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PubMed1985

Deleterious mutations as an evolutionary factor. II. Facultative apomixis and selfing.

A population with u deleterious mutations per genome per generation is considered in which only those individuals that carry less than a critical number k of mutations are viable. Besides a large number of loci subject to mutation and selection, the genome contains one or two special loci responsible for the mode of reproduction. Amphimixis vs. apomixis and amphimixis vs. selfing are considered separately. In the first case, the genome degradation rate v (= u/square root k) is found to play the decisive role, as in the case of recombination. When v greater than 1.25, obligate amphimixis is established. If v decreases below this value, the alleles with first low and then larger penetrance are fixed, until alleles conferring obligate asexual reproduction become advantageous. The proportion of resources allocated to produce seeds also increases with decrease of v. These results are unlikely to depend on the genetic basis of the mode of reproduction. The result of competition between outcrossing and selfing depends on both u and k, as well as on whether the mutations are recessive. The alleles for selfing with low penetrance are selected against if the mutations are at all recessive. The fitness of alleles with high penetrance depends primarily on u, decreasing when u increases. There may exist conditions when only the alleles providing intermediate selfing rates can be fixed in a population. In other cases a population may exist with either obligate outcrossing or selfing at a high rate. Thus, truncation selection against deleterious mutations may be a factor supporting obligate or facultative sex despite the twofold advantage of apomixis or selfing.

Alleles↗
PubMed2004

Unselected mutations in the human immunodeficiency virus type 1 genome are mostly nonsynonymous and often deleterious.

Mutation rates of human immunodeficiency virus type 1 (HIV-1) genomes have been estimated using purified reverse transcriptase or single-round infection system. Since small sequences were used as templates, the overall mutation rates could only be extrapolated and the biological significance of mutations is unknown. For direct estimation of HIV-1 mutation rates and understanding of the potential biological influences of mutations, we obtained 19 complete or nearly full-length proviral genomes from single-round-infected adherent cells of lymphocytes by using a lambda phage library method and a long-range PCR technique. Analysis of 160,000 bp of sequences showed that the overall mutation rate of HIV-1 genomes was 5.4 x 10(-5) per base per replication cycle. On average, 1.1 mutations (range, 0 to 3) were generated in each viral genome during one infection cycle. Inspection of the mutations in the HIV-1 genome revealed that all site mutations within protein-coding regions were nonsynonymous mutations. Among all mutations, half were deleterious (premature stop codon and deletions) and would result in defective genomes. By applying the same system to an HIV-1 genome with a G262A mutation in the thumb region of the reverse transcriptase, a significant increase was observed in deletion and insertion mutation rates but no increase in the overall mutation rate in viral genomes was found.

Base Sequence↗
PubMed1997

Mutations in the human factor XII gene.

The factor XII gene from 31 unrelated factor XII-deficient patients from Germany, Switzerland, and Austria was screened for mutations at the genomic level. Several novel mutations were detected and their absence in a control group of 74 healthy unrelated individuals was checked. Most changes are in the serine protease domain affecting the catalytic triad His-393-Asp-442-Ser-544; two missense mutations, R398Q (arginine 398 to glutamine; gene bank accession no. U71276) and L395M (leucine 395 to methionine; gene bank accession no. U71277), are close to the active site histidine at position 393. Another mutation detected in a cross-reacting material (CRM)-positive female with a history of three abortions affects the active site aspartic acid by changing it to asparagine (D442N; gene bank accession no. U71275). The novel mutation G570R (glycine 570 to arginine; gene bank accession no. U71274) giving rise to a CRM-positive phenotype is located next to Cys571, which forms a vital disulfide bridge. Two mutations are causing reading frame shifts: one single basepair deletion in exon 12 [exon 12: 10590(DelC); gene bank accession no. U71278] and one acceptor splice site mutation [exon 14: 11397(G --> A); gene bank accession no. L43615]. The putative regulatory mutation exon 1:-8 (g --> c) in the upstream region of the gene is associated with an aberrant Taq I restriction site allele in intron B of the gene (gene bank accession no. X80393).

Alleles↗
PubMed1999

Moderation of phenotypic severity in dystrophic and junctional forms of epidermolysis bullosa through in-frame skipping of exons containing non-sense or frameshift mutations.

