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PubMed2006

A common genetic factor for Parkinson disease in ethnic Chinese population in Taiwan.

BACKGROUND: Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized clinically by resting tremor, bradykinesia, postural instability and rigidity. The prevalence of PD is approximately 2% of the population over 65 years of age and 1.7 million PD patients (age > or = 55 years) live in China. Recently, a common LRRK2 variant Gly2385Arg was reported in ethnic Chinese PD population in Taiwan. We analyzed the frequency of this variant in our independent PD case-control population of Han Chinese from Taiwan. METHODS: 305 patients and 176 genetically unrelated healthy controls were examined by neurologists and the diagnosis of PD was based on the published criteria. The region of interest was amplified with standard polymerase chain reaction (PCR). PCR fragments then were directly sequenced in both forward and reverse directions. Differences in genotype frequencies between groups were assessed by the X2 test, while X2 analysis was used to test for the Hardy-Weinberg equilibrium. RESULTS: Of the 305 patients screened we identified 27 (9%) with heterozygous G2385R variant. This mutation was only found in 1 (0.5%) in our healthy control samples (odds ratio = 16.99, 95% CI: 2.29 to 126.21, p = 0.0002). Sequencing of the entire open reading frame of LRRK2 in G2385R carriers revealed no other variants. CONCLUSION: These data suggest that the G2385R variant contributes significantly to the etiology of PD in ethnic Han Chinese individuals. With consideration of the enormous and expanding aging Chinese population in mainland China and in Taiwan, this variant is probably the most common known genetic factor for PD worldwide.

Adult↗
PubMedDate not supplied

[The role of nontranscribable chromatin in the cellular mechanisms of morphogenesis].

The current ideas about realization of all the genetic information via stage-specific transcription and translation do not account for morphogenetic processes in space. The physical continuity of some cellular structures is only one of the mechanisms underlying the inheritance of morphofunctional properties. A suggestion was put forward that morphogenetic information is contained in nontranscribed DNA sequences. Specific interaction of these sequences with each other and with the nuclear membrane determine the spatial organization of the nucleus and program the functional properties of the endoplasmic reticulum membranes. Interaction between the nucleus and other cell structures, its localization and orientation determine the cell's polar properties and, consequently, morphogenesis of tissues and organs.

Animals↗
PubMed1978

The modification of induced genetic change in yeast by an amino acid analogue.

Treatment of diploid yeast cultures with the amino acid analogue, para-fluorophenylalanine (PFPA), at concentrations which caused inhibition of growth, resulted in up to 5 fold increases in the frequency of mitotic gene conversion at two different heteroallelic loci. With haploid yeast cultures, growth in PFPA increased the rate of forward mutation to canavanine resistance by at least 2 fold. Growth of diploids in PFPA prior to exposure to the deaminating agent nitrous acid, the cross-linking agent mitomycin C, the alkylating chemical ethylmethanesulphonate (EMS) and UV light resulted in significant changes in the potency of these diverse mutagens to induce intragenic recombination. For all four mutagens, increased frequencies of gene convertants/viable cell were observed in those cultures which had been exposed to the amino acid analogue prior to mutagen treatment. In haploid WT yeast cells, amino acid analogue incorporation resulted in an enhanced frequency of UV induced forward mutation to canavanine resistance whilst in a DNA repair deficient rad 6 mutant this interaction between UV and PFPA was abolished. The results have been interpreted on the basis of incorporation of the analogue into enzymes involved with DNA replication with a consequent loss of fidelity of such enzymes and increased errors in base incorporation.

Alleles↗
PubMed1981

The thymidine-kinase locus of Friend erythroleukaemic cells. 1. Mutation rates and properties of mutants.

