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2,336,400 |
Genetic predisposition to cancer.
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Over recent decades a number of genes causing predisposition to cancer have been identified. Some of these cause rare autosomal dominant monogenic cancer predisposition syndromes. In the majority of families, the increased incidence of cancers is due to a multifactorial aetiology with a number of lower penetrance cancer predisposition genes interacting with environmental factors. Identification of those at increased risk of cancer on account of their family history is important, as genetic testing, enhanced surveillance, prophylactic surgery and chemoprophylaxis may be indicated. In this article the issues surrounding genetic predisposition to cancer are considered by examining two common cancers: colorectal and breast cancer.
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2,336,401 |
Pharmacogenetics of irinotecan: a promoter polymorphism of UGT1A1 gene and severe adverse reactions to irinotecan.
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This review focuses on a pharmacogenetic association between genetic polymorphism of UGT1A1 gene and severe adverse reactions to irinotecan. Although many studies used pharmacokinetic parameters as surrogate measures for predicting clinical outcomes of irinotecan chemotherapy, they have not produced consistent evidence. On the other hand, genotyping results of UGT1A1 gene appear to predict severe adverse reactions more straightforward than the pharmacokinetic parameters or the phenotypes of the enzymatic activity. A case-control study of Japanese cancer patients revealed that those with the variant UGT1A1 alleles were at significantly higher risk of severe adverse reactions to irinotecan, suggesting that the genotyping strategy would be clinically useful. Nevertheless, clinical importance of the pharmacogenetic testing should differ for different patient groups and for different clinical situations. We need to keep this issue in mind in applying the pharmacogenetic evidence in clinical practice.
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2,336,402 |
A genomewide screen for petite-negative yeast strains yields a new subunit of the i-AAA protease complex.
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Unlike many other organisms, the yeast Saccharomyces cerevisiae can tolerate the loss of mitochondrial DNA (mtDNA). Although a few proteins have been identified that are required for yeast cell viability without mtDNA, the mechanism of mtDNA-independent growth is not completely understood. To probe the relationship between the mitochondrial genome and cell viability, we conducted a microarray-based, genomewide screen for mitochondrial DNA-dependent yeast mutants. Among the several genes that we discovered is MGR1, which encodes a novel subunit of the i-AAA protease complex located in the mitochondrial inner membrane. mgr1Delta mutants retain some i-AAA protease activity, yet mitochondria lacking Mgr1p contain a misassembled i-AAA protease and are defective for turnover of mitochondrial inner membrane proteins. Our results highlight the importance of the i-AAA complex and proteolysis at the inner membrane in cells lacking mitochondrial DNA.
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2,336,403 |
mILD: a tool for constructing and analyzing matrices of pairwise phylogenetic character incongruence tests.
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Pairwise comparisons of disagreement in phylogenetic datasets offer a powerful tool for isolating historical incongruence for closer analysis. Statistically significant phylogenetic character incongruence may reflect important differences in evolutionary history, such as horizontal gene transfer. Such testing can also be used to specify possible combinations of datasets for further phylogenetic analysis. The process of comparing multiple datasets can be very time consuming, and it is sometimes unclear how to combine data partitions given the observed patterns of incongruence. Here we present an application that automates the process of making pairwise comparisons between large numbers of phylogenetic datasets using the Incongruence Length Difference (ILD) test. The application also implements strategies for data combination based on the patterns of incongruence observed in pairwise comparisons.
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2,336,404 |
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.
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This work describes an approach to characterize the clinical significance of genetic variants detected during the genetic testing of BRCA1 in patients from hereditary breast/ovarian cancer families. Results from transgenic mice and extensive clinical testing support the hypothesis that biallelic BRCA1 mutations result in embryonic lethality. Therefore, it is reasonable to conclude that variants of uncertain clinical significance found to reside in trans with known deleterious mutations impart reduced risk for cancer. This approach was applied to a large data set of 55,630 patients who underwent clinical BRCA1 screening by whole gene direct DNA sequencing. Fourteen common single nucleotide polymorphisms (SNPs) were used to assign 10 previously defined common, recurrent, or canonical haplotypes in 99% of these cases. From a total of 1,477 genetic variants detected in these patients, excluding haplotype-tagging SNPs, 877 (59%) could be unambiguously assigned to one or more haplotypes. In 41 instances, variants previously classified as being of uncertain clinical significance, mostly missense variants, were excluded as fully penetrant mutations due to their coincidence in trans with known deleterious mutations. From a total of 1,150 patients that harbored these 41 variants, 956 carried one as the sole variant of uncertain clinical significance reported. This approach could have widespread application to other disease genes where compound heterozygous mutations are incompatible with life or result in obvious phenotypes. This largely computational technique is advantageous because it relies upon existing clinical data and is likely to prove informative for prevalent genetic variants in large data sets.
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2,336,405 |
Attack behaviors in mice: from factorial structure to quantitative trait loci mapping.
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The emergence or non-emergence of attack behavior results from interaction between the genotype and the conditions under which the mice are tested. Inbred mice of the same strain reared or housed under conditions do not react the same way; reactions also vary according to the place selected for testing and the different opponents. A factor analysis showed that the attack behavior in non-isolated males, tested in neutral area covaried with high testosterone and steroid sulfatase and low brain 5-hydroxytriptamine (5-HT), beta-endorphin and Adrenocorticotropic Hormone (ACTH) concentration, whereas, for isolated males tested in their own housing cage, it covaried with high testosterone activity and low brain 5-HT concentration. A wide genome scan was performed with two independent populations derived from C57BL/6J and NZB/BlNJ, each being reared, housed and tested under highly contrasting conditions, as described above, and confronted with A/J standard males. Common Quantitative Trait Loci emerged for two rearing/testing conditions. For rattling latency we detected Quantitative Trait Loci on Mus musculus chromosome 8 (MMU8) (at 44, LOD score=3.51 and 47 cM, LOD score=6.22, for the first and the second conditions) and on MMU12 (at 39 cM, LOD score=3.69 and at 41 cM, LOD score=2.99, respectively). For the number of attacks, Quantitative Trait Loci were common: on MMU11 at 39 cM LOD score=4.51 and 45 cM, LOD score=3.05, respectively, and on MMU12 (17 cM, LOD score=2.71 and 24 cM, LOD score=3.10). The steroid sulfatase gene (Sts), located on the X-Y pairing region, was linked, but only in non-isolated males, tested in neutral area for rattling latency, first attack latency, and number of attacks (LOD scores=4.9, 4.79 and 3.57, respectively). We found also that the Quantitative Trait Locus encompassing Sts region interacted with other Quantitative Trait Loci. These results indicate that attack behavior measured in different rearing and testing conditions have different biological and genetic correlates. This suggests that further explorations should be done with standardized tests and, in addition, with a wide range of tests, so as to gain an understanding of the true impact of genes or pharmacological treatments on specific categories of aggressive behavior.
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2,336,406 |
Proposed methods for testing and selecting the ERCC external RNA controls.
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The External RNA Control Consortium (ERCC) is an ad-hoc group with approximately 70 members from private, public, and academic organizations. The group is developing a set of external RNA control transcripts that can be used to assess technical performance in gene expression assays. The ERCC is now initiating the Testing Phase of the project, during which candidate external RNA controls will be evaluated in both microarray and QRT-PCR gene expression platforms. This document describes the proposed experiments and informatics process that will be followed to test and qualify individual controls. The ERCC is distributing this description of the proposed testing process in an effort to gain consensus and to encourage feedback from the scientific community. On October 4-5, 2005, the ERCC met to further review the document, clarify ambiguities, and plan next steps. A summary of this meeting and changes to the test plan are provided as an appendix to this manuscript.
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2,336,407 |
Multiple testing in the context of haplotype analysis revisited: application to case-control data.
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We have lately presented a testing procedure for family data which accounts for the multiple testing problem that is induced by the enormous number of different marker combinations that can be analyzed in a set of tightly linked markers. Most methods of haplotype based association analysis already require simulations to obtain an uncorrected P value for a specific marker combination. As shown before, it is nevertheless not necessary to carry out nested simulations to obtain a global P value that properly corrects for the multiple testing of different marker combinations without neglecting the dependency of the tests. We have now implemented this approach for case-control data in our program FAMHAP, as this data structure currently plays a dominant role in the field. We consider different ways to deal with phase ambiguities and two different statistical tests for the underlying single marker combinations to obtain uncorrected P values. One test statistic is chi-square based, the other is a haplotype trend regression. The performance of these different tests in the multiple testing situation is investigated in a large simulation study. We obtain a considerable gain in power with our global P values as opposed to Bonferroni corrected P values for all suggested test statistics. Good power was obtained both with the haplotype trend regression approach as well as with the simpler chi-square based test. Furthermore, we conclude that the better strategy to deal with phase ambiguities is to assign to each individual its list of weighted haplotype explanations, rather than to assign to each individual its most likely haplotype explanation. Finally, we demonstrate the usefulness of our approach by a real data example.
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2,336,408 |
Tests of association between quantitative traits and haplotypes in a reduced-dimensional space.
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Candidate gene association tests are currently performed using several intragenic SNPs simultaneously, by testing SNP haplotype or genotype effects in multifactorial diseases or traits. The number of haplotypes drastically increases with an increase in the number of typed SNPs. As a result, large numbers of haplotypes will introduce large degrees of freedom in haplotype-based tests, and thus limit the power of the tests. In this study we propose using the principal component method to reduce the dimension, and then construct association tests on the lower-dimensional space to test the association between haplotypes and a quantitative trait using population-based samples. The proposed method allows ambiguous haplotypes. We use simulation studies to evaluate the type I error rate of the tests, and compare the power of the proposed tests with that of the tests without dimension reduction, and the tests with dimension reduction by merging rare haplotypes. The simulation results show that the proposed tests have correct type I error rates and are more powerful than other tests in most cases considered in our simulation studies.
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2,336,409 |
Clinical and ethical implications of genetic counselling in familial adenomatous polyposis.
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The association of specific genetic disturbances with the development of hereditary cancer helps us to understand the risk of suffering from it, the possibility of an earlier diagnosis, and the treatment and prevention of this disease. Familial adenomatous polyposis (FAP) is a pre-neoplastic syndrome characterized by the presence of hundreds of adenomatous polyps in the colon, which develop into a carcinoma. FAP can be diagnosed using sequencing techniques to detect mutations in the germinal line of the APC (adenomatous polyposis coli) gene. The genetic diagnostic approach in families with FAP, previously followed up in the Gastrointestinal Clinic, has both advantages and disadvantages, and places us nearer the disease and patient. Disclosing the results of this genetic test entails relevant problems in clinical practice, which affect the health field and raise legal and ethical issues, along with the familial, occupational, and social implications that knowing the genetic status can have on the patient. Genetic analysis is rare in normal clinical practice, which involves errors in the interpretation of the results obtained, and during the process of genetic counselling. Specialized multidisciplinary units are necessary for the management of patients with FAP undergoing analysis and appropriate genetic counselling, thus providing an individualized service. The creation of FAP registers and protocols for this healthcare process should optimize the management of these patients and their families.
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2,336,410 |
Applying theological developments to bioethical issues such as genetic screening.
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Catholic movements within the centre of Roman Catholic doctrine recently have discussed Trinitarian theology as applied to sciences, arts, economics, health and other social areas. We explore the possibilities Trinitarian theology offers to bioethical debate, concentrating particularly on genetic screening and testing. It is important therefore to analyse the philosophical implications of this approach onto the bioethical world, where much disagreement occurs on fundamental issues. It is Catholic basic teaching to recognize and see God's hand in plurality, not merely as a cliche and then doing what we feel is right, but to recognize how to live in a pluralistic world. We recognize, in agreement with these theologians, that in order for a Trinitarian mode of understanding to be used by those doing bioethical debate, there is a need to depart from fundamentalism.
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2,336,411 |
Characterization of newly established oral cancer cell lines derived from six squamous cell carcinoma and two mucoepidermoid carcinoma cells.
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Since genetic abnormalities of human cancer are greatly geographically dependent, cultural and environmental backgrounds are thought to be closely related to the carcinogenic process. In the present study, eight human cell lines were established by culture from untreated carcinomas of the oral cancer, of which five were from primary oral squamous cell carcinomas (OSC), one from a mucoepidermoid carcinoma (MEC) and one each originating from metastatic OSC and MEC. All the studied tumor lines grew as monolayers, and showed: i) an epithelial origin by the presence of cytokeratin, and ii) tumorigenic potential in nude mice. Western blot analysis revealed i) over expression of EGFR in six of the cell lines ii) decreased expression of E-cadherin in six cell lines compared to normal human oral mucosa. A mutational analysis showed: point mutations of p53 at exon 7, with transversion, and at exon 8, with transition. These well-characterized human YD cell lines should serve as useful tools in the study of the molecular pathogenesis and biological characteristics of head and neck cancer cells, and in the future testing of new therapeutic reagents for oral cancer.
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2,336,412 |
Transmission of hepatitis C virus to several organ and tissue recipients from an antibody-negative donor.