Non-sense mutations on both alleles of either the type VII collagen gene (COL7A1) or the genes encoding laminin 5 (LAMA3, LAMB3, or LAMC2) usually result in clinically severe forms of recessive dystrophic or junctional epidermolysis bullosa, respectively. In this study we assessed two unrelated families whose mutations in genomic DNA predicted severe recessive dystrophic epidermolysis bullosa or junctional epidermolysis bullosa phenotypes but in whom the manifestations were milder than expected. The recessive dystrophic epidermolysis bullosa patients had a homozygous single base-pair frameshift mutation in exon 19 of COL7A1 (2470insG). Clinically, there was generalized blistering but only mild scarring. Skin biopsy revealed positive type VII collagen immunoreactivity and recognizable anchoring fibrils. The junctional epidermolysis bullosa patients were compound heterozygotes for a frameshift/non-sense combination of mutations in exons 3 and 17 of LAMB3 (29insC/Q834X). These patients did not have the lethal form of junctional epidermolysis bullosa but, as adults, displayed the milder generalized atrophic benign epidermolysis bullosa variant. There was undetectable laminin 5 staining at the dermal-epidermal junction using an antibody to the beta3 chain, but faintly positive alpha3 and gamma2 chain labeling, and there was variable hypoplasia of hemidesmosomes. To explain the milder recessive dystrophic epidermolysis bullosa and junctional epidermolysis bullosa phenotypes in these families, reverse transcription-polymerase chain reaction, using RNA extracted from frozen skin, was able to provide evidence for some rescue of mutant mRNA transcripts with restoration of the open- reading frame. In the recessive dystrophic epidermolysis bullosa patients, transcripts containing in-frame skipping of exon 19 of COL7A1 in the cDNA were detected, and in the junctional epidermolysis bullosa patients transcripts with in-frame skipping of exon 17 of LAMB3 were identified. The truncated proteins encoded by these transcripts are expected to lack certain critical domains involved in cell-matrix attachment, but may still be able to contribute to adhesion thereby moderating the severity of the skin blistering. This study shows the limitations in predicting phenotype in epidermolysis bullosa solely based on mutation analysis of genomic DNA and emphasizes the importance of immunohistochemistry, electron microscopy, and mRNA assessment as parallel investigations.

Adolescent↗
PubMed2004

Alpha-synuclein missense and multiplication mutations in autosomal dominant Parkinson's disease.

Missense mutations and genomic multiplications of the alpha-synuclein gene (SNCA) have been linked to autosomal dominant familial Parkinson's disease. We screened 50 probands of families with autosomal dominant parkinsonism for alpha-synuclein mutations by exon sequencing. No known or novel mutations were found. We also analyzed the genomic DNA for multiplications of the SNCA locus using multiplex panels of microsatellite markers. All samples were diploid with two normal copies of the SNCA locus. Hence, alpha-synuclein missense mutations and SNCA genomic multiplications remain a rare cause of disease.

Adult↗
PubMed1990

Promoter switching in Epstein-Barr virus during the initial stages of infection of B lymphocytes.

Transcription of the genes encoding the six viral nuclear antigens present in Epstein-Barr virus latently infected lymphocytes can be initiated from one of two promoters (Cp and Wp) mapping near the left end of the viral genome. These promoters are used in a mutually exclusive manner in clonal cell lines established from either Burkitt lymphoma tumors or in vitro infection of peripheral B lymphocytes. In this paper the role of Cp and Wp during viral latency is investigated. Cp appears to be the promoter normally employed during established latent infection. Analysis of two cell lines that use Wp revealed a deletion spanning Cp in the endogenous viral genomes, suggesting that cell lines exhibiting Wp activity harbor mutated viral genomes with a nonfunctional Cp. However, in contrast to the preferred usage of Cp exhibited by established Epstein-Barr virus-infected cell lines, Wp was shown to be exclusively utilized during the initial stages of viral infection. In addition to Wp activity, Cp usage was apparent by 6 days post-infection. A model is proposed involving B-lymphocyte differentiation-driven promoter switching during the establishment of viral latency.