Spontaneous mutation at the thymidine-kinase locus in clone 707 of the Friend cell line has been examined. The rate of mutation in BrdU resistance was found to be 2.6 x 10(-6) cell-1 generation-1. The rate of reversion to HAT resistance was found to vary from 1.1 x 10(-7) to 2.85 x 10(-6) cell-1 generation-1 in 4 BrdU-resistant clones. Of 14 mutant clones assayed for thymidine-kinase activity only one had greater than 13% the activity of wild-type cells. Fluctuation analysis showed that mutations occurred spontaneously and were not induced by the selective agent. The mutation rate at the thymidine-kinase locus is several orders of magnitude greater than those reported for several other cells lines. There does not appear to be a general genetic instability in this cell line as the mutation rate at the HGPRT locus is similar to those found in other established cell lines. It is suggested that the high forward mutation rate at the thymidine-kinase locus may be due to only one functional thymidine-kinase allele being present in cells of this clone.

Animals↗
PubMed1996

Responses of basal forebrain cholinergic neurons to damage in the adult brain.

The basal forebrain cholinergic system, which projects to all cortical areas, is a good model for the study of the responses of central nervous system (CNS) neurons to injury. Much is known about the specific neurotrophic factors of basal forebrain cholinergic neurons, and there are many techniques available to chart the progress of degeneration and recovery of cholinergic neurons after damage. There is also a clinical version of damage to cholinergic neurons which is part of the selective pathology of Alzheimer's disease. In general, CNS neurons do not regenerate well after brain damage. The first part of the review describes how the CNS promotes only limited neuronal regeneration, and that this is because of the presence of inhibitory factors and the lack of growth factors. Despite this, some CNS areas may provide a better environment for CNS regeneration than others. In the second part of the review, the degeneration and regeneration of basal forebrain cholinergic pathways in the adult rat are discussed. It is shown how the collateral sprouting of cholinergic axons occur more readily in the hippocampal formation than in neocortical areas, and that this could be linked with the more neuroplastic properties of the hippocampus. The third part of the review describes how the degeneration of cholinergic pathways in Alzheimer's disease is likely to be secondary to the pathology or degeneration of certain cortical areas. The hypothesis is put forward that the severity of the pathology in highly plastic limbic cortical areas could be linked with their susceptibility to risk factors of Alzheimer's disease such as ageing, and genetic and environmental factors.

Adult↗
PubMed2004

Genotoxicity testing of a fenugreek extract.

Fenugreek seeds have been used in traditional medicines as a remedy for diabetes. Rich in protein, fenugreek seeds contain the unique major free amino acid 4-hydroxyisoleucine (4-OH-Ile), which has been characterized as one of the active ingredients for blood glucose control. Current use of fenugreek in foodstuff has been limited to its role as a flavoring agent, and not as an ingredient to help mitigate the blood glucose response for people with diabetes. As part of a safety evaluation of novel ingredients for use in blood glucose control, the potential genotoxicity of a fenugreek seed extract (THL), containing a minimum of 40% 4-OH-ILE, was evaluated using the standard battery of tests (reverse mutation assay; mouse lymphoma forward mutation assay; mouse micronucleus assay) recommended by US Food and Drug Administration (FDA) for food ingredients. THL was determined not to be genotoxic under the conditions of the tested genetic toxicity battery. The negative assay results provide support that addition of THL to foodstuffs formulated for people with diabetes is expected to be safe. A wide safety margin is established, as anticipated doses are small compared to the doses administered in the assays.

Animals↗
PubMed2004

The absence of p53 is critical for the induction of apoptosis by 5-aza-2'-deoxycytidine.

