family history of AD. RESULTS: Forty-eight independent patients screened had a PS1 mutation including 21 novel mutations. In addition, 3% of subjects (11/413) had a known polymorphism, the Glu318Gly substitution. The majority of the mutations were missense substitutions but there were three insertions and Delta exon 10 mutation. With six exceptions (codons 35, 178, 352, 354, 358, and 365) most of the mutations occurred at residues conserved in the homologous PS2 gene or in PS1 of other species. CONCLUSIONS: Eleven percent of a referral-based series of patients with AD can be explained by coding sequence mutations in the PS1 gene. The high frequency of PS1 mutations in this study indicates that screening for PS1 mutations in AD is likely to be successful, especially when directed at patients with a positive family history with onset before 60 years (90% of those with PS1 mutations were affected by age 60 years). This will also have significance for the secondary identification of at-risk relatives who might be candidates for future prophylactic therapies for AD.

Adult↗
PubMed2004

Mutation accumulation in populations of varying size: the distribution of mutational effects for fitness correlates in Caenorhabditis elegans.

The consequences of mutation for population-genetic and evolutionary processes depend on the rate and, especially, the frequency distribution of mutational effects on fitness. We sought to approximate the form of the distribution of mutational effects by conducting divergence experiments in which lines of a DNA repair-deficient strain of Caenorhabditis elegans, msh-2, were maintained at a range of population sizes. Assays of these lines conducted in parallel with the ancestral control suggest that the mutational variance is dominated by contributions from highly detrimental mutations. This was evidenced by the ability of all but the smallest population-size treatments to maintain relatively high levels of mean fitness even under the 100-fold increase in mutational pressure caused by knocking out the msh-2 gene. However, we show that the mean fitness decline experienced by larger populations is actually greater than expected on the basis of our estimates of mutational parameters, which could be consistent with the existence of a common class of mutations with small individual effects. Further, comparison of the total mutation rate estimated from direct sequencing of DNA to that detected from phenotypic analyses implies the existence of a large class of evolutionarily relevant mutations with no measurable effect on laboratory fitness.

Amino Acid Substitution↗
PubMed2000

BCL-6 mutations are associated with immunoglobulin variable heavy chain mutations in B-cell chronic lymphocytic leukemia.

The cell of origin of B-cell chronic lymphocytic leukemia (B-CLL) is still uncertain. Recent studies have indicated that a fraction of B-CLL displays somatically mutated immunoglobulin variable heavy chain (IgV(H)) genes, which suggests an origin from a post-germinal center (GC) B cell. It has been shown that the 5' noncoding region of the BCL-6 proto-oncogene is affected by mutations in normal GC B-lymphocytes and in lymphoid malignancies displaying GC/post-GC phenotype. To further explore the cellular origin of B-CLL, we have analyzed 34 cases for mutations in the BCL-6 5' noncoding region and in the IgV(H) genes. We found somatically mutated IgV(H) genes in 24 (73%) of 33 samples (average frequency, 6.5 x 10(-2)/bp) and BCL-6 mutations in 8 (24%) of 34 cases (average frequency, 0.14 x 10(-2)/bp in the mutated cases). The occurrence of BCL-6 mutations was restricted to those cases displaying IgV(H) mutations. Analysis of BCL-6 protein expression as a marker of GC phenotype showed that, regardless of the presence of IgV(H) or BCL-6 mutations, B-CLLs express BCL-6 at levels clearly below those found in normal or transformed GC B cells. These results indicate that a subset of B-CLL derives from a cell that has been exposed to the somatic hypermutation mechanism and support the hypothesis that BCL-6 mutations result from the same process that targets immunoglobulin genes.

DNA-Binding Proteins↗
PubMed1985

The mutational specificity of DNA polymerase-beta during in vitro DNA synthesis. Production of frameshift, base substitution, and deletion mutations.

The frequency and specificity of mutations produced in vitro by eucaryotic DNA polymerase-beta have been determined in a forward mutation assay using a 250-base target sequence in M13mp2 DNA. Homogeneous DNA polymerase-beta, isolated from four different sources, produces mutations at a frequency of 4-6%/single round of gap-filling DNA synthesis. DNA sequence analyses of 460 independent mutants resulting from this error-prone DNA synthesis demonstrate a wide variety of mutational events. Frameshift and base substitutions are made at approximately equal frequency and together comprise about 90% of all mutations. Two mutational "hot spots" for frameshift and base substitution mutations were observed. The characteristics of the mutations at these sites suggest that certain base substitution errors result from dislocation of template bases rather than from direct mispair formation by DNA polymerase-beta. When considering the entire target sequence, single-base frameshift mutations occur primarily in runs of identical bases, usually pyrimidines. The loss of a single base occurs 20-80 times more frequently than single-base additions and much more frequently than the loss of two or more bases. Base substitutions occur at many sites throughout the target, representing a wide spectrum of mispair formations. Averaged over a large number of phenotypically detectable sites, the base substitution error frequency is greater than one mistake for every 5000 bases polymerized. Large deletion mutations are also observed, at a frequency more than 10-fold over background, indicating that purified DNA polymerases alone are capable of producing such deletions. These data are discussed in relation to the physical and kinetic properties of the purified enzymes and with respect to the proposed role for this DNA polymerase in vivo.