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Although hepatitis C virus (HCV) transmission through tissue transplantation has been rarely reported, a donor with undetected viremia may infect several recipients. A patient developed acute hepatitis C shortly after tissue transplantation. Ninety-one tissues or organs had been recovered from the donor.</AbstractText>To determine whether the donor was the source of infection and the extent of transmission to other organ and tissue recipients.</AbstractText>Descriptive epidemiologic study; serum testing for HCV infection.</AbstractText>Recipients were located in 16 states and 2 other countries.</AbstractText>Donor and graft recipients.</AbstractText>Hepatitis C virus infection was defined as the presence of anti-HCV or HCV RNA. The authors determined the genetic relatedness of viral isolates from the donor and recipients by genotype comparison and quasi-species analysis.</AbstractText>The donor was anti-HCV-negative but was HCV RNA-positive (genotype 1a). Forty persons received transplants during 22 months. Five persons were HCV-infected before transplantation or had a genotype other than 1a, and 5 persons had no post-transplantation serum specimens available. Of the remaining 30 recipients, HCV infection occurred in 8 recipients: 3 of 3 organ recipients, 1 of 2 saphenous vein recipients, 1 of 3 tendon recipients, and 3 of 3 tendon with bone recipients. These 8 recipients had viral isolates genetically related to those of the donor. No cases occurred in recipients of skin (n = 2), cornea (n = 1), or irradiated bone (n = 16).</AbstractText>Post-transplantation serum specimens were unavailable for 5 recipients.</AbstractText>An anti-HCV-negative donor was the source of HCV infection for 8 recipients of organs or tissues. Although HCV transmission from anti-HCV-negative donors is probably uncommon, changes in donor screening to include routine testing for HCV RNA merit further consideration to improve the safety of transplantation.</AbstractText>
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2,336,413 |
Variant translocation with a deletion of derivative (9q) in a case of Philadelphia chromosome positive (Ph +) essential thrombocythemia (ET), a variant of chronic myelogenous leukemia (CML) with a poor prognosis.
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Patients presenting with thrombocytosis require thorough clinical and laboratory evaluation to determine whether they suffer from essential thrombocythemia or another myeloproliferative disorder. This distinction becomes increasingly relevant as targeted agents become available to treat specific myeloproliferative diseases. Cytogenetic testing plays a major role in this analysis. This study presents a patient with Philadelphia chromosome positive (Ph + ) thrombocytosis and a cryptic der(9q)t(5;9)t(9;22) not found by conventional cytogenetics, whose disease progressed within 2 years to typical myeloblastic crisis of CML. It discusses the entity of Ph + ET, the utility of molecular cytogenetic testing in the diagnosis of this unusual disease entity and the importance of cytogenetic testing in the prognosis of ET.
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2,336,414 |
A rapid, physiologic protocol for testing transcriptional effects of thyroid-disrupting agents in premetamorphic Xenopus tadpoles.
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Increasing numbers of substances present in the environment are postulated to have endocrine-disrupting effects on vertebrate populations. However, data on disruption of thyroid signaling are fragmentary, particularly at the molecular level. Thyroid hormone (TH; triiodothyronine, T3) acts principally by modulating transcription from target genes; thus, thyroid signaling is particularly amenable to analysis with a transcriptional assay. Also, T3 orchestrates amphibian metamorphosis, thereby providing an exceptional model for identifying thyroid-disrupting chemicals. We combined these two advantages to develop a method for following and quantifying the transcriptional action of T3 in Xenopus laevis tadpoles. This technology provides a means of assessing thyroid activity at the molecular level in a physiologically relevant situation. Moreover, translucent tadpoles are amenable to "on-line" imaging with fluorescent reporter constructs that facilitate in vivo measurement of transcriptional activity. We adapted transgenesis with TH-responsive elements coupled to either luciferase or green fluorescent protein to follow T3-dependent transcription in vivo. To reduce time of exposure and to synchronize responses, we optimized a physiologic pretreatment protocol that induced competence to respond to T3 and thus to assess T3 effects and T3 disruption within 48 hr. This pretreatment protocol was based on a short (24 hr), weak (10(-12) M) pulse of T3 that induced TH receptors, facilitating and synchronizing the transcriptional responses. This protocol was successfully applied to somatic and germinal transgenesis with both reporter systems. Finally, we show that the transcriptional assay allows detection of the thyroid-disrupting activity of environmentally relevant concentrations (10(-8) M) of acetochlor, a persistent herbicide.
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2,336,415 |
Testing assumptions for endophenotype studies in ADHD: reliability and validity of tasks in a general population sample.
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Advances in both genetic and cognitive-experimental studies on attention deficit hyperactivity disorder (ADHD) have opened new opportunities for cognitive endophenotype research. In such genetic designs the focus is on individual differences in characteristics, associated with ADHD, that can be measured reliably over time. Genetic studies that take a 'quantitative trait loci' approach hypothesise that multiple susceptibility genes contribute to a continuous dimension of ADHD symptoms. As an important initial step, we aimed to investigate the underlying assumptions that (1) key cognitive-experimental tasks indicate adequate test-retest reliability and (2) ADHD symptom scores in a general population sample are associated with performance on these tasks.</AbstractText>Forty-nine children were assessed on a go/no-go task and a reaction time task (the 'fast task') that included manipulations with event rate and incentives. The children were assessed twice, with a test-retest interval of two weeks.</AbstractText>The majority of the task variables demonstrated moderate-to-good test-retest reliability. The correlations between teacher ratings of ADHD symptoms and key task variables were .4-.6: ADHD symptoms were associated with poor performance (especially high reaction time variability) in a slow baseline condition, whereas there was low or no association in conditions with a faster event rate or incentives. In contrast, no clear pattern of findings emerged based on parent ratings of ADHD symptoms.</AbstractText>The data support the usefulness of the go/no-go and fast tasks for genetic studies, which require reliable and valid indices of individual differences. The overall pattern of associations between teacher ratings of ADHD symptoms and task variables is consistent with effects of event rate and incentives on performance, as predicted by the model of activation and arousal regulation. The lack of a clear pattern of findings with parent ratings of ADHD symptoms warrants further study.</AbstractText>
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2,336,416 |
Resistance to abomasal nematodes and individual genetic variability in reindeer.
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Resistance to parasites is believed to have a widespread influence on demographic and adaptive processes. In systems where parasites impose a fitness cost on their host, heterozygotes may be selected because they are more resistant to parasites than homozygotes. Our objective was to assess the relationships between genomewide individual heterozygosity and abomasal nematode burdens in female Svalbard reindeer (Rangifer tarandus platyrhynchus) after the effects of host age, locality, season, and year had been accounted for. Samples were obtained from 306 female reindeer that were culled and genotyped at nine microsatellite loci. Reindeer in our study populations are mainly parasitized by the gastrointestinal nematodes Ostertagia gruehneri and Marshallagia marshalli. The infection intensity of each parasite differed between subpopulations, and among host age classes, seasons and years. We found no significant relationships between abomasal worm burdens, or lumen and mucosa larvae, of either O. gruehneri or M. marshalli and individual heterozygosity (or mean d(2)) alone or in interactions with host age, locality, and year. Although we analysed one of the largest data set available to date on gastrointestinal nematodes of a wild ruminant, we used a typical data set of nine genetic neutral markers that may have had low power to detect heterozygosity-fitness correlations. We conclude that the proportion of the variance in parasite resistance explained by individual heterozygosity for neutral genetic markers is low in Svalbard reindeer and in vertebrates in general, and we suggest that the candidate-gene approach might be more fruitful for further research on gene-fitness correlations.
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2,336,417 |
Intermediate phenotypes in schizophrenia: a selective review.
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Studies aiming to identify susceptibility genes for schizophrenia and other complex psychiatric disorders are faced with the confounds of subjective clinical criteria, commonly occurring phenocopies, significant between-subject variability of candidate traits, and the likelihood of allelic and locus heterogeneity that has been shown to define the genetics of other complex human brain and somatic disorders. Additionally, research aimed at identification of the molecular origins of schizophrenia must also deal with the confounding nature of the human brain. Unlike organs with a few common cellular phenotypes, transcriptomes, and proteomes, individual neurons are often distinct from one another in all of these respects. In this review, we present recent work testing the assumption that studies of genetic susceptibility in complex polygenic disorders such as schizophrenia might be enhanced by the identification of intermediate phenotypes related to more fundamental aspects of brain development and function. Progress in the identification of meaningful intermediate phenotypes in schizophrenia has been made possible by the advent of newer methods in cognitive neuroscience and neuroimaging, and the use of combined multimodal techniques.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Preston</LastName><ForeName>Gilbert A</ForeName><Initials>GA</Initials><AffiliationInfo><Affiliation>Genes, Cognition and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Room 4s235, MSC 1379, 9000 Rockville Pike, Bethesda, MD 20892-1379, USA. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Weinberger</LastName><ForeName>Daniel R</ForeName><Initials>DR</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Dialogues Clin Neurosci</MedlineTA><NlmUniqueID>101238198</NlmUniqueID><ISSNLinking>1294-8322</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D001921" MajorTopicYN="N">Brain</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName><QualifierName UI="Q000503" MajorTopicYN="N">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020022" MajorTopicYN="Y">Genetic Predisposition to Disease</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010641" MajorTopicYN="Y">Phenotype</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012559" MajorTopicYN="N">Schizophrenia</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading></MeshHeadingList><OtherAbstract Type="Publisher" Language="spa">Los estudios orientados a identificar la susceptibilidad genética a la esquizofrenia y otros trastornos psiquiátricos complejos se enfrentan con diferentes factores de confusión tales como los criterios clínicos subjetivos, las fenocopias que se dan comúnmente, la significativa variabilidad entre los sujetos de los rasgos candidatos y la probabilidad de heterogeneidad alélica y de locus que se ha tomado como evidencia para definir la genética de otros complejos trastornos cerebrales y somáticos humanos. Además, la investigación orientada a la identificación de los orígenes moleculares de la esquizofrenia también debe abordar la confusa naturaleza del cerebro humano. A diferencia de órganos con algunos fenotipos celulares, transcriptomas y proteomas comunes, las neuronas individuales a menudo son distintas unas de otras en todos estos aspectos. En esta revisión se presentan trabajos recientes que afirman tentativamente que los estudios de susceptibilidad genética en trastornos poligénicos complejos como la esquizofrenia debieran ser mejorados mediante la identificación de fenotipos intermediarios relacionados con aspectos más fundamentales del desarrollo y función del cerebro. El progreso en la identificación de fenotipos intermediarios significativos para la esquizofrenia ha sido posible gracias al avance de metodologías recientes en neurociencias cognitivas y neuroimágenes, y mediante el empleo de técnicas multimodales combinadas.</OtherAbstract><OtherAbstract Type="Publisher" Language="fre">Les études qui ont pour but d'identifier les gènes de susceptibilité à la schizophrénie et aux autres troubles psychiatriques complexes sont confrontées aux facteurs de confusion que sont les critères subjectifs cliniques, les fréquentes phénocopies, la variabilité significative intra-sujets des caractères étudiés, et la probabilité de l'hétérogénéité des locus et des allèles dont on sait qu'elle définit la génétique d'autres troubles somatiques et cérébraux complexes chez l'homme. De plus, la recherche consacrée à l'identification des origines moléculaires de la schizophrénie doit aussi composer avec la nature déconcertante du cerveau humain. Contrairement aux organes pourvus de peu de phénotypes cellulaires courants, les transcriptomes et les protéomes, les neurones individuels sont souvent distincts les uns des autres à tous égards. Dans cet article, nous présentons un travail récent qui évalue l'hypothèse selon laquelle les études de susceptibilité génétique dans les troubles complexes polygéniques comme la schizophrénie, pourraient, être améliorées par l'identification des phénotypes intermédiaires liés à des aspects plus fondamentaux de la fonction et du développement du cerveau, L'avènement, de nouvelles méthodes en neurosciences cognitives et en neuro-imagerie ainsi que l'utilisation de techniques multimodales combinées, ont permis de progresser dans l'identification de phénotypes intermédiaires significatifs dans la schizophrénie.
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2,336,418 |
The role of genetic factors in maintaining health.
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This article reviews the essential background information nurses need to help them understand how genetics influences health and ill-health. The typical human genetic make-up is described, along with an explanation of how changes to this can result in disease. The author also describes the characteristics of different patterns of inheritance.
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2,336,419 |
A new method for identifying informative genetic markers in selectively bred rats.
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Microsatellite length polymorphisms are useful for the mapping of heritable traits in rats. Over 4000 such microsatellites have been characterized for 48 inbred rat strains and used successfully to map phenotypes that differ between strains. At present, however, it is difficult to use this microsatellite database for mapping phenotypes in selectively bred rats of unknown genotype derived from outbred populations because it is not immediately obvious which markers might differ between strains and be informative. We predicted that markers represented by many alleles among the known inbred rat strains would also be most likely to differ between selectively bred strains derived from outbred populations. Here we describe the development and successful application of a new genotyping tool (HUMMER) that assigns "heterozygosity" (Het) and "uncertainty" (Unc) scores to each microsatellite marker that corresponds to its degree of heterozygosity among the 48 genotyped inbred strains. We tested the efficiency of HUMMER on two rat strains that were selectively bred from an outbred Sprague-Dawley stock for either high or low activity in the forced swim test (SwHi rats and SwLo rats, respectively). We found that the markers with high Het and Unc scores allowed the efficient selection of markers that differed between SwHi and SwLo rats, while markers with low Het and Unc scores typically identified markers that did not differ between strains. Thus, picking markers based on Het and Unc scores is a valuable method for identifying informative microsatellite markers in selectively bred rodent strains derived from outbred populations.
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2,336,420 |
Periconceptional clinics: a medical health care infrastructure of new genetics.