The absence of functional p53 has complex consequences on the cellular responses to cytotoxic drugs. Here, we have examined the role of p53 in the response to 5-aza-2'-deoxycytidine (5-aza-dC or decitabine). Primary mouse embryonic fibroblasts deficient for p53 undergo apoptosis after treatment with 5-aza-dC. When compared with other demethylating drugs or chemotherapeutic treatments, 5-aza-dC showed the highest selectivity ratio for triggering apoptosis in p53-deficient cells relative to wild-type cells. Moreover, the apoptotic efficacy of 5-aza-dC is proprietary of p53-deficient cells, not being observed in cells lacking other cell-cycle regulators, such as p19ARF, p16INK4a, p21(CIP1/WAF1), E2F-1, or E2F-2. Interestingly, treatment with 5-aza-dC results in the same degree of global genomic hypomethylation in wild-type and p53-null cells. However, wild-type cells activate p53 and arrest at G2/M, whereas p53-null cells accumulate severe chromosomal aberrations and undergo apoptosis. Significantly, the impact of p53-deficiency on the response to 5-aza-dC is not exclusive of primary non-neoplastic cells, but it is also present in neoplastically transformed cells. Finally, treatment of mice bearing genetically defined tumors with nontoxic doses of 5-aza-dC results in therapeutical responses only on tumors lacking p53, but not on tumors lacking p19ARF. Together, our results put forward the hypothesis that the absence of p53 may determine a higher chemotherapeutic index for 5-aza-dC.

Animals↗
PubMed2005

Drug resistance in epilepsy: putative neurobiologic and clinical mechanisms.

Drug-resistant epilepsy with uncontrolled severe seizures despite state-of-the-art medical treatment continues to be a major clinical problem for up to one in three patients with epilepsy. Although drug resistance may emerge or remit in the course of epilepsy or its treatment, in most patients, drug resistance seems to be continuous and to occur de novo. Unfortunately, current antiepileptic drugs (AEDs) do not seem to prevent or to reverse drug resistance in most patients, but add-on therapy with novel AEDs is able to exert a modest seizure reduction in as many as 50% of patients in short-term clinical trials, and a few become seizure free during the trial. It is not known why and how epilepsy becomes drug resistant, while other patients with seemingly identical seizure types can achieve seizure control with medication. Several putative mechanisms underlying drug resistance in epilepsy have been identified in recent years. Based on experimental and clinical studies, two major neurobiologic theories have been put forward: (a) removal of AEDs from the epileptogenic tissue through excessive expression of multidrug transporters, and (b) reduced drug-target sensitivity in epileptogenic brain tissue. On the clinical side, genetic and clinical features and structural brain lesions have been associated with drug resistance in epilepsy. In this article, we review the laboratory and clinical evidence to date supporting the drug-transport and the drug-target hypotheses and provide directions for future research, to define more clearly the role of these hypotheses in the clinical spectrum of drug-resistant epilepsy.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2004

Activation of the early-late switch in adenovirus type 5 major late transcription unit expression by L4 gene products.

The adenovirus major late transcription unit (MLTU) encodes multiple proteins from five regions, L1 to L5, through differential splicing and polyadenylation. MLTU expression is temporally regulated; only a single product from L1 (52/55K) is expressed prior to replication, but a subsequent switch, the mechanism of which has not been defined, leads to full expression that encompasses L1 IIIa and all L2 to L5 products. Transfection of a plasmid containing the complete MLTU gave a full array of proteins in proportions similar to those in a late infection, and in a time course, the temporal pattern of expression in a natural infection was reproduced. However, a plasmid truncated after the L3 poly(A) site exclusively expressed the L1 52/55K protein and was defective in the switch to full gene expression from L1 to L3. The L4 33K protein, supplied in trans, was sufficient to upregulate cytoplasmic mRNA for MLTU products characteristic of the late pattern of expression to levels comparable to those produced by the full-length MLTU. There was a corresponding increase in expression of the L1 IIIa, L2, and L3 proteins, except hexon. Hexon protein expression additionally required both the L4 100K protein in trans and sequences downstream of the L3 poly(A) site in cis. These results indicate that induction of L4 protein expression is a key event in the early-late switch in MLTU expression, which we propose is precipitated by small amounts of L4 expression in a feed-forward activation mechanism.