Adult↗
PubMed1994

A genetic selection method for the transfer of HSV-1 glycoprotein B mutations from plasmid to the viral genome: preliminary characterization of transdominance and entry kinetics of mutant viruses.

A genetic selection procedure has been devised to transfer mutations from a plasmid to the viral genome. Reagents were constructed so that the recombination events that occur during cotransfection rescue a mutation in a recipient viral genome and, simultaneously, transfer a mutation in an adjacent (target) gene to the viral genome. In the example presented here the two adjacent genes are essential for viral replication, so that a transformed cell line that expresses both genes and another cell line that expresses only the target gene are required. Ideally the recipient viral genome should be deleted for the entire target gene, and the deletion should extend a short distance into the adjacent gene. In the present study UL27 (glycoprotein gB) of herpes simplex virus type 1 (KOS) is the target gene for mutation transfer and the upstream gene UL28, which specifies the ICP18.5 polypeptide, is the marker-rescue gene. A recipient virus that was deleted for DNA sequences encoding the C-terminal 74 residues of ICP18.5 and the N-terminal 711 residues of gB was constructed. All of the gB mutant plasmids used overlap the ICP18.5 deletion, and therefore, recombination events that rescue the ICP18.5 deletion must transfer a gB mutation present in codons 1-711 of the rescuing plasmid. Recombinant viruses that contain the gB mutation, unlike the parental gB-/18.5- virus, will grow on cells that express only gB (D6). This procedure has been used to transfer insertion, deletion, and chain termination mutations into the gB gene of the KOS genome. Southern blot analysis confirmed the transfer of the mutations to the viral genome. Analysis of radioactively labeled, infected cell lysates by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), before and after immune precipitation with gB-specific antibodies, confirmed the presence of the mutant polypeptides in the lysates. The incorporation of the mutant polypeptides into the envelopes of purified released viruses was measured. The yield of plaque forming units per cell was determined from single step growth curves after infection of permissive D6 cells. Virus yield, a measure of transdominance, varied for the different mutants. The maximum reduction in virus yield observed was sixfold relative to the wild-type virus. Transdominance was a result of both the lack of glycoprotein processing and the presence of gB-oligomerization sites. A reduced yield was also observed for a previously isolated gB-null mutant virus, K082. The amount of gB produced in D6 cells, infected with K082, was less than that produced in KOS infected cells, which may account for the reduced yield.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Line↗
PubMed2003

Spontaneous mutations in the human gene for p53 in recombinant adenovirus during multiple passages in human embryonic kidney 293 cells.

Infectious recombinant adenovirus (rAd) is usually produced in human embryonic kidney 293 cells that harbor the E1 gene and rAd has been shown to be an efficient tool for gene transfer both in vivo and in vitro. It also has considerable potential in human gene therapy. However, rates of spontaneous mutations in genes introduced into host cells after multiple passages remain to be clarified. We have characterized the spontaneous mutation of genomes derived from human adenovirus type 5 (Ad5) and of human p53-rAd during multiple passages by two different methods, namely, a plaque assay and a molecular cloning assay, with subsequent direct nucleotide sequencing. Using the plaque assay, we found no mutations in the E1A and p53 genes derived from infectious Ad5 and p53-rAd, respectively. By contrast, we found spontaneous mutations in the E1A gene of Ad5, with a mutation rate of 9.28 x 10(-8) per base pair per plaque, in the molecular cloning assay. The rate of mutation of the p53 gene of p53-rAd, as determined by the molecular cloning assay, ranged from 1.50 x 10(-7) to 3.25 x 10(-7) per base pair per passage. The mutations in the p53 gene of p53-rAd were localized mainly in the transcriptional activation domain, the SH3 domain, and the regulation domain and they were rarely found in the DNA-binding domain, which is a major site for mutations in human cancers. Our results indicate that multiple passages can generate a heterogeneous population of p53-rAd and that the molecular cloning assay is an efficient technique with which to search for mutations in the genome of p53-rAd that cannot be detected by a plaque assay.

Adenoviridae↗
PubMed2006

Efficiency of carcinogenesis with and without a mutator mutation.