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The necessary paradigm shift of medical prevention and health promotion from general prevention to specific genetic-oriented prevention require two crucial points: the selection of the optimal time for the primary prevention of birth defects and predictive genetic testing and the establishment of the appropriate healthcare infrastructure. The optimal time for the primary prevention of birth defects (e.g. neural-tube defects) and predictive genetic testing is the preconceptional period, i.e. the preparatory time for the planned conception, particularly before the first pregnancy, and the most acceptable time for the concrete diagnosis of the expected serious genetic diseases is the early postconceptional period. Theoretically, preimplantation genetic diagnosis is the optimal option for offspring of couples at high risk including autosomal and X-linked recessive, dominant disorders and chromosomal aberrations. The pre- and early postconceptional health can be addressed jointly in a new type of the health care infrastructure entitled periconceptional clinic. Periconceptional clinics seem to be appropriate for the starting point for the primary prevention of common complex diseases as well.
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2,336,421 |
Expression of vascular endothelial growth factor (VEGF) and its receptors in thyroid carcinomas of follicular origin: a potential autocrine loop.
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The aim of this study was to clarify the role of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) pathways in thyroid tumourigenesis.</AbstractText>We examined VEGF, VEGFR-1 and VEGFR-2 expression on 34 papillary thyroid carcinomas (PTCs), 18 follicular thyroid carcinomas (FTCs), eight poorly differentiated thyroid carcinomas (PDTCs) and on a thyroid tumour-derived cell line (NPA'87) by immunohistochemistry, reverse transcriptase PCR, immunofluorescence and Western blotting.</AbstractText>We have demonstrated that VEGF expression was significantly (P < 0.05) more prevalent in PTCs (79%) than in FTCs (50%) or PDTCs (37%). Similarly, 76% of PTCs, 83% of FTCs and 25% of PDTCs expressed VEGFR-1, whereas 68% of PTCs, 56% of FTCs and 37% of PDTCs expressed VEGFR-2. Coexpression of VEGF and its receptors was observed in 50% of PTCs, 39% of FTCs and 12% of PDTCs, raising the possibility that VEGF may signal in an autocrine loop in these neoplasias, as observed previously for other types of cancer. In agreement with the idea that autocrine VEGF signalling plays an important role in thyroid carcinogenesis, the blockade of either VEGF or its receptors with neutralizing antibodies significantly reduced cell viability and increased apoptosis levels of the VEGFR-positive thyroid tumour cell line NPA'87.</AbstractText>Our results highlight a previously undefined VEGF autocrine action in thyroid carcinomas which could play a crucial role in tumour cell survival and could represent a useful therapeutic target for thyroid tumours.</AbstractText>
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2,336,422 |
Interest of adolescents in genetic testing for nicotine addiction susceptibility.
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Genetic tests for nicotine addiction susceptibility may someday offer preventive medicine specialists new tools to reduce smoking among adolescents. This paper examines adolescents' interest in, and reasons behind interest in, such testing and correlates of interest.</AbstractText>The sample included 211 healthy patients (ages 13-21) recruited from Georgetown University Medical Center's adolescent medicine clinic. Subjects completed a one-time behavioral survey immediately prior to or following a general medical check-up during calendar years 2001-2005. A 4-point self-report survey item served as the dependent variable.</AbstractText>Sixty-two percent of adolescents were interested in genetic testing. Among the 72% of adolescents who provided a reason for their interest, 35% would find the information interesting for general or nonspecific reasons, 30% would find it personally useful, 8% noted it would be irrelevant, and 13% stated it would be unimportant; school performance and interest in cancer susceptibility testing were associated with interest in nicotine addiction susceptibility testing (adjusted r2 = 21%; P < 0.0001).</AbstractText>Adolescent primary care patients will likely be receptive to comprehensive tobacco control programs incorporating genetic testing. Higher levels of educational achievement and greater interest in DNA-based preventive medicine may characterize those most interested. Offering testing will be contingent upon the development of safe and effective genetic tests.</AbstractText>
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2,336,423 |
[Genetic polymorphism analysis of 6 STR loci on the X chromosome in Xi'an Han population].
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To investigate the alleles and genotypes frequency of 6 short tandem repeat (STR) loci (DXS8378, DXS7132, DXS6789, DXS101, HPRTB and DXS7423) on the X chromosome in Han population.</AbstractText>The six X-chromosome STR loci were analyzed by PCR following polyacylamide gel electrophoresis and silver stain.</AbstractText>Among 120 females from Xi'an Han population, the number of alleles in the 6 loci (DXS8378, DXS7132, DXS6789, DXS101, HPRTB and DXS7423) were 5, 6, 11, 10, 8, and 4 respectively; the number of genotypes in the 6 loci were 10, 17, 29, 32, 22, and 7 respectively; Exact tests demonstrated genotype frequencies in females had no departure from Hardy-Weinberg equilibrium.</AbstractText>The six X-chromosome STR loci are appropriate for individual identification, paternity testing involving a female child and for study on related disease.</AbstractText>
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2,336,424 |
Fetal therapy and cytogenetic testing: prenatal detection of chromosome aberration during thoracocentesis for congenital chylothorax by karyotyping from pleural effusion fluid and review of the literature.
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This report serves to emphasize the necessity of rapid cytogenetic testing during fetal therapy for congenital hydrothorax and to review the literature. A 31-year-old primigravid woman was noted to have bilateral fetal hydrothorax, polyhydramnios, and preterm labor at 32 weeks' gestation. Echo-guided thoracocentesis was performed to draw 50 ml of golden/yellow pleural effusion fluid and 500 ml of amniotic fluid. Cytogenetic analysis of the lymphocytes obtained from the pleural effusion fluid revealed a karyotype of 47, XY, + 21. The pleural effusion fluid was predominantly lymphocytic and positive for the Rivalta test. A sonographic examination at 33 weeks' gestation revealed recurrent pleural effusion, but the woman refused repeat thoracocentesis and tocolytic management. A 2,568-g male baby with characteristic phenotypic findings of Down syndrome was delivered vaginally and expired after birth. The present case reinforces the notions that fetuses with congenital chylothorax are at risk for chromosomal abnormalities, and drainage of pleural effusion must include a rapid diagnosis of fetal karyotype. The cytogenetic information acquired is useful for genetic counseling and perinatal obstetric management.
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2,336,425 |
Incidence of the del35G/GJB2 mutation in Croatian newborns with hearing impairment.
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The de135G mutation in the GJB2 gene is the most common cause of prelingual deafness. The mutation frequency has so far been estimated either by testing symptomatic children or adults, or by carrier testing of the general population. The purpose of our study was to establish the incidence of the del35G/GJB2 mutation in newborns with hearing impairment--in congenital deafness.</AbstractText><AbstractText Label="MATERIAL/METHODS" NlmCategory="METHODS">Patients were identified through a neonatal screening program (performed on a regular basis in Croatia since 2002). Otoacoustic emission testing was performed on 3275 newborns, and allele-specific PCR was performed on newborns diagnosed with hearing impairment.</AbstractText>Hearing impairment was found in 9 newborns, the frequency of congenital hearing impairment being 1/363; the del35G mutation was found in 3 of these 9 newborns. The established incidence of the mutation in the studied population of Croatian newborns with hearing impairment is 1/1091 (95CI: 1/372-1/3205).</AbstractText>This particular approach to patient identification, based on exact clinical examination supplemented with molecular testing, allowed for complete diagnosis and precise estimation of the incidence of the mutation in cases of congenital deafness, which proved to be higher than previously reported in prelingual deafness. This finding has important implications in clinical evaluation and genetic counseling of patients and their families.</AbstractText>
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2,336,426 |
Mass spectrometry-based loss of heterozygosity analysis of single-nucleotide polymorphism loci in paraffin embedded tumors using the MassEXTEND assay: single-nucleotide polymorphism loss of heterozygosity analysis of the protein tyrosine phosphatase receptor type J in familial colorectal cancer.
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As the number of identified single-nucleotide polymorphisms (SNPs) increases, high-throughput methods are required to characterize the informative loci in large patient series. We investigated the feasibility of MassEXTEND LOH analysis using Sequenom's MassArray RT software, a mass spectrometry method, as an alternative to determine loss of heterozygosity (LOH). For this purpose, we studied the c.827A>C SNP (1176A>C p.Gln276Pro) in protein tyrosine phosphatase receptor type-J (PTPRJ), which is frequently deleted in human cancers. In sporadic colorectal cancer (CRC), c.827A>C showed allele-specific LOH of the c.827A allele, which is important because LOH of PTPRJ may be an early event during sporadic CRC. To elucidate the impact of this low-penetrance gene on familial CRC, we studied c.827A>C in 222 familial CRC cases and 156 controls. In 6.2% of the A/C genotyped CRC samples, LOH of c.827A was observed with MassEXTEND LOH analysis and confirmed by conventional sequencing. Furthermore, a case with LOH of c.827A showed no LOH in 22 synchronously detected adenomas, including one with malignant transformation. The importance of the PTPRJ- c.827A>C SNP appears to be limited in familial CRC. We conclude that MassEXTEND LOH analysis (using Sequenom's MassARRAY RT software) is a sensitive, high-throughput, and cost-effective method to screen SNP loci for LOH in formalin-fixed paraffin-embedded tissue.
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2,336,427 |
Simultaneous genotyping of DRB1/3/4/5 loci by oligonucleotide microarray.
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Matching of the HLA antigens for donor-recipient in transplantation, disease predisposition or protection, population studies, and forensic testing requires accurate but simple typing methods. Here, we describe a DNA-based tissue-typing assay that determines the haplotype of the DRB1/3/4/5 loci in hy-bridization of oligonucleotide array after sample amplification. Using this multianalyte DNA hybridization system, we analyzed seven regions of exon 2 of DRB loci that have single-base discrimination. Thirty-six oligonucleotide probes complementary to the alleles of interest were immobilized on each microslide. The efficiency and specificity of identifying DRB genotypes using the oligonucleotide arrays was evaluated by blinded analysis of 147 samples from reference standards and subjects. The established method provides a rapid and inexpensive DRB "low-resolution" typing tool for prescreening a large number of samples.
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2,336,428 |
[Expression and activity determination of TNFR domain of osteoprotegerin in E.coli and corresponding antibody preparation].
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Osteoprotegerin (OPG) plays an important role in the regulation of bone resorption and remodeling. The TNFR domain of OPG, which is involved in the inhibition of formation and activity of osteoclasts, was amplified by PCR and inserted into multiple cloning site of PET-28a. The recombinant plasmid was transferred into E.coli BL21 to express recombinant protein. It was found that expressed product existed in the form of inclusion body. The inclusion body was solubilized, renatured and purified by affinity chromatography. Polyclonal antibodies with high specificity were obtained from the serum of rabbit immunized with purified recombinant protein. Mice were used to determine the hypocalcemic effect of the recombinant protein. Results showed that the recombinant protein expressed in E.coli had the proper bioactivity.
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2,336,429 |
Development of an interactive computer-assisted instruction (ICAI) program for patient prenatal genetic screening and carrier testing for use in clinical settings.
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Educating patients on prenatal genetic screening and carrier testing in a timely and effective manner is faced with barriers including, providers' limited knowledge, and little time available to spend discussing screening and testing during a visit. This paper describes the use of cognitive response interviews (CRI) and usability testing (UT) in the development of an interactive computer assisted instruction (ICAI) program for use by prenatal patients in clinical settings. Lessons learned during the program development process included simplification of content and adaptation of navigational features in response to observations and interviews of a sample of patients representing the intended population. The resulting program functions as a targeted patient education program that maintains the level of medical information needed, as specified by professional practices guidelines, in a patient friendly format. In addition, this ICAI program functions as a research tool that can collect data on program effectiveness. Researchers developing other patient education programs will benefit from the lessons learned during development of this ICAI program by considering rephrasing of content to fit patient understanding, and adding navigational features to help further facilitate effective program use.
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2,336,430 |
Development of real-time diagnostic assays specific for Mycoplasma mycoides subspecies mycoides Small Colony.
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Rapid and specific detection of Mycoplasma mycoides subsp. mycoides Small Colony (M. mycoides SC) is important for the effective control of contagious bovine pleuropneumonia. Although the United States has been free of this disease for over 100 years, it is necessary to develop modern diagnostic assays that are sensitive and specific for biological agents that would affect the US agricultural industry following accidental or intentional introduction into the US agricultural population. With this aim in mind, we have identified M. mycoides SC-specific genetic loci and developed TaqMan-based PCR assays for the detection of M. mycoides SC. The TaqMan assay allows for real-time detection of specific, amplified PCR products using portable equipment, enabling testing to be performed in the field. These assays are specific for M. mycoides SC, failing to amplify DNA from other organisms belonging to the M. mycoides cluster or two phylogenetically unrelated bovine mycoplasma species. Standard curves were drawn based on the linear relationships measured between the threshold fluorescence (C(T)) values and a measured quantity of genomic DNA. M. mycoides SC was successfully detected in bronchoalveolar lavage samples obtained from experimentally infected cattle. These TaqMan-based real-time PCR assays will allow for the rapid and specific detection of M. mycoides SC.
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2,336,431 |
Analysis of the PINK1 gene in a cohort of patients with sporadic early-onset parkinsonism in Taiwan.
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Mutations in the PINK1 gene have been shown to cause autosomal recessive Parkinson's disease (PD) and/or early onset sporadic PD in Italy, Spain, North America, Ireland, and Asia. However, there are limited data on PINK1 mutations in sporadic early onset Asian PD patients. To determine the prevalence of PINK1 mutation in Taiwanese population, we conducted genetic analysis of PINK1 mutation in 73 early onset sporadic PD and 94 normal control subjects. We only identified a novel single heterozygous mutation R 407Q mutation in exon 6 of this gene in one patient at the age onset of 54. Overall, these data indicate that PINK1 mutations are rare in our population. Based on our results, unless common mutational hotspots are identified, routine testing for this mutation at least in our population may not be cost-effective.
