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PubMed1996

Bilateral sensorineural hearing loss associated with the point mutation in mitochondrial genome.

Mitochondrial DNA (mtDNA) mutation associated with sensorineural hearing loss (SNHL) has previously been described in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and in aminoglycoside-induced deafness. The authors of this study report three cases of SNHL associated with mtDNA mutation (3243A-->G). They examined the clinical features of this type of SNHL by audiologic studies and examined the mtDNA mutation by the polymerase chain reaction technique. In the three cases described, the SNHL had an adult onset and was bilateral and symmetrical. All patients had adult-onset diabetes mellitus. Audiologic studies revealed that the SNHL in all patients derived from the cochlea rather than from retrocochlear sites. It is presumed that mtDNA mutation results in mitochondrial dysfunction in cochlear tissues (i.e., hair cells and stria vascularis) and in neurons of the auditory pathway. Genetic analysis of mtDNA offers new insight into the diagnosis and treatment of SNHL.

Adolescent↗
PubMed2005

Defining the ends of Parkin exon 4 deletions in two different families with Parkinson's disease.

Autosomal recessive juvenile parkinsonism (AR-JP, PARK2) is characterized by an early onset parkinsonism, often presenting with dystonia as an early feature. Mutations in Parkin are a relatively common cause of AR-JP and are estimated to be present in approximately 30% of familial young onset Parkinson disease (PD) [Abbas et al. (1999); Hum Mol Genet 8:567-574]. These mutations include exon rearrangements (deletions and duplications), point mutations, and small deletions. Similar genomic mutations have been described in unrelated patients, thereby indicating independent mutational events or ancient founder effects. We have identified homozygous deletion mutations of exon 4 in Parkin in two unrelated families, one from Brazil and the other from Turkey [Dogu et al. (2004); Mov Dis 9:812-816; Khan et al., Mov Dis, in press]. We have performed molecular analysis of the deletion breakpoints and this data indicates these mutations originated independently. We present here data demonstrating that the mutation responsible for disease in the Brazilian kindred consists of two separate deletions (1,069 and 1,750 bp) surrounding and including exon 4. The deletion removing parkin exon 4 identified in the Turkish family extended 156,203 bp. In addition to demonstrating that disease in these families is not caused by a single founder mutation, these data show that there is no common fragile site between these mutational events.

Base Sequence↗
PubMed1997

Evolving methods in genetic epidemiology. IV. Approaches to non-Mendelian inheritance.

From this overview it can be concluded that the understanding of the biologic properties and the development of analytic tools to identify repeat sequence mutations, genomic imprinting effects, and mitochondrial mutations are only beginning. Development of approaches to identify such phenomena as modifying effects or genetic components of complex traits is a new area of research. Not mentioned here are the ways in which locating a gene with such properties (i.e., linkage analysis) would be affected if such properties were not accounted for, or how to alter such analyses to obtain full information. Again, this is an exciting new area of research that will continue to motivate epidemiologists and geneticists. Hopefully, we have learned a lesson from the earlier conclusions of the studies on myotonic dystrophy: keep an open mind and never assume that the "geneticist should know best about behavior of genes".

Epidemiologic Methods↗
PubMed1998

Quasispecies nature of three maize streak virus isolates obtained through different modes of selection from a population used to assess response to infection of maize cultivars.

Three maize streak virus (MSV) isolates were derived from an MSV population used to assess the response to infection of maize cultivars. Isolate SP1 was obtained from this population through short acquisition and inoculation periods (1 and 5 min, respectively), using a single Cicadulina mbila vector. Isolate SP2 was derived from SP1 after transmission to a wild perennial host (Coix lacryma-jobi), on which it was maintained for about 4 years without insect transmission. Isolate N2A, the most pathogenic isolate, was obtained from the initial population after serial passages on almost completely resistant inbred maize lines. The complexity of each isolate was analysed by RFLP analysis and sequencing based on 120 SP1 clones, 36 SP2 clones and 40 N2A clones. All three isolates were composed of different but related clones, consistent with a quasispecies structure. The mutations were distributed throughout the genome. Mutation frequencies, based on all available sequences, were 3.8 x 10(-4) for SP1, 10.5 x 10(-4) for SP2 and 6.9 x 10(-4) for N2A. As expected from the bottleneck selection step, the intra-isolate variability of SP1 was relatively low. Comparison between SP1 and SP2 showed that SP1 heterogeneity increased during maintenance on the wild host. Furthermore, the consensus sequences of SP1 and SP2 differed by two non-synonymous substitutions in the complementary sense gene repA. N2A had a relatively low degree of heterogeneity, but was composed of several sub-populations. The results reflect the influence of the mode of selection of MSV isolates on their quasispecies organization, i.e. distribution of variants, and master sequence.