Carcinogenesis involves the acquisition of multiple genetic changes altering various cellular phenotypes. These changes occur within the fixed time period of a human lifespan, and mechanisms that accelerate this process are more likely to result in clinical cancers. Mutator mutations decrease genome stability and, hence, accelerate the accumulation of random mutations, including those in oncogenes and tumor suppressor genes. However, if the mutator mutation is not in itself oncogenic, acquiring that mutation would add an extra, potentially time-consuming step in carcinogenesis. We present a deterministic mathematical model that allows quantitative prediction of the efficiency of carcinogenesis with and without a mutator mutation occurring at any time point in the process. By focusing on the ratio of probabilities of pathways with and without mutator mutations within cell lineages, we can define the frequency or importance of mutator mutations in populations independently of absolute rates and circumvent the question of whether mutator mutations are "necessary" for cancers to evolve within a human lifetime. We analyze key parameters that predict the relative contribution of mutator mutants in carcinogenesis. Mechanisms of carcinogenesis involving mutator mutations are more likely if they occur early. Involvement of mutator mutations in carcinogenesis is favored by an increased initial mutation rate, by greater fold-increase in mutation rate due to the mutator mutation, by increased required steps in carcinogenesis, and by increased number of cell generations to the development of cancer.

Animals↗
PubMed1989

Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS).

We have improved the "polymerase chain reaction" (PCR) to permit rapid analysis of any known mutation in genomic DNA. We demonstrate a system, ARMS (Amplification Refractory Mutation System), that allows genotyping solely by inspection of reaction mixtures after agarose gel electrophoresis. The system is simple, reliable and non-isotopic. It will clearly distinguish heterozygotes at a locus from homozygotes for either allele. The system requires neither restriction enzyme digestion, allele-specific oligonucleotides as conventionally applied, nor the sequence analysis of PCR products. The basis of the invention is that unexpectedly, oligonucleotides with a mismatched 3'-residue will not function as primers in the PCR under appropriate conditions. We have analysed DNA from patients with alpha 1-antitrypsin (AAT) deficiency, from carriers of the disease and from normal individuals. Our findings are in complete agreement with allele assignments derived by direct sequencing of PCR products.

Base Sequence↗
PubMed1993

New variant of von Willebrand disease type II with markedly increased levels of von Willebrand factor antigen and dominant mode of inheritance: von Willebrand disease type IIC Miami.

A variant of von Willebrand disease (vWD) was identified in six members of a kindred spanning four generations. The proband was a 46-year-old woman with a lifelong history of bleeding, a prolonged bleeding time (> 15 minutes), markedly elevated von Willebrand factor (vWF) antigen (vWF:Ag = 2.09 U/mL), slightly reduced ristocetin cofactor activity, and a plasma vWF multimer pattern similar to that of vWD type IIC. Similar findings were observed in her three children, mother, and brother. In affected family members, platelet and plasma vWF multimer patterns were discrepant with higher molecular weight multimers observed in platelet vWF. Following a 1-Des-amino-8-D-arginine vasopressin (DDAVP) challenge, the proband failed to normalize her bleeding time even though vWF: Ag rose by 70% and higher molecular weight multimers were increased slightly. Genetic studies were consistent with autosomal dominant inheritance of a mutation within the vWF gene. By sequencing of cloned genomic DNA, mutations were excluded in exons 4, 5, 14, and 15, which encode regions of the vWF propeptide proposed to be important in multimer biosynthesis. Mutations also were excluded in exons 28 to 31, which encompass the known mutations that cause vWD types IIA, IIB, and B. This new variant of vWD, characterized by autosomal dominant inheritance, a qualitative defect that resembles vWD type IIC, and increased plasma vWF:Ag, was tentatively designated vWD type IIC Miami.

Base Sequence↗
PubMed1997

Heteroplasmic point mutations of mitochondrial DNA affecting subunit I of cytochrome c oxidase in two patients with acquired idiopathic sideroblastic anemia.