Adenoviruses, Human↗
PubMed2005

[Artificial neural network forecasting method in monitoring technique by spectrometric oil analysis].

The spectrometric oil analysis (SOA) is an important technique for machine state monitoring and fault diagnosis, and forecasting machine state through SOA results has an advantage of finding out machine system wear fault early. Because Artificial Neural Network (ANN) possesses obvious advantages over traditional forecasting models for identifyingnon-linear model and forecasting non-even signal, the ANN forecasting approach was applied to monitoring technique by SOA, and the monitoringtechnique by SOA based on ANN forecasting was put forward. In the forecasting model, a 3-layer BP network structure was adopted.Aiming at the problem that ANN structure has a great effect on forecasting precision, the authors utilized the Genetic Algorithm (GA) to optimize the node number of input layer, the node number of hidden layer, and MSE (Mean of Squared Error) target value which was required for ANN training, and obtained the optimum forecasting model of ANN. Finally, the practical SOA data of some engine was analyzed and forecasted by ANN, and the forecasting result was compared with that of traditional ARMA model. The result fully showsthe superiority and effectivity of the new method.

Algorithms↗
PubMed2024

A review focusing on mechanisms and ecological risks of enrichment and propagation of antibiotic resistance genes and mobile genetic elements by microplastic biofilms.

Microplastics (MPs) are emerging ubiquitous pollutants in aquatic environment and have received extensive global attention. In addition to the traditional studies related to the toxicity of MPs and their carrier effects, their unique surface-induced biofilm formation also increases the ecotoxicity potential of MPs from multiple perspectives. In this review, the ecological risks of MPs biofilms were summarized and assessed in detail from several aspects, including the formation and factors affecting the development of MPs biofilms, the selective enrichment and propagation mechanisms of current pollution status of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) in MPs biofilms, the dominant bacterial communities in MPs biofilms, as well as the potential risks of ARGs and MGEs transferring from MPs biofilms to aquatic organisms. On this basis, this paper also put forward the inadequacy and prospects of the current research and revealed that the MGEs-mediated ARG propagation on MPs under actual environmental conditions and the ecological risk of the transmission of ARGs and MGEs to aquatic organisms and human beings are hot spots for future research. Relevant research from the perspective of MPs biofilm should be carried out as soon as possible to provide support for the ecological pollution prevention and control of MPs.

Biofilms↗
PubMed2000

Genetics and evolution of ultraviolet vision in vertebrates.

Various vertebrates use ultraviolet (UV) vision for such basic behaviors as mating, foraging, and predation. We have successfully interchanged the color-sensitivities of the mouse UV pigment and the human blue pigment by introducing forward and reverse mutations at five sites. This unveils for the first time the general mechanism of UV vision. Most contemporary UV pigments in vertebrates have maintained their ancestral functions by accumulating no more than one of the five specific amino acid changes. The avian lineage is an exception, where the ancestral pigment lost UV-sensitivity but some descendants regained it by one amino acid replacement at an entirely different site.

Amino Acid Sequence↗
PubMed1998

Breast cancer and genetic instability: the molecules behind the scenes.

Germline mutations in either the BRCA1 or the BRCA2 gene are responsible for the majority of hereditary breast cancers. The proposition that BRCA1 might play a role as a caretaker of the genome was first put forward by the demonstration that, in mitotic and meiotic cells, BRCA1 can interact with Rad51, which plays a major role in repair and/or recombination processes. From there, a fair body of observations have converged to support the concept that BRCA1 and BRCA2 play a role in monitoring and/or repairing DNA lesions. The relaxation of this monitoring caused by mutations of either of these two genes leaves unrepaired events, leading to the accumulation of mutations and ultimately to cancer. Understanding the precise biochemical function of BRCA1 and BRCA2 should provide a basis for early diagnosis and prevention in women carrying a predisposition to breast cancer.

Animals↗
PubMed1993

Molecular and genetic analysis of unc-7, a Caenorhabditis elegans gene required for coordinated locomotion.