Base Sequence↗
PubMed2005

Epstein-Barr virus mRNA export factor EB2 is essential for intranuclear capsid assembly and production of gp350.

Most human herpesviruses, including Epstein-Barr virus (EBV), express a protein which functions primarily as an mRNA export factor. Previously, we deleted the gene for the Epstein-Barr virus mRNA export factor EB2 from the EBV genome and then introduced the mutated genome into 293 cells. Using a transcomplementation assay in which ectopic expression of the transcription factor EB1/ZEBRA was sufficient to induce the EBV productive cycle, we showed that Ori-Lyt-dependent replication of the EBV DNA occurs in the absence of EB2, indicating that EB2 is not essential for the expression and export of early mRNAs. However, in the absence of EB2, no infectious viral particles are produced (H. Gruffat, J. Batisse, D. Pich, B. Neuhierl, E. Manet, W. Hammerschmidt, and A. Sergeant, J. Virol. 76:9635-9644, 2002). In this report, we now show that EB2 is essential for the nuclear export of most, but not all, late mRNAs produced from intronless genes that translate into proteins involved in intranuclear capsid assembly and maturation. As a consequence, we show that EB2 is essential for the proper assembly of intranuclear capsids. Interestingly, the late BLLF1 gene contains an intron, and both unspliced and spliced mRNAs must be exported to the cytoplasm to be translated into gp350 and gp220, respectively (M. Hummel, D. A. Thorley-Lawson, and E. Kieff, J. Virol. 49:413-417, 1984). Our results also demonstrate that although BLLF1 spliced mRNAs are exported to the cytoplasm independently of EB2, EB2 is essential for the nuclear export of unspliced BLLF1 mRNA. In the same assay, herpes simplex virus 1 ICP27 completely inhibited the nuclear export of BLLF1 spliced mRNAs whereas unspliced BLLF1 mRNAs were exported, confirming that in a physiological assay, ICP27 inhibits splicing.

Base Sequence↗
PubMed2006

Methods for detection of subtle mutations in cancer genomes.

With the realization that cancer is a genetic disease, detection of mutations in genomic DNA has become an important discipline in many areas of cancer research. Although the publication of the human genome sequence and the immense technological advancements have facilitated the analysis of cancer genomes, detection of mutations in tumor specimens may still be challenging and fraught with technical problems. In this review, we describe current technologies for detection of small DNA mutations, including mutation scanning techniques to search for unknown mutations, and diagnostic techniques to detect known cancer mutations. We outline the principles of the different techniques and discuss their advantages and limitations. We also discuss critical issues that must be considered before choosing methodology, including sensitivity, specificity, limit of detection, throughput and cost, quantity and quality of template DNA, available equipment, and personnel expertise.

DNA Fingerprinting↗
PubMed2000

Evolutionary origin and consequences of uniparental mitochondrial inheritance.

In the great majority of sexual organisms, cytoplasmic genomes such as the mitochondrial genome are inherited (almost) exclusively through only one, usually the maternal, parent. This rule probably evolved to minimize the potential spread of selfish cytoplasmic genomic mutations through a species. Maternal inheritance creates an asymmetry between the sexes from which several evolutionary consequences follow. Because natural selection on mitochondria operates only in females, mitochondrial mutations may have more deleterious effects in males than in females. Strictly uniparental inheritance creates asexual mitochondrial lineages that are vulnerable to mutation accumulation (Muller's ratchet). There is evidence that over evolutionary time mitochondrial genomes have indeed accumulated slightly deleterious mutations. Mutation accumulation in animal mitochondrial genomes is probably slowed down mainly by two processes: a severe reduction in germline mitochondrial genome copy number at some point in the life cycle, enabling more effective elimination of mutations by natural selection, and occasional recombination between maternal and paternal mitochondrial genomes following paternal leakage.