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2,336,432 |
Mlh1-dependent suppression of specific mutations induced in vivo by the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP).
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Disruption of the DNA mismatch repair (MMR) pathway results in elevated mutation rates, inappropriate survival of cells bearing DNA damage, and increased cancer risk. Relatively little is known about the potential impact of environmentally relevant carcinogens on cancer risk in individuals with MMR-deficiency. We determined the effect of MMR status (Mlh1+/+ versus Mlh1-/-) on mutagenesis induced by the cooked-meat mutagen, 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) within cII and supFG1 transgene reporters. Despite being a lymphomagen in mice, PhIP was not mutagenic in thymus. In colon, PhIP exposure induced 3-fold more mutations in Mlh1-deficient mice compared to their Mlh1+/+ littermates. Similar induction was seen in Mlh1-/- small intestine. Analysis of mutational spectra revealed that G/C to T/A transversions, the "signature PhIP mutation", were induced to similar levels regardless of Mlh1 status. In contrast, Mlh1-/- mice exhibited hypermutability to frameshifts, G/C to A/T transitions, and G/C to C/G transversions. Thus, both the level and types of mutation induced by PhIP are influenced by the activity of the MMR system. MMR may suppress PhIP-induced mutation through recognition and processing of specific mispairs (PhIP-G/T, PhIP-G/G, and PhIP-G/loop mispairs). In contrast, the PhIP-G/A mispair is unlikely to be a MMR substrate. In addition, the similar induction of both transversions and transitions in Mlh1-/- mice suggests that mutagenic bypass of PhIP-G is similarly efficient with dATP, dTTP, and dGTP, in contrast to previously published conclusions. Our data suggests that MMR-deficiency would increase the likelihood of PhIP-induced carcinogenic mutations. Further evaluation of the risk that consumption of heterocyclic amines may impart to MMR-deficient individuals therefore is warranted.
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2,336,433 |
Microsatellite analysis of pooled Schistosoma mansoni DNA: an approach for studies of parasite populations.
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Human parasites are often distributed in metapopulations, which makes random sampling for genetic epidemiology difficult. The typical approach to sampling Schistosoma mansoni involves laboratory passage to obtain individual worms with small sample size and selection bias as a consequence. By contrast, the naturally pooled samples from egg output in stool or urine directly represent the genetic composition of current populations. To test whether pooled samples could be used to estimate population allele frequencies, DNA from individual cloned parasites was pooled and amplified by PCR for 7 microsatellites. By polyacrylamide gel analysis, the relative band intensities of the products from the major alleles in the pooled samples differed by 0-6% from the summed intensities of the individual clones (mean = 2.1%+/-2.1% S.D.). The number of PCR cycles (25-40) did not influence the accuracy of the estimate. Varying the frequency of 1 allele in pooled samples from 32 to 69% likewise did not affect accuracy. Allele frequency estimates from aggregate samples such as eggs will be a better foundation for studies of parasite population dynamics as well as the basis for large-scale association studies of host and parasite characteristics.
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2,336,434 |
Early B-cell Factor gene association with multiple sclerosis in the Spanish population.
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The etiology of multiple sclerosis (MS) is at present not fully elucidated, although it is considered to result from the interaction of environmental and genetic susceptibility factors. In this work we aimed at testing the Early B-cell Factor (EBF1) gene as a functional and positional candidate risk factor for this neurological disease. Axonal damage is a hallmark for multiple sclerosis clinical disability and EBF plays an evolutionarily conserved role in the expression of proteins essential for axonal pathfinding. Failure of B-cell differentiation was found in EBF-deficient mice and involvement of B-lymphocytes in MS has been suggested from their presence in cerebrospinal fluid and lesions of patients.</AbstractText>The role of the EBF1 gene in multiple sclerosis susceptibility was analyzed by performing a case-control study with 356 multiple sclerosis patients and 540 ethnically matched controls comparing the EBF1 polymorphism rs1368297 and the microsatellite D5S2038.</AbstractText>Significant association of an EBF1-intronic polymorphism (rs1368297, A vs. T: p = 0.02; OR = 1.26 and AA vs. [TA+TT]: p = 0.02; OR = 1.39) was discovered. This association was even stronger after stratification for the well-established risk factor of multiple sclerosis in the Major Histocompatibility Complex, DRB1*1501 (AA vs. [TA+TT]: p = 0.005; OR = 1.78). A trend for association in the case-control study of another EBF1 marker, the allele 5 of the very informative microsatellite D5S2038, was corroborated by Transmission Disequilibrium Test of 53 trios (p = 0.03).</AbstractText>Our data support EBF1 gene association with MS pathogenesis in the Spanish white population. Two genetic markers within the EBF1 gene have been found associated with this neurological disease, indicative either of their causative role or that of some other polymorphism in linkage disequilibrium with them.</AbstractText>
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2,336,435 |
Specificity and overlap in gene segment-defined antibody repertoires.
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To date several studies have sought to catalog the full suite of antibodies that humans naturally produce against single antigens or other specificities (repertoire). Here we analyze the properties of all sequenced repertoires in order to better understand the specificity of antibody responses. Specifically, we ask whether the large-scale sequencing of antibody repertoires might provide a diagnostic tool for detecting antigen exposure. We do this by examining the overlap in VH-, D-, and JH- segment usage among sequenced repertoires.</AbstractText>We find that repertoire overlap in VH-, D-, and JH-segment use is least for VH segments and greatest for JH segments, consistent with there being more VH than JH segments in the human genome. We find that for any two antigens chosen at random, chances are 90 percent that their repertoires' VH segments will overlap by less than half, and 98 percent that their VDJH combinations will overlap by < or =10 percent. We ran computer simulations to test whether enrichment for specific VDJH combinations could be detected in "antigen-exposed" populations, and found that enrichment is detectable with moderate-to-high sensitivity and high specificity, even when some VDJH combinations are not represented at all in some test sets.</AbstractText>Thus, as large-scale sequencing becomes cost-effective for clinical testing, we suggest that sequencing an individual's expressed antibody repertoire has the potential to become a useful diagnostic modality.</AbstractText>
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2,336,436 |
Role of nucleic acid testing in cadaver organ donor screening: detection of hepatitis C virus RNA in seropositive and seronegative donors.
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Hepatitis C virus (HCV) transmission by both seropositive and seronegative cadaver organ donors has been documented, yet nucleic acid testing is not routinely used to identify active infection in these donors prior to transplantation. Between November 2001 and February 2004, we screened 1445 cadaver organ donors for anti-HCV antibodies with either HCV EIA-2.0 (Abbott Diagnostics, Chicago, IL, USA) and/or Ortho HCV Version 3.0 ELISA (Ortho-Clinical Diagnostics, Raritan, NJ, USA) and confirmed seropositive samples with Chiron RIBA3.0 SIA (Chiron Corporation, Emeryville, CA, USA). Samples with sufficient volume (n = 726) were tested by the VERSANT HCV [transcription-mediated amplification (TMA)] Qualitative assay (Bayer Healthcare LLC, Tarrytown, NY, USA) which can be performed in approximately 5 h. Those with detectable HCV RNA and sufficient volume were quantified by the VERSANT HCV 3.0 (bDNA) Assay (Bayer Healthcare LLC) and/or the HCV RNA TMA Quantitative Assay (n = 23) and genotyped (n = 57). Seventy-seven of 1445 (5.3%) donors were seropositive, reactive by either one or both anti-HCV assays. Fifty-two of 63 (82.5%) of the seropositive samples had detectable HCV RNA and were genotyped. Seventeen of these samples had quantifications ranging from 128,123 to >7,692,307 IU/mL. Six of 663 (0.9%) seronegative samples had detectable HCV RNA. Their quantifications ranged from <9.3 to 1,464,799 IU/mL, and five of these six were successfully genotyped. As HCV RNA was demonstrated in samples from both our seropositive and seronegative cadaver organ donors, we are now incorporating nucleic acid testing into our donor screening/diagnostic algorithm.
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2,336,437 |
Evolution of prenatal genetics: from point mutation testing to chromosomal microarray analysis.
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Molecular genetic testing involves DNA analysis using various methods for the purpose of diagnosing genetic disorders. In the prenatal DNA diagnostic setting, fetal DNA is usually tested for a specific single-gene disorder for which the fetal risk is 25% or more. In contrast, cytogenetic testing is often used to detect fetal chromosomal abnormalities in cases that involve a wider range of indications. Classic cytogenetic and DNA-based testing methods provide a range of aberrations detected with different levels of genomic resolution. More recently developed molecular cytogenetic methods provide powerful tools to bridge the technical divide between these related areas. One such hybrid method is microarray-based comparative genomic hybridization. Chromosomal microarray analysis has been applied to clinical testing for unbalanced gains or losses of genomic regions associated with genetic disorders. This technology is poised to have a substantial impact on clinical genetics, including prenatal genetic testing.
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2,336,438 |
Genetic testing for hearing impairment.
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For some patients, genetic testing can reveal the etiology of their hearing impairment, and can provide evidence for a medical diagnosis. However, a gap between fundamental genetic research on hereditary deafness and clinical otology emerges because of the steadily increasing number of discovered genes for hereditary hearing impairment (HHI) and the comparably low clinical differentiation of the HHIs. In an attempt to keep up with the scientific progress, this article enumerates the indications of genetic testing for HHI from a clinical point of view and describes the most frequently encountered HHIs in Belgium. Domains of recent scientific interest, molecular biological aspects, and some pitfalls with HHIs are highlighted. The overview comprises bilateral congenital hearing loss, late-onset progressive high frequency hearing loss, progressive bilateral cochleo-vestibular deficit, and progressive low frequency hearing loss. Also, several syndromal forms of HHI are summarized, and the availability of genetic tests mentioned. Finally, the requirements for successful linkage analysis, an important genetic research tool for localizing the potential genes of a trait on a chromosome, are briefly described.
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2,336,439 |
Utility and limitations of genetic testing and information.
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This article introduces some of the issues involved in genetic testing and information, particularly the utility and limitations of such testing. Psychosocial and ethical issues that may arise in this area are also discussed. The aim of this article is to stimulate readers' awareness of and insight into these matters in the hope that practitioners will examine and reflect on the applicability of these to their area of practice.
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2,336,440 |
MEFV analysis is of particularly weak diagnostic value for recurrent fevers in Western European Caucasian patients.
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Familial Mediterranean fever (FMF) is an autosomal-recessive disorder characterized by recurrent attacks of fever, with abdominal, thoracic, or articular pain. FMF is particularly common in Mediterranean populations, while other populations are rarely affected. MEFV gene analysis provides the only objective diagnostic criterion for FMF. However, the spectrum of MEFV mutations, which was first established in classically affected populations, remains insufficiently studied in other populations. The purpose of this study was to assess involvement of MEFV in the phenotype of western European Caucasian patients with a clinical diagnosis of FMF.</AbstractText>Mutation analysis was performed in 208 Caucasian patients from western Europe, by screening for the most common MEFV mutations in exons 2, 3, 5, and 10, and by sequencing the promoter region and the whole MEFV coding sequence in 21 of these patients.</AbstractText>None of the patients carried 2 mutated alleles. Only 2 patients carried 1 mutated allele.</AbstractText>FMF-like syndromes in western European Caucasian populations cannot be explained by MEFV mutations. These results should be helpful in avoiding laborious and costly MEFV molecular analyses that, at the population level, seem to be of poor diagnostic value in the case of western European Caucasian patients, and rather should prompt a search for other causes in those patients.</AbstractText>
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2,336,441 |
Performance of the revised Bethesda guidelines for identification of colorectal carcinomas with a high level of microsatellite instability.
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Criteria for microsatellite instability (MSI) testing to rule out hereditary nonpolyposis colorectal cancer were recently revised and include parameters such as age and specific histologic features that can be identified by the pathologist, triggering reflex MSI testing.</AbstractText>To review the performance of the revised Bethesda guidelines to identify MSI-positive colorectal cancers.</AbstractText>Seventy-five patients with colorectal cancer were included; 68 patients younger than 50 years and 7 patients between 50 and 60 years were selected based on histopathologic criteria. Microsatellite instability testing with the National Cancer Institute--recommended panel and immunohistochemistry for hMLH1 and hMSH2 were performed. Tumors were classified into microsatellite instability high (MSI-H), low (MSI-L), or stable (MSS) categories.</AbstractText>Overall, 17 (23%) of 75 colorectal cancer cases were classified as MSI-H, including 13 patients younger than 50 years and 4 patients between 50 and 60 years. Among the MSI-H tumors, 10 (59%) were characterized by loss of hMLH1 and 6 (35%) were hMSH2 negative. Histologic features suggestive of MSI-H phenotype were present in 80% of MSI-H and 35% of MSS/MSI-L tumors. The number of positive lymph nodes was higher in MSS/MSI-L adenocarcinomas (P = .04).</AbstractText>By selecting for age and histologic features, we detected MSI-H tumors in approximately one quarter of colorectal cancer cases meeting the revised Bethesda guidelines and identified 17 MSI-H cases, whereas only 8 would have been recognized by the prior guidelines. These data indicate that reflex testing requested by pathologists based on the revised Bethesda guidelines increases the detection of MSI-H and potential hereditary nonpolyposis colorectal cancer cases.</AbstractText>
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2,336,442 |
Testing for defective DNA mismatch repair in colorectal carcinoma: a practical guide.