Mutations in the Caenorhabditis elegans gene unc-7 confer an uncoordinated phenotype. Wild-type animals trace smooth, sinuous waves as they move; unc-7 mutants make irregular bends or kinks along their bodies, particularly when they move forward. The unc-7 locus has also been implicated in the nematode's response to volatile anesthetics. We have cloned unc-7 by transposon tagging: an unc-7 mutation was correlated with the insertion of the transposon Tc1, and reversion of the mutant phenotype was correlated with loss of the Tc1 element. We have physically mapped the region flanking the sites of Tc1 insertion and identified DNA rearrangements corresponding to eight additional unc-7 alleles. Northern analysis indicates that a 2.7-kb unc-7 message is present in all developmental stages but is most abundant in L1-L3 larvae. The 5' end of the message contains a trans-spliced leader SL1. An 18-kb intron is located upstream of the predicted translational start site of the gene, and DNA breakpoints of four gamma-ray-induced alleles were located within this intron. We determined the sequence of a cDNA corresponding to the unc-7 message. The message may encode a 60-kd protein whose amino acid sequence is unrelated to any other available protein sequence; a transmembrane location for the unc-7 protein is predicted. We predict from our analysis of unc-7 genetic mosaics that the unc-7 gene product is not required in muscle cells for wild-type coordination but is probably required in motor neurons (although a hypodermal role has not been excluded). We speculate that unc-7 may be involved in the function of neuronal ion channels.

Alleles↗
PubMed2003

Genomic characterization of MOZ/CBP and CBP/MOZ chimeras in acute myeloid leukemia suggests the involvement of a damage-repair mechanism in the origin of the t(8;16)(p11;p13).

The t(8;16)(p11;p13), which is strongly associated with acute myeloid leukemia (AML) displaying monocytic differentiation, erythrophagocytosis by the leukemic cells, and a poor response to chemotherapy, fuses the MOZ gene (8p11) with the CBP gene (16p13). Although genomic rearrangements of MOZ and CBP have been detected using fluorescence in situ hybridization and Southern blot analyses, characterization of the breakpoints at the sequence level has never been performed. We have sequenced the breakpoints in four t(8;16)-positive AML cases with the aim to identify molecular genetic mechanisms underlying the origin of this translocation. In addition, an exon/intron map of the MOZ gene was constructed, which was found to be composed of 17 exons. Long-range-PCR with CBP forward primers in exon 2 and MOZ reverse primers in exon 17 as well as with a MOZ forward primer in exon 16 and a CBP reverse primer in intron 2 successfully amplified CBP/MOZ and MOZ/CBP hybrid genomic DNA fragments in all four AMLs. The breaks clustered in both CBP intron 2 and MOZ intron 16, and were close to repetitive elements, and in one case an Alu-Alu junction for the CBP/MOZ hybrid was identified. Additional genomic events (i.e., deletions, duplications, and insertions) in the breakpoint regions in both the MOZ and CBP genes were found in all four cases. Thus, the t(8;16) does not originate through a simple end-to-end fusion. The findings of multiple breaks and rearrangements rather suggest the involvement of a damage-repair mechanism in the origin of this translocation.

Acetyltransferases↗
PubMed1997

Detecting linkage for a complex disease using simulated extended pedigrees.