DNA Repair↗
PubMed2004

Characterization of severe acute respiratory syndrome coronavirus genomes in Taiwan: molecular epidemiology and genome evolution.

Since early March 2003, the severe acute respiratory syndrome (SARS) coronavirus (CoV) infection has claimed 346 cases and 37 deaths in Taiwan. The epidemic occurred in two stages. The first stage caused limited familial or hospital infections and lasted from early March to mid-April. All cases had clear contact histories, primarily from Guangdong or Hong Kong. The second stage resulted in a large outbreak in a municipal hospital, and quickly spread to northern and southern Taiwan from late April to mid-June. During this stage, there were some sporadic cases with untraceable contact histories. To investigate the origin and transmission route of SARS-CoV in Taiwan's epidemic, we conducted a systematic viral lineage study by sequencing the entire viral genome from ten SARS patients. SARS-CoV viruses isolated from Taiwan were found closely related to those from Guangdong and Hong Kong. In addition, all cases from the second stage belonged to the same lineage after the municipal hospital outbreak, including the patients without an apparent contact history. Analyses of these full-length sequences showed a positive selection occurring during SARS-CoV virus evolution. The mismatch distribution indicated that SARS viral genomes did not reach equilibrium and suggested a recent introduction of the viruses into human populations. The estimated genome mutation rate was approximately 0.1 per genome, demonstrating possibly one of the lowest rates among known RNA viruses.

Base Pairing↗
PubMed1995

Multiple mechanisms account for genomic instability and molecular mutation in neoplastic transformation.

Neoplastic cells typically possess numerous genomic mutations and chromosomal aberrations, including point mutations, gene amplifications and deletions, and replication errors. Acquisition of such genomic instability may represent an early step in the process of carcinogenesis. Proteins involved in DNA replication, DNA repair, cell cycle progression, and others are all components of complex overlapping biochemical pathways that function to maintain cellular homeostasis. Therefore, mutational alteration of genes encoding proteins involved in these cellular processes could contribute to genomic instability. Loss of normal cellular mechanisms that guard against genomic mutation and the ensuing genomic instability might lead to accumulation of multiple stable mutations in the genome of affected cells, perhaps resulting in neoplastic transformation when some critical number of transformation-related target genes become damaged. Thus, interactions of fundamental cellular processes play significant roles in sustaining cellular normality, and alteration of any of these homeostatic processes could entrain cells to the progressive genomic instability and phenotypic evolution characteristic of carcinogenesis. Here, we discuss possible molecular mechanisms governing DNA mutation and genomic instability in genetically normal cells that might account for the acquisition of genomic instability in somatic cells, leading to the development of neoplasia. These include (a) molecular alteration of genes encoding DNA repair enzymes, (b) molecular alteration of genes responsible for cell-cycle control mechanisms, and (c) direct molecular alteration of dominantly transforming cellular protooncogenes. We also discuss normal cellular processes involved with DNA replication and repair that can contribute to the mutational alteration of critical genes: e.g., slow repair of damaged DNA in specific genes, and the timing of normal gene-specific replication.

Animals↗
PubMed2004

Evolution: bacterial mutation in stationary phase.

A recent study indicates that the genomic mutation rate of the gut bacterium Escherichia coli is substantially higher in nongrowing than growing cultures. These findings are important in the light of the ongoing controversy over the generality and robustness of stationary phase mutagenesis and its evolutionary implications.

Analysis of Variance↗
PubMed2000

A brief history of Drosophila's contributions to genome research.

The sequence of the Drosophila melanogaster genome presented in this issue of Science is the latest milestone in nine decades of research on this organism. Genetic and physical mapping, whole-genome mutational screens, and functional alteration of the genome by gene transfer were pioneered in metazoans with the use of this small fruit fly. Here we look at some of the instances in which work on Drosophila has led to major conceptual or technical breakthroughs in our understanding of animal genomes.

Animals↗
PubMed2000

The molecular biology of cancer.