Base Sequence↗
PubMed1994

Self-assembly of collagen I from a proband homozygous for a mutation that substituted serine for glycine at position 661 in the alpha 2(I) chain. Possible relationship between the effects of mutations on critical concentration and the severity of the phenotype.

Procollagen I was isolated from cultured skin fibroblasts from a proband who was homozygous for a mutation in the COL1A2 gene that substituted a serine codon for a glycine codon at position 661 of the alpha 2(I) chain. The procollagen I was cleaved to pCcollagen I by procollagen N-proteinase and the pCcollagen I was used as a substrate for assay of self-assembly of collagen I into fibrils. The mutated pCcollagen I was cleaved to collagen I by procollagen C-proteinase at the same rate as control pCcollagen I. However, self-assembly of the mutated collagen I had a lag period that was 15-fold greater than the lag period observed with normal collagen I under the same conditions. Also, self-assembly of the mutated collagen I had a propagation rate of about one-fourth of the propagation rate of normal collagen I. In addition, the critical concentration for fibril assembly was slightly increased. Rotary shadowing electron microscopy of the mutated procollagen I did not reveal any increased flexibility of the triple helix as was seen previously with two mutated procollagens I in which there were substitutions of cysteine for glycine residues in the alpha 1(I) chain (Vogel, B. E., Doelz, R., Kadler, K. E., Hojima, Y., Engel, J., and Prockop, D. J. (1988) J. Biol. Chem. 263, 19249-19255; Lightfoot, S. J., Holmes, D. F., Brass, A., Grant, M. E., Byers, P. H., and Kadler, K. E. (1992) J. Biol. Chem. 267, 25521-25528). However, morphometric analysis by dark-field light microscopy and electron microscopy showed that the fibrils formed from the mutated collagen I appeared thicker in diameter than the fibrils formed from the normal collagen I. Comparison of the results with similar data on four mutated procollagens previously studied raised the possibility that mutations which markedly increase the critical concentration of fibril assembly produce more severe phenotypes than mutations which change other parameters of fibril assembly.

Amino Acid Sequence↗
PubMed1998

A beta-catenin mutation in a sporadic colorectal tumor of the RER phenotype and absence of beta-catenin germline mutations in FAP patients.

As a signaling protein in the Wnt pathway beta-catenin plays a crucial role in the regulation of cellular proliferation. Recently, oncogenic beta-catenin mutations were described in human colorectal cancer and melanoma cell lines. Since activating mutations in the beta-catenin gene have similar effects on the biochemical level as inactivating mutations in the tumor suppressor gene APC, it is speculated that beta-catenin mutations may substitute APC gene inactivation in carcinogenesis. To address this question we analyzed twenty-three sporadic colorectal tumors of different progression states for mutations in the beta-catenin gene. Eighteen of these tumors showed the wildtype APC gene sequence. In only one of the tumors with wildtype APC a beta-catenin gene mutation was found. This tumor was of the RER (replication error) phenotype which may explain the finding that the mutation occurred in a sequential repeat motif of the beta-catenin gene. The second aim of this study was to investigate whether differences in the phenotypic variability in FAP (familial adenomatous polyposis coli) might be due to inherited alterations in the beta-catenin gene. For this we analyzed DNA from fourteen FAP patients from eight different families for germline mutations in the beta-catenin gene. We did not find any beta-catenin gene alteration in these samples. Our results indicate that somatic beta-catenin activating mutations contribute only to a minor part of human colorectal tumors and that germline beta-catenin mutations do not play a role in the variability of symptoms in FAP.

Adenomatous Polyposis Coli↗
PubMed1998

The mutation rate and the distribution of mutational effects of viability and fitness in Drosophila melanogaster.

The empirical distributions of the average viability and fitness of mutation accumulation lines of Drosophila melanogaster were analyzed using minimum distance estimation. Data come from two different experimental designs where mutations were allowed to accumulate: 1) in copies of chromosome II protected from natural selection and recombination (viability: Mukai et al., 1972; Ohnishi, 1977; fitness: Houle et al., 1992), 2) in inbred lines derived from the same isogenic stock (viability: Fernández & López-Fanjul, 1996; fitness: this paper). Information from all data sets converged, indicating that the mutational rates were small, about 1% for viability and 3% for fitness. For both traits, the rate of mutational decline appears to be smaller than suggested by previous studies (about one-fifth of the latter), the average mutational effect was neither severe nor very slight, ranging from -0.1 to -0.3, and the distribution of mutant effects was, at most, slightly leptokurtic. Therefore, the mutational load in natural populations is one to two orders of magnitude smaller than previously thought (as based upon analyses conditional to estimates of the mutational decline of viability or fitness that appear to be biased upward). Over 95% of the mutational variance of each trait was contributed by non-slightly deleterious mutations (absolute homozygous effect larger than 0.03 or 0.1, depending on the data set considered) occurring at a rate not higher than 0.025 per haploid genome and generation. Our data suggest that most deleterious mutations affecting fitness act mainly through a single component-trait.

Animals↗