Mitochondrial iron overload in acquired idiopathic sideroblastic anemia (AISA) may be attributable to mutations of mitochondrial DNA (mtDNA), because these can cause respiratory chain dysfunction, thereby impairing reduction of ferric iron (Fe3+) to ferrous iron (Fe2+). The reduced form of iron is essential to the last step of mitochondrial heme biosynthesis. It is not yet understood to which part of the respiratory chain the reduction of ferric iron is linked. In two patients with AISA we identified point mutations of mtDNA affecting the same transmembrane helix within subunit I of cytochrome c oxidase (COX I; ie, complex IV of the respiratory chain). The mutations were detected by restriction fragment length polymorphism analysis and temperature gradient gel electrophoresis. One of the mutations involves a T --> C transition in nucleotide position 6742, causing an amino acid change from methionine to threonine. The other mutation is a T --> C transition at nt 6721, changing isoleucine to threonine. Both amino acids are highly conserved in a wide range of species. Both mutations are heteroplasmic, ie, they establish a mixture of normal and mutated mitochondrial genomes, which is typical of disorders of mtDNA. The mutations were present in bone marrow and whole blood samples, in isolated platelets, and in granulocytes, but appeared to be absent from T and B lymphocytes purified by immunomagnetic bead separation. They were not detected in buccal mucosa cells obtained by mouthwashes and in cultured skin fibroblasts examined in one of the patients. In both patients, this pattern of involvement suggests that the mtDNA mutation occurred in a self-renewing bone marrow stem cell with myeloid determination. Identification of two point mutations with very similar location suggests that cytochrome c oxidase plays an important role in the pathogenesis of AISA. COX may be the physiologic site of iron reduction and transport through the inner mitochondrial membrane.

Aged↗
PubMed1998

A point mutation (D79N) of the alpha2A adrenergic receptor abolishes the antiepileptogenic action of endogenous norepinephrine.

Norepinephrine serves as a neurotransmitter for a population of neurons the cell bodies of which reside in a brainstem nucleus and the axons of which project widely to discrete subsets of forebrain neurons. Norepinephrine powerfully inhibits epileptogenesis in the kindling model. Pharmacological methods have demonstrated that the antiepileptogenic actions of norepinephrine are exerted via alpha2 adrenergic receptors residing on targets of noradrenergic neurons. The existence of three alpha2 adrenergic receptor subtypes together with the lack of subtype-specific ligands has precluded understanding the role of individual alpha2 adrenergic receptor subtypes in the antiepileptogenic actions of norepinephrine. Gene targeting was used to introduce a point mutation into the alpha2A adrenergic subtype in the mouse genome. The mutation produced a marked enhancement of epileptogenesis and abolished the proepileptogenic actions of the alpha2 adrenergic receptor antagonist idazoxan. These studies reveal the crucial contribution of the alpha2A receptor subtype in suppression of epileptogenesis. Development of agents that promote selective activation of the alpha2A receptor subtype may provide novel therapeutic strategies for the prophylaxis of epilepsy.

Adrenergic alpha-Agonists↗
PubMed2002

Deterministic mutation rate variation in the human genome.

Several studies of substitution rate variation have indicated that the local mutation rate varies over the mammalian genome. In the present study, we show significant variation in substitution rates within the noncoding part of the human genome using 4.7 Mb of human-chimpanzee pairwise comparisons. Moreover, we find a significant positive covariation of lineage-specific chimpanzee and human local substitution rates, and very similar mean substitution rates down the two lineages. The substitution rate variation is probably not caused by selection or biased gene conversion, and so we conclude that mutation rates vary deterministically across the noncoding nonrepetitive regions of the human genome. We also show that noncoding substitution rates are significantly affected by G+C base composition, partly because the base composition is not at equilibrium.

Amino Acid Substitution↗
PubMed2004

PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2.

Pelizaeus-Merzbacher disease (PMD) and its allelic disorder, spastic paraplegia type 2 (SPG2), are among the best-characterized dysmyelinating leukodystrophies of the central nervous system (CNS). Both PMD and SPG2 are caused by mutations in the proteolipid protein 1 (PLP1) gene, which encodes a major component of CNS myelin proteins. Distinct types of mutations, including point mutations and genomic duplications and deletions, have been identified as causes of PMD/SPG2 that act through different molecular mechanisms. Studies of various PLP1 mutants in humans and animal models have shed light on the genomic, molecular, and cellular pathogeneses of PMD/SPG2. Recent discoveries include complex mutational mechanisms and associated disease phenotypes, novel cellular pathways that lead to the degeneration of oligodendrocytes, and genomic architectural features that result in unique chromosomal rearrangements. Here, I review the previous and current knowledge of the molecular pathogenesis of PMD/SPG2 and delineate future directions for PMD/SPG2 studies.