The process by which normal cells become progressively transformed to malignancy is now known to require the sequential acquisition of mutations which arise as a consequence of damage to the genome. This damage can be the result of endogenous processes such as errors in replication of DNA, the intrinsic chemical instability of certain DNA bases or from attack by free radicals generated during metabolism. DNA damage can also result from interactions with exogenous agents such as ionizing radiation, UV radiation and chemical carcinogens. Cells have evolved means to repair such damage, but for various reasons errors occur and permanent changes in the genome, mutations, are introduced. Some inactivating mutations occur in genes responsible for maintaining genomic integrity facilitating the acquisition of additional mutations. This review seeks first to identify sources of mutational damage so as to identify the basic causes of human cancer. Through an understanding of cause, prevention may be possible. The evolution of the normal cell to a malignant one involves processes by which genes involved in normal homeostatic mechanisms that control proliferation and cell death suffer mutational damage which results in the activation of genes stimulating proliferation or protection against cell death, the oncogenes, and the inactivation of genes which would normally inhibit proliferation, the tumor suppressor genes. Finally, having overcome normal controls on cell birth and cell death, an aspiring cancer cell faces two new challenges: it must overcome replicative senescence and become immortal and it must obtain adequate supplies of nutrients and oxygen to maintain this high rate of proliferation. This review examines the process of the sequential acquisition of mutations from the prospective of Darwinian evolution. Here, the fittest cell is one that survives to form a new population of genetically distinct cells, the tumor. This review does not attempt to be comprehensive but identifies key genes directly involved in carcinogenesis and demonstrates how mutations in these genes allow cells to circumvent cellular controls. This detailed understanding of the process of carcinogenesis at the molecular level has only been possible because of the advent of modern molecular biology. This new discipline, by precisely identifying the molecular basis of the differences between normal and malignant cells, has created novel opportunities and provided the means to specifically target these modified genes. Whenever possible this review highlights these opportunities and the attempts being made to generate novel, molecular based therapies against cancer. Successful use of these new therapies will rely upon a detailed knowledge of the genetic defects in individual tumors. The review concludes with a discussion of how the use of high throughput molecular arrays will allow the molecular pathologist/therapist to identify these defects and direct specific therapies to specific mutations.

Animals↗
PubMed2003

Novel mutations involving the NF1 gene coding sequence in neurofibromatosis type 1 patients from Taiwan.

Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome affecting the nervous system. The disease is one of the most common autosomal dominant diseases in all ethnic groups. Although the gene was mapped to human chromosome 17 and isolated in 1990, the detection of NF1 mutation is still considered to be a challenge as the gene is large and contains multiple exons. Here we report the detection of three genomic mutations in three Chinese patients living in Taiwan. A DNA diagnosis procedure was established to investigate the NF1 gene mutation at both the transcript and genomic DNA levels. Mutations causing transcript alteration were uncovered in three patients. In the first case, we detected a deletion involving exons 39-45 (nucleotide 7260-8167 in GenBank accession No. M89914). In the second case, a 2199-2448 deletion resulted in skipping of exon 13. The third case skipped the exon 3 in the mutant transcript. We further investigated what caused the cDNA deletion by PCR using genomic DNA as a template. In the first patient, we identified an approximately 17.5 kbp deletion in the NF1 gene. In the other two patients, we identified a single-base substitution (IVS13+1G>A) at the splicing donor site in the second case, and an IVS3+1G>T substitution in the third case. We conclude that genomic deletion and alteration of splicing signal caused abnormal transcripts and truncated proteins in the three Taiwanese NF1 cases.

DNA Mutational Analysis↗
PubMed2001

Molecular characterization and sequence analysis of polyomavirus strains isolated from needle biopsy specimens of kidney allograft recipients.

We retrospectively examined 29 renal allograft biopsy specimens from 42 kidney transplant recipients by means of molecular biologic techniques (nested polymerase chain reaction), immunohistochemical analysis (anti-SV40 antibody), and histologic examination to evaluate the presence of polyomaviruses (PVs), viral genotypes, genomic mutations, and their pathologic significance. PV genomes were found in six cases (21%); restriction fragment length polymorphism analysis characterized 4 as JC virus (JCV) and 2 as BK virus (BKV). The latter also were positively stained immunohistochemically and showed histologically typical intranuclear viral inclusions; JCV cases were negative. DNA sequence analysis revealed only minor changes in the 4 JCV cases (3 archetypes and 1 JCV type 3, not associated with a known pathogenic genotype) but identified 2 specific variants in the BKV isolates (AS and WW strains). Given the different histologic findings (mixed inflammatory infiltration in the AS and no inflammation in the WW strain), we speculate that different BKV strains may cause differential damage in transplanted kidneys. Finally, the negative histologic and immunohistochemical JCV results, as well as the absence of viral mutations, indicate that JCV renal infection is latent in transplant recipients.