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Significant bench and clinical data have been generated during the last decade regarding DNA mismatch repair in colorectal carcinoma.</AbstractText>To review clinically relevant aspects of defective DNA mismatch repair in colorectal carcinoma and to suggest testing algorithms for identification of these tumors in the sporadic and familial settings.</AbstractText>This article is based on literature review and clinical testing experience of more than 2000 patient samples.</AbstractText>Approximately 15% of colorectal carcinomas arise as a result of defective DNA mismatch repair. Ninety percent of these carcinomas are sporadic, arising as a result of methylation of the MLH1 gene promoter, silencing expression. These sporadic carcinomas have improved stage-specific prognosis and can be identified by demonstrating aberrant loss of expression with an MLH1 immunoperoxidase stain. Familial colorectal carcinomas with defective DNA mismatch repair (Lynch syndrome) are due to a germline defect in one of several DNA mismatch repair genes. The familial carcinomas are best identified with a combination of immunohistochemistry and molecular microsatellite analysis. This testing facilitates subsequent directed genetic testing of the proband and family members.</AbstractText>
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2,336,443 |
Assessment of allied health graduates' preparation to integrate genetic knowledge and skills into clinical practice.
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Allied health professionals are in a unique position to address the concerns of and provide information to clients with genetic disorders. This study assessed the preparation of recent graduates of allied health training programs to provide these services by determining their (1) professional practices, (2) confidence in performing skills that require genetic knowledge, (3) extent of genetic training, and (4) interest in genetic topics. A survey was sent to 698 alumni of six allied health training programs who graduated between 1997 and spring 2002 from a midwestern university. A total of 235 alumni responded to the survey (34%). Forty-three percent of respondents reported discussing at least one of eight topics, such as patterns of inheritance, recurrence risks, genetic testing, and characteristics of genetic conditions and/or prognosis. Referrals for genetic services were made by 12.6% of respondents. Of the 10 genetic assessment, counseling, and referral skills that were assessed, eliciting family history was the skill most commonly performed. Many respondents discussed the genetic basis of disorders, provided guidance to clients about the impact of their condition, and corrected misconceptions. Only 22% of the respondents rated the amount of genetic knowledge/skills covered in training as satisfactory, and 78% rated it as marginal or none. However, there is strong interest in genetic topics, especially related to common disorders. A correlation was found between the respondents' training and confidence in performing these skills. Allied health professionals are providing genetic-related services in clinical settings. However, sufficient instruction in genetic knowledge and skills is not being provided in their undergraduate and graduate training programs. Preservice and continuing educational interventions designed to prepare allied health professionals for the genetic age are needed. This study establishes baseline data regarding professional practices and perceived clinical confidence related to genetics that can be used to develop and evaluate the effectiveness of future educational interventions.
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2,336,444 |
Surveillance behavior and prophylactic surgery after predictive testing for hereditary breast/ovarian cancer.
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This article describes breast or ovarian cancer surveillance practices and prophylactic surgery involving 34 carriers and 34 noncarriers of a BRCA1/2 mutation within the year after predictive testing. It also evaluates the effect of the predictive test result on cancer screening practices and provides insight into factors important in the decision-making process about health-related behavior. Within the year following predictive testing, 9% (3 of 34) of the carriers decided to have a prophylactic mastectomy. The majority of the carriers was adherent to recommendations regarding regular cancer surveillance following predictive testing. Furthermore, carriers' adherence to clinical breast examination and mammography recommendations significantly increased from pre- to posttest and was significantly higher than noncarriers' utilization after testing. Of the carriers eligible for prophylactic salpingo-oophorectomy, 75% had this operation. All carriers who were advised to have regular surveillance of the ovaries had ovarian ultrasounds. The authors gave major attention to factors playing a part in the decision-making process about health-related behavior.
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2,336,445 |
Multicapillary electrophoresis of unlabeled DNA fragments with high-sensitive laser-induced fluorescence detection by counter-current migration of intercalation dye.
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Analysis of PCR fragments for applications, such as screening of nucleotide polymorphisms, detection of somatic mutations, or quantification of reverse-transcription PCR products, becomes central in clinical research as well as preventive testing, diagnostic screening, and pharmacogenomic genotyping. A variety of CE techniques, utilizing great potential of multicapillary-array sequencers, is now commonly applied in prevention, diagnosis, and treatment of a wide range of genetic diseases (cancer, cardiovascular, and neurodegenerative diseases, etc.). Costs of fluorescently labeled primers is often a major factor in large-scale projects requiring mutation analysis in hundreds or thousands of samples. In the present paper we introduce a simple approach of detecting unlabeled DNA fragments through intercalation without a need for adding intercalator to the separation polymer matrix. The dye is only added to the anode reservoir, and mixing with the separated DNA fragments takes place upon its migration opposite to the direction of the CE separation. Using two common intercalating dyes (ethidium bromide and SYBR Green II) we present this method as a tool for routine PCR detection and quantification.
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2,336,446 |
Molecular evolution of evolutionary novelties: the vagina and uterus of therian mammals.
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Innovations are an integral part of the evolutionary process if we accept the fact that more complex organisms derived from anatomically simple ones. All major taxa are distinguished not only by their closer genealogical relatedness relative to other species but also by the possession of novel anatomical and physiological features. The question is whether the origin of these novel characters can be simply understood as adaptations, like all other phenotypic differences that arise by natural selection, or whether the origin of these characters requires more profound genetic changes. In this paper, we argue that innovations constitute a distinct class of evolutionary processes that require a research program complementary to the study of adaptation. The distinguishing feature of innovations is the origin of novel organ identity gene functions specific to the novel character. By implication, research into the origin of novel characters has to identify the developmental regulatory links that were involved in the evolution of these characters. We suggest that novel regulatory links will include the evolution of cis-regulatory elements as well as novel protein-protein interactions among transcription factor proteins. The latter hypothesis suggests that innovations should leave a trace in the evolution of the protein coding regions of transcription factor genes. We illustrate this idea with results on the evolution of HoxA-11 and HoxA-13 in the stem lineage of placental mammals. These genes are essential for female reproductive tract development and function. We show that, as predicted, these genes experience strong directional selection in the stem lineage of placental mammals and that these amino acid substitutions affect residues at the surface of the protein, consistent with their expected role in protein-protein interactions. We conclude that a careful analysis of sequence variation in developmental genes can aid in testing which developmental changes were instrumental in the origin of novel morphological characters.
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2,336,447 |
Interaction analysis between 5-HTTLPR and TNFA -238/-308 polymorphisms in schizophrenia.
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This study investigated the potential interaction between the polymorphisms of serotonin transporter gene (SLC6A4, a 44 base pair insertion/deletion in the promoter region, 5-HTTLPR) and tumor necrosis factor-alpha gene (TNFA; -238G/A and -308G/A polymorphisms) on the development of schizophrenia, as well as the interaction of the three polymorphisms in relation to symptomatology, family history, onset age and antipsychotic treatment response. Genomic DNA analyses with polymerase chain reaction (PCR) was used for the genotyping. One hundred and fifty-two (152) patients with schizophrenia and 152 normal controls participated in the study. Any associations between the individual polymorphism and schizophrenia were not found. However, marginal association between subjects with both TNFA -238 A allele (genotype AA plus AG) and 5-HTTLPR s allele (ss plus sl) and presence of family history was found (p = 0.023; p = 0.026). The subjects with TNFA -308 AG genotype showed higher change in PANSS total score (p = 0.028). No significant interaction effect between 5-HTTLPR and TNFA -238/-308 polymorphisms either on the development of schizophrenia or on antipsychotics treatment response and psychopathology was found, although a significant interaction effect for subjects carrying TNFA -238 AG and -308 AA genotypes on a positive family history was observed (p = 0.017). These results suggest that the interaction effects between 5-HTTLPR and TNFA -238/-308 polymorphisms gives no significant contribution to the susceptibility to schizophrenia, and is not associated with clinical variables, antipsychotic treatment response and psychopathological features, except for family history of disease, at least in the Korean population.
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2,336,448 |
DBH*444G/A polymorphism of the dopamine-beta-hydroxylase gene is associated with alcoholism but not with severe alcohol withdrawal symptoms.
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As the enzyme dopamine-beta-hydroxylase (DbetaH) converts dopamine to norepinephrine and both transmitters seem to be involved in the pathology of alcoholism and severe alcohol withdrawal symptoms, the gene encoding DbetaH (DBH) was applied to explore the genetic background of alcoholism and severe withdrawal symptoms. 102 healthy control subjects and 208 alcoholics, including 97 patients with a history of mild withdrawal symptoms, 57 with a history of alcohol withdrawal seizure (AWS) and 82 with a history of delirium tremens (DT) were genotyped for the DBH*444G/A polymorphism revealing a significantly elevated frequency of genotypes carrying the A-allele (p = 0.02; after Bonferroni adjustment for multiple tests) in alcoholics compared to healthy controls. Frequencies of alleles and genotypes of individuals with mild withdrawal symptoms did not differ significantly from those of patients with DT or AWS.
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2,336,449 |
Genetically indistinguishable SNPs and their influence on inferring the location of disease-associated variants.
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As part of a recent high-density linkage disequilibrium (LD) study of chromosome 20, we obtained genotypes for approximately 30,000 SNPs at a density of 1 SNP/2 kb on four different population samples (47 CEPH founders; 91 UK unrelateds [unrelated white individuals of western European ancestry]; 97 African Americans; 42 East Asians). We observed that approximately 50% of SNPs had at least one genetically indistinguishable partner; i.e., for every individual considered, their genotype at the first locus was identical to their genotype at the second locus, or in LD terms, the SNPs were in "perfect" LD (r2 = 1.0). These "genetically indistinguishable SNPs" (giSNPs) formed into clusters of varying size. The larger the cluster, the greater the tendency to be located within genes and to overlap with giSNP clusters in other population samples. As might be expected for this map density, many giSNPs were located close to one another, thus reflecting local regions of undetected recombination or haplotype blocks. However, approximately 1/3 of giSNP clusters had intermingled, non-indistinguishable SNPs with incomplete LD (D' and r2 <1), sometimes spanning hundreds of kilobases, comprising up to 70 indistinguishable markers and overlapping multiple haplotype blocks. These long-range, nonconsecutive giSNPs have implications for disease gene localization by allelic association as evidence for association at one locus will be indistinguishable from that at another locus, even though both loci may be situated far apart. We describe the distribution of giSNPs on this map of chromosome 20 and illustrate the potential impact they can have on association mapping.
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2,336,450 |
Ascertainment bias in studies of human genome-wide polymorphism.
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Large-scale SNP genotyping studies rely on an initial assessment of nucleotide variation to identify sites in the DNA sequence that harbor variation among individuals. This "SNP discovery" sample may be quite variable in size and composition, and it has been well established that properties of the SNPs that are found are influenced by the discovery sampling effort. The International HapMap project relied on nearly any piece of information available to identify SNPs-including BAC end sequences, shotgun reads, and differences between public and private sequences-and even made use of chimpanzee data to confirm human sequence differences. In addition, the ascertainment criteria shifted from using only SNPs that had been validated in population samples, to double-hit SNPs, to finally accepting SNPs that were singletons in small discovery samples. In contrast, Perlegen's primary discovery was a resequencing-by-hybridization effort using the 24 people of diverse origin in the Polymorphism Discovery Resource. Here we take these two data sets and contrast two basic summary statistics, heterozygosity and F(ST), as well as the site frequency spectra, for 500-kb windows spanning the genome. The magnitude of disparity between these samples in these measures of variability indicates that population genetic analysis on the raw genotype data is ill advised. Given the knowledge of the discovery samples, we perform an ascertainment correction and show how the post-correction data are more consistent across these studies. However, discrepancies persist, suggesting that the heterogeneity in the SNP discovery process of the HapMap project resulted in a data set resistant to complete ascertainment correction. Ascertainment bias will likely erode the power of tests of association between SNPs and complex disorders, but the effect will likely be small, and perhaps more importantly, it is unlikely that the bias will introduce false-positive inferences.
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2,336,451 |
Expression of the mef(E) gene encoding the macrolide efflux pump protein increases in Streptococcus pneumoniae with increasing resistance to macrolides.
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Active macrolide efflux is a major mechanism of macrolide resistance in Streptococcus pneumoniae in many parts of the world, especially North America. In Canada, this active macrolide efflux in S. pneumoniae is predominantly due to acquisition of the mef(E) gene. In the present study, we assessed the mef(E) gene sequence as well as mef(E) expression in variety of low- and high-level macrolide-resistant, clindamycin-susceptible (M-phenotype) S. pneumoniae isolates (erythromycin MICs, 1 to 32 microg/ml; clindamycin MICs, < or = 0.25 microg/ml). Southern blot hybridization with mef(E) probe and EcoRI digestion and relative real-time reverse transcription-PCR were performed to study the mef(E) gene copy number and expression. Induction of mef(E) expression was analyzed by Etest susceptibility testing pre- and postincubation with subinhibitory concentrations of erythromycin, clarithromycin, azithromycin, telithromycin, and clindamycin. The macrolide efflux gene, mef(E), was shown to be a single-copy gene in all 23 clinical S. pneumoniae isolates tested, and expression post-macrolide induction increased 4-, 6-, 20-, and 200-fold in isolates with increasing macrolide resistance (erythromycin MICs 2, 4, 8, and 32 microg/ml, respectively). Sequencing analysis of the macrolide efflux genetic assembly (mega) revealed that mef(E) had a 16-bp deletion 153 bp upstream of the putative start codon in all 23 isolates. A 119-bp intergenic region between mef(E) and mel was sequenced, and a 99-bp deletion was found in 11 of the 23 M-phenotype S. pneumoniae isolates compared to the published mega sequence. However, the mef(E) gene was fully conserved among both high- and low-level macrolide-resistant isolates. In conclusion, increased expression of mef(E) is associated with higher levels of macrolide resistance in macrolide-resistant S. pneumoniae.