Gene Duplication↗
PubMed1995

A genetic analysis of the 63E-64A genomic region of Drosophila melanogaster: identification of mutations in a replication factor C subunit.

We have performed an F2 genetic screen to identify lethal mutations within the 63E-64A genomic region. We have isolated 122 mutations in 20 different complementation groups. Of these groups, 16 are represented by multiple alleles. We have also established that the Rop and Ras2 genes are located within the 63E-64A genomic domain at 64A10,11. We have sequenced 10.2 kb of DNA surrounding this gene pair and find that in addition to Rop and Ras2 there is another gene located within this DNA sequence. The gene product, which we have named Rfc40, shows 68% identity to the 40-kDa subunit of replication factor C. We find that the members of one complementation group (13 alleles) derived from our screen correspond to mutations in the Rop gene, whereas the members of another (five alleles) correspond to mutations in the Rfc40 gene. In addition we have isolated 11 new mutant alleles of the disembodied gene.

Amino Acid Sequence↗
PubMed2006

Pentachlorophenol treatment in vivo elevates point mutation rate in zebrafish p53 gene.

Pentachlorophenol (PCP), a probable human carcinogen, has been heavily used as an aseptic and a biocide throughout the world, and is widely present in the environment. Recent survey in Germany revealed that the average PCP amount in the urine of general German populations was 1.04 microg/L while the peak concentration could reach up to 19.1 microg/L. PCP was reported to cause DNA damage, but whether it can be involved in inducing point mutations in genome is unknown. To determine the genotoxicity of PCP on vertebrate, we first performed acute toxicity test on zebrafish for the effect of PCP exposure. The LC50 values of zebrafish exposed to PCP at 24, 48, 72 and 96 h were determined to be 0.196, 0.130, 0.130 and 0.130 mg/L, respectively. We then treated zebrafish with PCP for 10 days at 0 (control), 0.5, 5 and 50 microg/L, respectively, to determine whether PCP could be involved in inducing point mutations. Employing denaturing high-performance liquid chromatography analysis and DNA sequencing, we demonstrated that exposure of PCP to zebrafish at a concentration as low as 5 microg/L for 10 days elevates point mutation rate in p53 gene in liver cells. This is the first direct evidence revealing that PCP can elevate point mutation rate in the vertebrate genomes. The result implies PCP might be involved in carcinogenesis by elevating point mutation rate in the somatic genomes.

Animals↗
PubMed2004

Novel germline hMSH2 genomic deletion and somatic hMSH2 mutations in a hereditary nonpolyposis colorectal cancer family.

Germline and somatic mutations of the hMSH2 gene were determined in a Japanese hereditary nonpolyposis colorectal cancer (HNPCC) family fulfilling the Amsterdam criteria. PCR-SSCP-sequencing of genomic DNA detected a somatic hMSH2 mutation of an A deletion at codon 227-229 in a duodenal carcinoma and a somatic hMSH2 mutation of an A insertion at codon 21 in a gastric carcinoma from affected family members, both carcinomas exhibiting high microsatellite instability. However, no germline hMSH2 mutation was detected by the PCR-SSCP-sequencing method. Genomic DNA was then analyzed by Southern blot hybridization using three hMSH2 cDNA probes (probe A involving exons 1-5, probe B involving exons 4-11 and probe C involving exons 9-16) after digestion by restriction enzymes, EcoRI, HindIII and NsiI. The NsiI digest of DNA from normal tissues of affected members exhibited an aberrant 8.6 kb restriction fragment, in addition to the normal 10.6 kb fragment, when hybridized to probes A and B. This suggested the presence of a heterozygous 2kb genomic deletion encompassing exon 4, 5 or 6. RT-PCR-sequencing revealed that the deleted region encompassed exon 5. This novel genomic deletion of the hMSH2 gene was confirmed to be pathogenic, and the Southern hybridization pattern was applied to the pre-symptomatic diagnosis.

Adolescent↗