The simulated extended pedigree data of the Genetic Analysis Workshop 10 were used to examine the relationship between several quantitative traits (Q1-Q5), an environmental factor, age and sex and to identify genes contributing to the quantitative traits. A forward selection procedure was used to identify regression models for each trait. Residuals from these regression models were used as quantitative traits in linkage analysis. Two-point sib-pair analysis was performed on Replicate 1 of the data set using SIBPAL. Sixteen regions on 8 chromosomes yielded two-point p-values < 0.005 in Replicate 1. Two strategies for utilizing a second data set were evaluated. In a two-stage approach, only those regions with p-value < 0.005 in Replicate 1 were followed up in the second data set. Nine of these regions had p-values < 0.05 in Replicate 2; four were associated with major genes included in the generating model and the remaining five regions were false positives. An alternative strategy was to perform a repeat genome wide screen in the second data set. This strategy resulted in the identification of 20 regions with p-values < 0.05 in both replicates; five of which included major genes included in the generating model. Although the false positive rate increased when a complete genome screen was performed on both data sets, the two-stage screen, with a more stringent initial criterion for identifying suggestive linkages, had a higher rate of false negatives. For some studies, conducting two complete genome screens in a split-sample design may be worthwhile.

Age Distribution↗
PubMed1999

[Methodology for analyzing censored correlated data: application of marginal and frailty approaches in human genetics. The European Community Alport Syndrome Concerted Action Group (ECASCA)].

BACKGROUND: Statistical analysis for correlated censored data allows to study censored events in clustered structure designs. Considering a possible correlation among failure times of the same group, standard methodology is no longer applicable. We investigated proposed models in this context to study familial data about a genetic disease, Alport syndrome. Alport syndrome is a severe hereditary disease due to abnormal collagenous chains. Renal failure is the main symptom of the disease. It progresses toward end-stage renal failure (IRT) according to a high time variability. As shown by genetic studies, mutations of COL4A5 gene are involved in the X-linked Alport Syndrome. Due to the large range of the mutation types, the aim of this study was to search for a possible genetic origin of the heterogeneity of the disease severity. METHODS: Marginal survival models and mixed effects survival models (so-called frailty models) were proposed to take into account the possible non independence of the observations. In this study, time until end-stage renal failure is a rightly censored end point. Possible intra-familial correlations due to shared environmental and/or genetic factors could induce dependence among familial failure times. In this paper, we fit marginal and frailty proportional hazards models to evaluate the effect of mutation type on the risk of IRT and an interfamilial heterogeneity of failure times. RESULTS: In this study, the use of these models allows to show the presence of an interfamilial heterogeneity of the failure times to IRT. Moreover, the results suggest that some mutation types are linked to a higher risk of fast evolution to IRT, which explains partially the interfamilial heterogeneity of the failure times. CONCLUSIONS: This paper shows the interest of marginal and frailty models to evaluate the heterogeneity of censored responses and to study relationships between a censored criterion and covariables. This study puts forward the importance of characterizing the mutation at a molecular level to understand the relationship between genotype and phenotype.

Data Interpretation, Statistical↗
PubMed2006

Can biochemical properties serve as selective pressure for gene selection during inter-species and endosymbiotic lateral gene transfer?

During the evolution of endosymbiosis, only one orthologous gene, either from the invader or the invaded genome, is preserved. Genetic and environmental factors are usually invoked to explain this gene preference. How biochemical parameters can play a role in the selection of genes that code for enzymes that constitute a metabolic pathway is explored. Simple Michaelis-Menten-like enzymes are considered whose kinetic parameters are randomly generated to construct two parallel homologous pathways to account for the contributions of the invaded and the invader. Steady-state fluxes as targets of natural selection are focused. Enzymes are eliminated one by one so that the total flux through the pathway is least disturbed. Analysis of the results, done by different criteria, indicate that the maximal velocities, both forward and backward, are more influential in selection than the respective Michaelis constants. This inclination disappears as metabolite concentrations are increased. It is shown that kinetic selection criteria can result in a mosaicism of enzymes in the same pathway in terms of their genetic origin. Analysis of the results using the control coefficient paradigm disclosed an expected robust correlation between flux control coefficients of enzymes and their selective elimination. Similar analyses, performed for the case of single gene transfer or for gene replication with subsequent mutation, yielded essentially similar results. The results conform with the phenomenon of genetic mosaicism found in phylogenetic analyses of single or double endosymbioses and lateral gene transfer.

Animals↗