BK Virus↗
PubMed2001

Identification of seven novel mutations including the first two genomic rearrangements in SLC26A3 mutated in congenital chloride diarrhea.

Congenital chloride diarrhea (CLD) is an autosomal recessive disorder characterized by defective intestinal electrolyte absorption, resulting in voluminous osmotic diarrhea with high chloride content. A variety of mutations in the solute carrier family 26, member 3 gene (SLC26A3, previously known as CLD or DRA) are responsible for the disease. Since the identification of the SLC26A3 gene and the determination of its genomic structure, altogether three founder and 17 private mutations have been characterized within miscellaneous ethnic groups. We screened for mutations in seven unrelated families with CLD. The diagnoses were confirmed by fecal chloride measurements. The combined PCR-SSCP and sequencing analyses revealed altogether seven novel mutations including two missense mutations (S206P, D468V), two splicing defects (IVS12-1G>C, IVS13-2delA), one nonsense mutation (Q436X), one insertion/deletion mutation (2104-2105delGGins29-bp), and an intragenic deletion of SLC26A3 exons 7 and 8. Two previously identified mutations were also found. This is the first report of rearrangement mutations in SLC26A3. Molecular features predisposing SLC26A3 for the two rearrangements may include repetitive elements and palindromic-like sequences. The increasingly wide diversity of SLC26A3 mutations suggests that mutations in the SLC26A3 gene may not be rare events.

Antiporters↗
PubMed2006

Characterization of cycA mutants of Escherichia coli. An assay for measuring in vivo mutation rates.

Quantitative assessment of the spontaneous or induced genomic mutation rate, a fundamental evolutionary parameter, usually requires the use of well-characterized mutant selection systems. Although there is a great number of genetic selection schemes available in Escherichia coli, the selection of D-cycloserine resistant mutants is shown here to be particularly useful to yield a general view of mutation rates and spectra. The combination of a well-defined experimental protocol with the Ma-Sandri-Sarkar maximum likelihood method of fluctuation analysis results in reproducible data, adequate for statistical comparisons. The straightforward procedure is based on a simple phenotype-genotype relationship, and detects mutations in the single-copy, chromosomal cycA gene, involved in the uptake of D-cycloserine. In contrast to the widely used rifampicin resistance assay, the procedure selects mutations which are neutral in respect of cell growth. No specific genetic background is needed, and practically the entire mutation spectrum (base substitutions, frameshifts, deletions, insertions) can simultaneously be measured. A systematic analysis of cycA mutations revealed a spontaneous mutation rate of 6.54 x 10(-8) in E. coli K-12 MG1655. The mutation spectrum was dominated by point mutations (base substitutions, frameshifts), spread over the entire gene. IS insertions, caused by IS1, IS2, IS3, IS4, IS5 and IS150, represented 24% of the mutations.

Amino Acid Transport Systems↗
PubMed1998

Measles viruses with altered envelope protein cytoplasmic tails gain cell fusion competence.

The cytoplasmic tail of the measles virus (MV) fusion (F) protein is often altered in viruses which spread through the brain of patients suffering from subacute sclerosing panencephalitis (SSPE). We transferred the coding regions of F tails from SSPE viruses in an MV genomic cDNA. Similarly, we constructed and transferred mutated tail-encoding regions of the other viral glycoprotein hemagglutinin (H) gene. From the mutated genomic cDNAs, we achieved rescue of viruses that harbor different alterations of the F tail, deletions in the membrane-distal half of the H tail, and combinations of these mutations. Viruses with alterations in any of the tails spread rapidly through the monolayer via enhanced cell-cell fusion. Double-tail mutants had even higher fusion competence but slightly decreased infectivity. Analysis of the protein composition of released mutant viral particles indicated that the tails are necessary for accurate virus envelope assembly and suggested a direct F tail-matrix (M) protein interaction. Since even tail-altered glycoproteins colocalized with M protein in intracellular patches, additional interactions may exist. We conclude that in MV infections, including SSPE, the glycoprotein tails are involved not only in virus envelope assembly but also in the control of virus-induced cell fusion.

Amino Acid Sequence↗