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2,336,452 |
Mutational and Biological Analysis of alpha-actinin-4 in focal segmental glomerulosclerosis.
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Mutations in the alpha-actinin-4 gene (ACTN4) cause an autosomal dominant form of focal segmental glomerulosclerosis (FSGS). A mutational analysis was performed of ACTN4 in DNA from probands with a family history of FSGS as well as in individuals with nonfamilial FSGS. The possible contribution of noncoding variation in ACTN4 to the development of FSGS also was assessed. Multiple nucleotide variants were identified in coding and noncoding sequence. The segregation of nonsynonymous coding sequence variants was examined in the relevant families. Only a small number of nucleotide changes that seemed likely to be causing (or contributing to) disease were identified. Sequence changes that predicted I149del, W59R, V801M, R348Q, R837Q, and R310Q changes were identified. For studying their biologic relevance and their potential roles in the pathogenesis of FSGS, these variants were expressed as GFP-fusion proteins in cultured podocytes. F-actin binding assays also were performed. Three of these variants (W59R, I149del, and V801M) showed clear cellular mislocalization in the form of aggregates adjacent to the nucleus. Two of these mislocalized variants (W59R and I149del) also showed an increased actin-binding activity. The I149del mutation segregated with disease; W59R was found to be a de novo mutation in the proband. A total of five ACTN4 mutations that are believed to be disease causing (three reported previously and two novel) as well as a number of variants with unclear contribution to disease now have been identified. The possibility that some of these other variants increase the susceptibility to FSGS cannot be excluded. ACTN4 mutations seem to account for approximately 4% of familial FSGS.
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2,336,453 |
Mouse models in preclinical studies for pachyonychia congenita.
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The similarities between the human and mouse genomes often allow researchers to make accurate predictions about the roles of their human counterparts. Because of the similar physiology between these two mammals, mice are used extensively in the laboratory to investigate the mechanisms of human diseases. Furthermore, mice provide us with the option of testing the toxicity of drugs and the safety of therapeutic approaches prior to human application. Here, we review the existing mouse models involving the keratin genes (K6a, K6b, K16, and K17) that cause the human genetic disorder pachyonychia congenita (PC). We also suggest methods to more accurately model this autosomal dominant skin condition in the mouse in order to better understand the pathophysiological processes underlying PC and importantly, provide a test-bed for testing emerging therapies in vivo.
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2,336,454 |
Finnish HLA studies confirm the increased risk conferred by HLA-B27 homozygosity in ankylosing spondylitis.
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To determine the influence of HLA-B27 homozygosity and HLA-DRB1 alleles in the susceptibility to, and severity of, ankylosing spondylitis in a Finnish population.</AbstractText>673 individuals from 261 families with ankylosing spondylitis were genotyped for HLA-DRB1 alleles and HLA-B27 heterozygosity/homozygosity. The frequencies of HLA-B27 homozygotes in probands from these families were compared with the expected number of HLA-B27 homozygotes in controls under Hardy-Weinberg equilibrium (HWE). The effect of HLA-DRB1 alleles was assessed using a logistic regression procedure conditioned on HLA-B27 and case-control analysis.</AbstractText>HLA-B27 was detected in 93% of cases of ankylosing spondylitis. An overrepresentation of HLA-B27 homozygotes was noted in ankylosing spondylitis (11%) compared with the expected number of HLA-B27 homozygotes under HWE (4%) (odds ratio (OR) = 3.3 (95% confidence interval, 1.6 to 6.8), p = 0.002). HLA-B27 homozygosity was marginally associated with reduced BASDAI (HLA-B27 homozygotes, 4.5 (1.6); HLA-B27 heterozygotes, 5.4 (1.8) (mean (SD)), p = 0.05). Acute anterior uveitis (AAU) was present in significantly more HLA-B27 positive cases (50%) than HLA-B27 negative cases (16%) (OR = 5.4 (1.7 to 17), p<0.004). HLA-B27 positive cases had a lower average age of symptom onset (26.7 (8.0) years) compared with HLA-B27 negative cases (35.7 (11.2) years) (p<0.0001).</AbstractText>HLA-B27 homozygosity is associated with a moderately increased risk of ankylosing spondylitis compared with HLA-B27 heterozygosity. HLA-B27 positive cases had an earlier age of onset of ankylosing spondylitis than HLA-B27 negative cases and were more likely to develop AAU. HLA-DRB1 alleles may influence the age of symptom onset of ankylosing spondylitis.</AbstractText>
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2,336,455 |
Study of the role of functional variants of SLC22A4, RUNX1 and SUMO4 in systemic lupus erythematosus.
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Functional polymorphisms of the solute carrier family 22, member 4 (SLC22A4), runt related transcription factor 1 (RUNX1) and small ubiquitin-like modifier 4 (SUMO4) genes have been shown to be associated with several autoimmune diseases.</AbstractText>To test the possible role of these variants in susceptibility to or severity of systemic lupus erythematosus (SLE), on the basis that common genetic bases are shared by autoimmune disorders.</AbstractText>597 SLE patients and 987 healthy controls of white Spanish origin were studied. Two additional cohorts of 228 SLE patients from Sweden and 122 SLE patients from Colombia were included. A case-control association study was carried out with six single nucleotide polymorphisms (SNP) spanning the SLC22A4 gene, one SNP in RUNX1 gene, and one additional SNP in SUM04 gene.</AbstractText>No significant differences were observed between SLE patients and healthy controls when comparing the distribution of the genotypes or alleles of any of the SLC22A4, RUNX1, or SUMO4 polymorphisms tested. Significant differences were found in the distribution of the SUMO4 genotypes and alleles among SLE patients with and without nephritis, but after multiple testing correction, the significance of the association was lost. The association of SUMO4 with nephritis could not be verified in two independent SLE cohorts from Sweden and Colombia.</AbstractText>These results suggest that the SLC22A4, RUNX1, and SUMO4 polymorphisms analysed do not play a role in the susceptibility to or severity of SLE.</AbstractText>
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2,336,456 |
Determinants of transcription initiation by archaeal RNA polymerase.
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Transcription in Archaea is catalyzed by an RNA polymerase that is most similar to eukaryotic RNA polymerases both in subunit composition and in transcription initiation factor requirements. Recent studies on archaeal transcription in diverse members of this domain have contributed new details concerning the functions of promoters and transcription factors in guiding initiation by RNA polymerase, and phylogenetic arguments have allowed modeling of archaeal transcription initiation complexes by comparison with recently described models of eukaryotic and bacterial transcription initiation complexes. Important new advances in reconstitution of archaeal transcription complexes from fully recombinant components is permitting testing of hypotheses derived from and informed by these structural models, and will help bring the study of archaeal transcription to the levels of understanding currently enjoyed by bacterial and eukaryotic RNA polymerase II transcription.
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2,336,457 |
Epigenetics of cervical cancer. An overview and therapeutic perspectives.
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Cervical cancer remains one of the greatest killers of women worldwide. It is difficult to foresee a dramatic increase in cure rate even with the most optimal combination of cytotoxic drugs, surgery, and radiation; therefore, testing of molecular targeted therapies against this malignancy is highly desirable. A number of epigenetic alterations occur during all stages of cervical carcinogenesis in both human papillomavirus and host cellular genomes, which include global DNA hypomethylation, hypermetylation of key tumor suppressor genes, and histone modifications. The reversible nature of epigenetic changes constitutes a target for transcriptional therapies, namely DNA methylation and histone deacetylase inhibitors. To date, studies in patients with cervical cancer have demonstrated the feasibility of reactivating the expression of hypermethylated and silenced tumor suppressor genes as well as the hyperacetylating and inhibitory effect upon histone deacetylase activity in tumor tissues after treatment with demethylating and histone deacetylase inhibitors. In addition, detection of epigenetic changes in cytological smears, serum DNA, and peripheral blood are of potential interest for development of novel biomolecular markers for early detection, prediction of response, and prognosis.
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2,336,458 |
DNA extraction and analysis from processed coffee beans.
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The authenticity of coffee is an important issue for both producers and consumers. Premium Arabica material is especially prone to being adulterated, and a number of different techniques have been employed to determine the quality of both roasted and instant coffee. Currently, assessment of coffee authenticity relies on chemical methods which can discriminate between coffee species, but not varieties. Several genetic markers are available for assessing coffee origin, but their suitability to testing commercial coffee is limited by the ability to extract DNA from highly processed beans. In this paper, we demonstrate that PCR-grade DNA may be obtained from roasted beans and even instant coffee. This would allow analysis of commercial samples, provided that suitable markers for species/variety identification are found.
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2,336,459 |
Fragile X syndrome: diagnostic and carrier testing.
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This guideline is designed primarily as an educational resource for medical geneticists and other health care providers to help them provide quality medical genetic services. Adherence to this guideline does not necessarily assure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from this guideline.
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2,336,460 |
Technical standards and guidelines: molecular genetic testing for ultra-rare disorders.
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These standards and guidelines are designed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical molecular geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the laboratory record the rationale for any significant deviation from these standards and guidelines.
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2,336,461 |
Newborn blood spot screening and genetic services: a survey of Minnesota primary care physicians.
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To (1) obtain guidance on the preferred content and format of quick reference newborn blood spot screening information from the Minnesota Department of Health; (2) determine primary care physicians' perceptions of the benefits of genetic services; and (3) determine primary care physicians' satisfaction with genetic counseling services.</AbstractText>A written survey was mailed to family physicians and pediatricians in Minnesota (n = 300).</AbstractText>Eighty physicians responded (28% response rate). Whereas 70% of respondents felt previous information received from the newborn screening program was adequate, 83% were interested in quick reference information. The majority of physicians preferred this information as a laminated sheet (63%). Physician procedure for an abnormal screen, newborn screening program protocol for an abnormal screen, and disease treatment and follow-up information were recommended for inclusion on quick reference. Over half of physicians agreed with the following benefits of genetic services: provide testing options (88%); evaluate family members (88%); reduce parental anxiety (87%); provide resources (83%); provide diagnostic information (76%); determine medical needs (67%); and determine emotional needs (51%). Ninety-nine percent of physicians were satisfied with genetic counseling services.</AbstractText>Physicians indicated that reference material for primary care physicians should include a quick reference card with specific categories of information. Newborn screening programs should attempt to increase physician awareness of genetic services, including the subsequent medical and psychosocial benefits for their patients.</AbstractText>
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2,336,462 |
Patient acceptability of genotypic testing for hemochromatosis in primary care.
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Genetic screening can enable timely detection and treatment of hereditary hemochromatosis (HH). Little is known about patient acceptability of DNA testing as compared to conventional phenotypic testing.</AbstractText>Within the HEIRS Study, a large primary-care screening study of HH and iron overload, we randomly assigned participants to receive brief information on either HH genotypic or phenotypic testing, and assessed the willingness to accept this test. The study was designed to recruit an equal number of African Americans and Caucasians.</AbstractText>A total of 2500 participants were recruited from waiting rooms of primary care practices; 2165 participants who self-identified as African Americans and Caucasians were included in the analyses. Overall, 56% had accepted a genotypic test versus 58% for a phenotypic test. Adjusting for Field Center (FC), age, gender, race, educational attainment, global health rating, and knowledge of the test, the odds ratio of accepting a genotypic versus phenotypic test was 0.85 (95% CI: 0.71, 1.02; P = 0.078). Characteristics associated with test acceptance were age 45-64 years, female gender, Caucasian race, self-rated health less than ''very good'', and knowledge of the test. Test acceptance was associated with interest in knowing more about health (81%) and in helping family members (71%). Refusal reasons included a need to talk with a doctor (44%), concern about privacy (32%), and dislike of blood drawing (29%).</AbstractText>In this diverse sample of primary care patients, stated acceptance of genotypic testing for HH mutations was similar to phenotypic testing for blood iron. Patient education regarding the nature of test, importance of disease detection, and privacy protection appear to be essential for achieving high rates of screening participation.</AbstractText>
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2,336,463 |
Comparison of genotypic and phenotypic strategies for population screening in hemochromatosis: assessment of anxiety, depression, and perception of health.
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Hemochromatosis is a treatable disorder with a major genetic predisposition. It provides an example in which genotypic and phenotypic strategies for screening may be compared. We previously showed noninferiority of uptake of a genotypic population screening strategy for hemochromatosis compared with a phenotypic strategy. In this article we present the psychologic effects of each strategy.</AbstractText>A sample of 3000 individuals from primary care were randomly allocated to a phenotypic or genotypic screening strategy for hemochromatosis, and the 939 individuals who accepted screening provide the sample for this article. Standardized assessments of anxiety, general health, and depression were made at invitation, testing, result-giving, and 6 months.</AbstractText>Screening did not lead to significant changes in the self-rated assessments of anxiety, depression, and general health over time, and there were no significant differences between the two screening strategies. The unemployed or permanently disabled had lower ratings of health and higher anxiety and depression.</AbstractText>The two screening strategies appeared to cause little adverse psychologic disturbance in the short term, and there was no difference between the two strategies This study provides some empiric data to support arguments against "genetic exceptionalism" and suggests that genetic testing when used for population screening for a treatable disease has few adverse effects.</AbstractText>
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2,336,464 |
Developing a sustainable process to provide quality control materials for genetic testing.
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To provide a summary of the outcomes of two working conferences organized by the Centers for Disease Control and Prevention (CDC), to develop recommendations for practical, sustainable mechanisms to make quality control (QC) materials available to the genetic testing community.</AbstractText>Participants were selected to include experts in genetic testing and molecular diagnostics from professional organizations, government agencies, industry, laboratories, academic institutions, cell repositories, and proficiency testing (PT)/external Quality Assessment (EQA) programs. Current efforts to develop QC materials for genetic tests were reviewed; key issues and areas of need were identified; and workgroups were formed to address each area of need and to formulate recommendations and next steps.</AbstractText>Recommendations were developed toward establishing a sustainable process to improve the availability of appropriate QC materials for genetic testing, with an emphasis on molecular genetic testing as an initial step.</AbstractText>Improving the availability of appropriate QC materials is of critical importance for assuring the quality of genetic testing, enhancing performance evaluation and PT/EQA programs, and facilitating new test development. To meet the needs of the rapidly expanding capacity of genetic testing in clinical and public health settings, a comprehensive, coordinated program should be developed. A Genetic Testing Quality Control Materials Program has therefore been established by CDC in March 2005 to serve these needs.</AbstractText>
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2,336,465 |
Analysis of LRRK2 functional domains in nondominant Parkinson disease.
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A comprehensive sequence analysis of 29 exons that code for the functional domains of LRRK2 in 160 nondominant Parkinson disease (PD) patients was performed. Novel variant screening in a further 470 sporadic PD patients and 630 controls revealed two novel variants (R1067Q and IVS33 + 6 T>A), which are likely to be pathogenic in five patients. One patient presented initially with a typical essential tremor phenotype, expanding the phenotypic spectrum of LRRK2 mutations.
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2,336,466 |
Early-onset toe walking in rippling muscle disease due to a new caveolin-3 gene mutation.
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The authors describe a family with autosomal dominant rippling muscle disease (RMD) and prominent early-onset toe walking. Molecular analysis revealed a novel heterozygous G > A transition at nucleotide position 136 in exon 2 of the caveolin-3 gene (CAV3). The role of Achilles tendon lengthening in more severe forms of RMD is discussed.
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2,336,467 |
A review of juvenile polyposis syndrome.
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Juvenile Polyposis Syndrome is an uncommon hamartomatous disorder with significant gastrointestinal malignant potential. Mutations in SMAD4 and BMPR1A, implicated in the Transforming Growth Factor beta pathway, have recently been characterized, and hold significance in the management of patients and at risk family members. This article reviews our knowledge to date of the genetics and clinicopathological features of the Juvenile Polyposis Syndrome, and discusses the current expert recommendations for genetic testing, disease screening and management.
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2,336,468 |
Evolutionary comparison provides evidence for pathogenicity of RMRP mutations.
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Cartilage-hair hypoplasia (CHH) is a pleiotropic disease caused by recessive mutations in the RMRP gene that result in a wide spectrum of manifestations including short stature, sparse hair, metaphyseal dysplasia, anemia, immune deficiency, and increased incidence of cancer. Molecular diagnosis of CHH has implications for management, prognosis, follow-up, and genetic counseling of affected patients and their families. We report 20 novel mutations in 36 patients with CHH and describe the associated phenotypic spectrum. Given the high mutational heterogeneity (62 mutations reported to date), the high frequency of variations in the region (eight single nucleotide polymorphisms in and around RMRP), and the fact that RMRP is not translated into protein, prediction of mutation pathogenicity is difficult. We addressed this issue by a comparative genomic approach and aligned the genomic sequences of RMRP gene in the entire class of mammals. We found that putative pathogenic mutations are located in highly conserved nucleotides, whereas polymorphisms are located in non-conserved positions. We conclude that the abundance of variations in this small gene is remarkable and at odds with its high conservation through species; it is unclear whether these variations are caused by a high local mutation rate, a failure of repair mechanisms, or a relaxed selective pressure. The marked diversity of mutations in RMRP and the low homozygosity rate in our patient population indicate that CHH is more common than previously estimated, but may go unrecognized because of its variable clinical presentation. Thus, RMRP molecular testing may be indicated in individuals with isolated metaphyseal dysplasia, anemia, or immune dysregulation.
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2,336,469 |
Efficiency and power in genetic association studies.
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We investigated selection and analysis of tag SNPs for genome-wide association studies by specifically examining the relationship between investment in genotyping and statistical power. Do pairwise or multimarker methods maximize efficiency and power? To what extent is power compromised when tags are selected from an incomplete resource such as HapMap? We addressed these questions using genotype data from the HapMap ENCODE project, association studies simulated under a realistic disease model, and empirical correction for multiple hypothesis testing. We demonstrate a haplotype-based tagging method that uniformly outperforms single-marker tests and methods for prioritization that markedly increase tagging efficiency. Examining all observed haplotypes for association, rather than just those that are proxies for known SNPs, increases power to detect rare causal alleles, at the cost of reduced power to detect common causal alleles. Power is robust to the completeness of the reference panel from which tags are selected. These findings have implications for prioritizing tag SNPs and interpreting association studies.
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2,336,470 |
The patent is political: the consequences of patenting the BRCA genes in Britain.
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The paper explores the attempt by an American biotechnology company, Myriad Genetics, to use its patent rights over the BRCA genes to transfer its technology of genetic testing for breast and ovarian cancer to Britain. It also investigates the responses of British scientists, health care professionals and patient advocates to this attempted technology transfer.</AbstractText>This paper is based on approximately 100 in-depth interviews, document analysis and ethnographic observation conducted in the United States and Britain from 1998 to 2001.</AbstractText>The BRCA gene patents inspired political resistance and mobilized opposition to the patenting of genes in general. They also provided an opportunity for the British to assert their national identity as they argued that a British BRCA testing service needed to be available within the context of the National Health Service to all citizens equally.</AbstractText>Patents are not only legal documents and technical descriptions, but political tools as well. As they are increasingly deemed vital to economic globalization, patents have become mobilizing tools for anti-globalization activists and non-governmental organizations from less developed countries, and for asserting local and national identities.</AbstractText>Copyright 2005 S. Karger AG, Basel</CopyrightInformation>
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2,336,471 |
Balancing innovation and access to healthcare through the patent system--an Australian perspective.
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This article examines the enforcement of gene and other research tool patents in Australia. An empirical analysis of patenting practices in the Australian medical biotechnology industry showed heightened concern about the impact of patents on research and diagnostic testing, but provided little evidence to support these concerns at that time. Since then, the Australian company Genetic Technologies Ltd. has been enforcing its patents for non-coding DNA sequences. The governments of Australia are encouraging the biotechnology industry to better protect and enforce intellectual property rights, but recognize these needs to be balanced against access to healthcare. The article discusses proposals made by the Australian Law Reform Commission to adjust the balance, both by tightening the requirements for obtaining patents and by introducing various options to assist providers of diagnostic services and others in using patented inventions, but at the same time maintaining the incentive to innovate.
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2,336,472 |
What are gene patents and why are people worried about them?
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This article examines what it means to patent a gene. Numerous ethical concerns have been raised about the effects of such patents on clinical medical practice as well as on research and development. We describe what kinds of inventions are covered by human gene patents, give several examples and summarize the small body of empirical research performed in the US examining the effects of these patents. There is little evidence that early fears about gene patenting placing substantial restraints on research and clinical medicine have come to fruition. Nonetheless, there are areas of concern, and policy makers, physicians and the public should be alert to ensure that the net social benefits of patenting human genes are maintained.
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2,336,473 |
Cobalt chloride administration in athletes: a new perspective in blood doping?
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Blood doping is an illegal and unfair way of enhancing athletic performance by increasing the oxygen carrying capacity of the blood. Currently used methods usually involve stimulation of erythropoiesis. Gene therapy targeting the hypoxia inducible factor pathway may be an attractive alternative to traditional blood doping techniques. Hypoxia activates a large number of genes with essential roles in cell and tissue adaptation to low oxygen. Cobalt chloride is a well established chemical inducer of hypoxia-like responses such as erythropoiesis. Cobalt supplementation is not banned and therefore would not be detected by current anti-doping testing. Although there is as yet no direct or anecdotal evidence of cobalt chloride administration to athletes, its use should be warned against as being not only unfair but potentially dangerous.
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2,336,474 |
Markedly elevated neonatal immunoreactive trypsinogen levels in the absence of cystic fibrosis gene mutations is not an indication for further testing.
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To investigate the immunoreactive trypsinogen (IRT) values above the usual 99th centile laboratory cut-off and determine the value of offering further testing to those infants with a markedly elevated IRT but no cystic fibrosis transmembrane regulator (CFTR) gene mutation identified by the screening programme.</AbstractText>All babies born in Victoria, Australia, between 1991 and 2003, were screened by IRT followed by CF gene mutation analysis.</AbstractText>Of the 806,520 babies born, 9268 with the highest IRT levels had CFTR mutation analysis. There were 123 DeltaF508 homozygotes and 703 heterozygotes (86 with CF, 617 carriers). A total of 8442 babies had no CFTR gene mutation, of whom 18 (0.21%) had CF. The total number of CF babies with IRT greater than the laboratory cut-off was 227 (2.4%). The IRT results of the CF patients were distributed normally, with the majority above the laboratory cut-off of newborn IRT results. There was no evidence of an excess of babies with CF in the very highest levels of IRT above the 99th centile.</AbstractText>Only a small proportion of babies with a neonatal IRT >99th centile have CF. Additional CF testing for infants with an elevated IRT but no CFTR gene mutation has an extremely low yield, no matter how high the IRT result.</AbstractText>
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2,336,475 |
An empirical assessment of long-branch attraction artefacts in deep eukaryotic phylogenomics.
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In the context of exponential growing molecular databases, it becomes increasingly easy to assemble large multigene data sets for phylogenomic studies. The expected increase of resolution due to the reduction of the sampling (stochastic) error is becoming a reality. However, the impact of systematic biases will also become more apparent or even dominant. We have chosen to study the case of the long-branch attraction artefact (LBA) using real instead of simulated sequences. Two fast-evolving eukaryotic lineages, whose evolutionary positions are well established, microsporidia and the nucleomorph of cryptophytes, were chosen as model species. A large data set was assembled (44 species, 133 genes, and 24,294 amino acid positions) and the resulting rooted eukaryotic phylogeny (using a distant archaeal outgroup) is positively misled by an LBA artefact despite the use of a maximum likelihood-based tree reconstruction method with a complex model of sequence evolution. When the fastest evolving proteins from the fast lineages are progressively removed (up to 90%), the bootstrap support for the apparently artefactual basal placement decreases to virtually 0%, and conversely only the expected placement, among all the possible locations of the fast-evolving species, receives increasing support that eventually converges to 100%. The percentage of removal of the fastest evolving proteins constitutes a reliable estimate of the sensitivity of phylogenetic inference to LBA. This protocol confirms that both a rich species sampling (especially the presence of a species that is closely related to the fast-evolving lineage) and a probabilistic method with a complex model are important to overcome the LBA artefact. Finally, we observed that phylogenetic inference methods perform strikingly better with simulated as opposed to real data, and suggest that testing the reliability of phylogenetic inference methods with simulated data leads to overconfidence in their performance. Although phylogenomic studies can be affected by systematic biases, the possibility of discarding a large amount of data containing most of the nonphylogenetic signal allows recovering a phylogeny that is less affected by systematic biases, while maintaining a high statistical support.
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2,336,476 |
Preliminary studies on the effect of moderate physical activity on blood levels of glutathione.
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Molecular epidemiological approaches are being used to study how physical activity may protect against cancer. Prior epidemiological data suggest that physical activity protects against lung cancer; however, interpretation of these data is complicated by potential confounding by smoking. Glutathione (GSH) detoxifies cigarette smoke carcinogens and the paper tests whether physical activity levels are associated with blood GSH levels. Study subjects were enrolled in a chemoprevention trial testing whether antioxidant micronutrient supplementation reduces genetic damage from cigarette smoking. Physical activity data were collected by questionnaire from 178 subjects at 12 months of follow-up in the trial. Total GSH (tGSH), which is the sum of free and protein-bound GSH and glutathione disulfide levels, was measured using the 5,5'-dithiobis-(2-nitrobenzenoic acid) colormetric assay with red blood cell samples collected at the 12-month time point. In multivariate linear regression analyses that controlled for gender and cigarettes smoked per day, tGSH was positively associated with hours per week of moderate intensity activity (beta=0.005, p=0.02). Hours per week of vigorous intensity activity were unassociated with tGSH and the effect of moderate activity remained after control for vigorous activity. The results are consistent with prior research showing differential effects of moderate and vigorous activity and suggest a mechanism through which physical activity may influence lung cancer risk.
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2,336,477 |
Simultaneous detection of isoniazid, rifampin, and ethambutol resistance of Mycobacterium tuberculosis by a single multiplex allele-specific polymerase chain reaction (PCR) assay.
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Prompt detection of drug resistance of Mycobacterium tuberculosis is essential for effective control of tuberculosis (TB). We developed a multiplex allele-specific polymerase chain reaction (MAS-PCR) that detects the most commonly observed isoniazid (INH), rifampin (RIF), and ethambutol resistance-associated mutations in a single assay. The usefulness of the newly developed method was evaluated with 174 clinical isolates of M. tuberculosis obtained from Turkey. Distinct PCR banding patterns were observed for different mutation profiles and the correlation between MAS-PCR results and DNA sequencing findings was 99.4%. With culture-based phenotypic drug susceptibility testing as a reference standard, the sensitivity and specificity of the newly developed MAS-PCR assay for drug resistance-related genetic mutation detection were determined to be 81.1% and 97.5% for INH, 93.0% and 98.9 % for RIF, and 54.5% and 68.0 % for ethambutol. MAS-PCR provides a rapid, potentially more cost-effective, method of detecting multidrug-resistant TB.
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2,336,478 |
Autosomal recessive and sporadic deafness in Morocco: high frequency of the 35delG GJB2 mutation and absence of the 342-kb GJB6 variant.
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Deafness is a heterogeneous disorder showing different pattern of inheritance and involving a multitude of different genes. Mutations in the gene, GJB2 Gap junction type 1), encoding the gap junction protein connexin-26 on chromosome 13q11 may be responsible for up 50% of autosomal recessive nonsyndromic hearing loss cases (ARNSHL), and for 15-30% of sporadic cases. However, a large proportion (10-42%) of patients with GJB2 has only one GJB2 mutant allele. Recent reports have suggested that a 342-kb deletion truncating the GJB6 gene (encoding connexin-30), was associated with ARNSHL through either homozygous deletion of Cx30, or digenic inheritance of a Cx30 deletion and a Cx26 mutation in trans. Because mutations in Connexin-26 (Cx26) play an important role in ARNSHL and that distribution pattern of GJB2 variants differs considerably among ethnic groups, our objective was to find out the significance of Cx26 mutations in Moroccan families who had hereditary and sporadic deafness. One hundred and sixteen families with congenital deafness (including 38 multiplex families, and 78 families with sporadic cases) were included. Results show that the prevalence of the 35delG mutation is 31.58% in the family cases and 20.51% in the sporadic cases. Further screening for other GJB2 variants demonstrated the absence of other mutations; none of these families had mutations in exon 1 of GJB2 or the 342-kb deletion of GJB6. Thus, screening of the 35delG in the GJB2 gene should facilitate routinely used diagnostic for genetic counselling in Morocco.
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2,336,479 |
What influences participation in genetic carrier testing? Results from a discrete choice experiment.
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This study explores factors that influence participation in genetic testing programs and the acceptance of multiple tests. Tay Sachs and cystic fibrosis are both genetically determined recessive disorders with differing severity, treatment availability, and prevalence in different population groups. We used a discrete choice experiment with a general community and an Ashkenazi Jewish sample; data were analysed using multinomial logit with random coefficients. Although Jewish respondents were more likely to be tested, both groups seem to be making very similar tradeoffs across attributes when they make genetic testing choices.
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2,336,480 |
Reduced transcriptional activity in individuals with IL-18 gene variants detected from functional but not association study.
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Genetic polymorphisms of IL-18 and its receptor were reported to be associated with elevated serum IgE levels, atopy, and/or asthma. However, conflicting results were observed in various association studies and functional activity of these polymorphisms remains unclear. A total of 393 unrelated subjects were involved in this study. Direct PCR-sequencing method was used to screen novel polymorphisms. The functional significance of these polymorphisms was investigated using reporter gene assay. Three known (-137, +113, and +127) polymorphisms in the IL-18 promoter were identified with a perfect linkage disequilibrium (Delta=1, p<0.001) among them. No significant difference in the genotype frequencies of these polymorphisms between atopy and atopic phenotypes in Singaporean Chinese, Malays, and Indians was observed. However, transcriptional activities were significantly increased in HepG2 cultured cells with wild-type IL-18 genotype (-137/G, +113/T, and +127/C) than mutated genotype (-137/C, +113/G, and +127/T). Although these polymorphisms appear to have no association with atopic phenotypes in our population, subsequent functional studies suggest that polymorphisms in the IL-18 promoter region could affect significantly its activity.
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2,336,481 |
Genetic epidemiology and public health: hope, hype, and future prospects.
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Genetic epidemiology is a rapidly expanding research field, but the implications of findings from such studies for individual or population health are unclear. The use of molecular genetic screening currently has some legitimacy in certain monogenic conditions, but no established value with respect to common complex diseases. Personalised medical care based on molecular genetic testing is also as yet undeveloped for common diseases. Genetic epidemiology can contribute to establishing the causal nature of environmentally modifiable risk factors, through the application of mendelian randomisation approaches and thus contribute to appropriate preventive strategies. Technological and other advances will allow the potential of genetic epidemiology to be revealed over the next few years, and the establishment of large population-based resources for such studies (biobanks) should contribute to this endeavour.
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2,336,482 |
Tree disagreement: measuring and testing incongruence in phylogenies.
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The branching patterns of phylogenetic trees often disagree even when they have been constructed using different portions of the same data. This phylogenetic discord (incongruence) can be explained by real differences in evolutionary process or history, but also may be due simply to random chance or sampling error. Techniques for measuring and testing the significance of phylogenetic incongruence are used widely in systematic biology, and are necessary when considering genome-scale datasets composed of multiple genes that may or may not have different histories. They are also applicable wherever tree algorithms are used for ordering and interpreting data (e.g., DNA microarrays). Here, I review the different incongruence tests and use them to test the phylogenetic discord of a potentially mobile genetic element (the widespread colonization Island) in the gamma-proteobacteria. I then consider how incongruence tests may be used as a starting point for phylogenetic analysis that accounts for horizontal transfer and duplication events as explanations for homoplasy.
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2,336,483 |
First case report of X linked dystonia parkinsonism (XDP) or 'lubag' in Australia.
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To present the first genetically supported case of X linked dystonia parkinsonism (XDP) or 'lubag' reported in an Australian hospital.</AbstractText>We performed PCR amplification of microsatellite markers in and around the previously described segregating region for the XDP haplotype.</AbstractText>Linkage was confirmed using markers ZNF261, DXS10017, and DXS10018.</AbstractText>We present the first case of XDP or 'lubag' reported in an Australian hospital. It highlights the enlarging role of genetic testing in facilitating the diagnosis of dystonia in a clinical environment where a disease like XDP is rare, and where a corroborating family history may be unavailable.</AbstractText>
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2,336,484 |
A literature review of the psychological impact of genetic testing on breast cancer patients.
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Easier access and increased awareness results in more referral for genetic testing for hereditary breast cancer in healthy at-risk women and breast cancer patients. To investigate the psychological impact of genetic testing on breast cancer patients, literature pertaining to this group was reviewed.</AbstractText>Medline and PsychInfo databases were searched over the period 1995-2004 for studies aimed at breast cancer patients referred for genetic testing. Qualitative and quantitative psychological outcome measures were identified.</AbstractText>Eight papers were identified focusing on women affected by breast cancer and undergoing genetic counseling and DNA testing.</AbstractText>Genetic testing does not lead to an increase in psychological distress in breast cancer patients. However, a recent breast cancer diagnosis adds to general and cancer-specific distress prior to genetic counseling and after DNA test disclosure.</AbstractText>Clinicians need to be aware of possible high psychological distress and additional counseling needs of recently diagnosed breast cancer patients taking part in genetic testing. Further research should focus on patients who decline genetic counseling or receive an inconclusive test result, including age upon and time since diagnosis.</AbstractText>
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2,336,485 |
[Bat lyssavirus in Thailand].
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A study of bat lyssavirus survey was done in Thailand from 2001 to 2003. A total of 932 bats of 11 species were captured in 8 provinces for blood collection and testing for neutralizing antibodies against rabies virus (RABV), Australian bat lyssavirus (ABLV) and broader panel of other lyssaviruses (Irkut, Aravan and Khujand). All Thai bat samples were negative to RABV Sixteen samples of 394 with sufficient volume of serum had detectable neutralizing antibodies against Irkut, Aravan, Khujand and ABL viruses. Another 13 samples were also found to have antibody to ABLV. However, due to insufficient volume, further analysis to other lyssaviruses could not be performed. Nevertheless, this showed that the prevalence of lyssavirus infection in Thai bats could be as high as 7.3% (29/396). The present study showed that natural occurrence of lyssavirus antibodies found in Thai bats were related to newer putative lyssavirus genotype(s) other than those previously described. These data also suggest that several lyssaviruses are in circulation throughout Thailand as well as other Asian countries, such as in the Philippines, Central Asia, and in certain parts of Russia. The present study and preparation of this article was supported by grants from the Thailand Research Fund and the National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Thailand.
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2,336,486 |
Familial influences on alcohol use in adolescent female twins: testing for genetic and environmental interactions.
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Both genetic and common environmental influences contribute to twin associations for substance use; however, twin concordance rates may vary by environmental setting, indicating the presence of genetic-environmental interactions. The present study examined whether measures of family adaptability and cohesion may moderate the genetic influence on risk for alcohol use among female adolescents.</AbstractText>We examined such interactions through the application of log-linear models using data from the Virginia Twin Study of Adolescent Behavioral Development, a longitudinal study with extensive home interviews of adolescent (8-17 year old) female twins (386 monozygotic [MZ] pairs, 185 dizygotic [DZ] pairs) and their parents.</AbstractText>Twin concordance for alcohol use varied by average twin/parent reports of parental closeness. Differences between MZ-DZ correlations for alcohol use in families with low parental closeness, for example, were 0.97 and 0.67 (p < .001), respectively, compared with 0.79 and 0.73 (p = .24) for high parental closeness families. In addition, differences in twin concordance regardless of zygosity were found with greater twin similarities for alcohol use in strict families compared with leniently disciplined families, suggesting that the twin association interacts with common environmental influences on alcohol use.</AbstractText>These results indicate that the genetic effects on adolescent alcohol use interact with the measured family environment and that the heritability of alcohol use may vary according to quality of the parental relationship. If confirmed, prevention programs may benefit from this knowledge, tailoring their intervention to quality of parental relationship.</AbstractText>
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2,336,487 |
Haplotype interaction analysis of unlinked regions.
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Genetically complex diseases are caused by interacting environmental factors and genes. As a consequence, statistical methods that consider multiple unlinked genomic regions simultaneously are desirable. Such consideration, however, may lead to a vast number of different high-dimensional tests whose appropriate analysis pose a problem. Here, we present a method to analyze case-control studies with multiple SNP data without phase information that considers gene-gene interaction effects while correcting appropriately for multiple testing. In particular, we allow for interactions of haplotypes that belong to different unlinked regions, as haplotype analysis often proves to be more powerful than single marker analysis. In addition, we consider different marker combinations at each unlinked region. The multiple testing issue is settled via the minP approach; the P value of the "best" marker/region configuration is corrected via Monte-Carlo simulations. Thus, we do not explicitly test for a specific pre-defined interaction model, but test for the global hypothesis that none of the considered haplotype interactions shows association with the disease. We carry out a simulation study for case-control data that confirms the validity of our approach. When simulating two-locus disease models, our test proves to be more powerful than association methods that analyze each linked region separately. In addition, when one of the tested regions is not involved in the etiology of the disease, only a small amount of power is lost with interaction analysis as compared to analysis without interaction. We successfully applied our method to a real case-control data set with markers from two genes controlling a common pathway. While classical analysis failed to reach significance, we obtained a significant result even after correction for multiple testing with our proposed haplotype interaction analysis. The method described here has been implemented in FAMHAP.
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2,336,488 |
Spastin mutations in sporadic adult-onset upper motor neuron syndromes.
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Mutation of the spastin gene is the single most common cause of pure hereditary spastic paraparesis. In patients with an unexplained sporadic upper motor neuron (UMN) syndrome, clinical distinction between primary lateral sclerosis and sporadic hereditary spastic paraparesis may be problematic. To investigate whether spastin mutations are present in patients with primary lateral sclerosis and sporadic hereditary spastic paraparesis, we screened the spastin gene in 99 Dutch patients with an unexplained, apparently sporadic, adult-onset UMN syndrome. We found 6 mutations, of which 4 were novel, in the subgroup of 47 patients with UMN symptoms restricted to the legs (13%). Another novel spastin mutation was found in a patient with a rapidly progressive spinal and bulbar UMN syndrome that progressed to amyotrophic lateral sclerosis. In the patients with arm or bulbar UMN symptoms and slow progression, no spastin mutations were found. Our study shows that spastin mutations are a frequent cause of apparently sporadic spastic paraparesis but not of primary lateral sclerosis.
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2,336,489 |
Genotype-phenotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease.
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The incidence of early-onset CD in Scotland is among the highest worldwide. Three single nucleotide polymorphisms (SNPs) R702W, G908R and Leu1007finsC in the NOD2/CARD15 gene predispose to adult CD. We investigated the contribution of these variants to disease susceptibility and phenotype in the Scottish early-onset IBD population.</AbstractText>906 individuals including 247 Scottish IBD patients aged <16 years at diagnosis, 414 parents and 245 controls were genotyped. Transmission disequilibrium testing (TDT), case-control analysis and detailed genotype-phenotype analysis were performed.</AbstractText>The Leu1007finsC variant was associated with susceptibility to CD by case-control (4.2% versus. 1.4%, P = 0.01) and TDT analysis (P = 0.006). The Population Attributable Risk (PAR) for the 3 NOD2/CARD15 mutations was 7.9%. Carriage of NOD2/CARD15 variants was associated with, at diagnosis: decreased albumin (31.0% versus. 9.0%, P = 0.001) and raised CRP (25% versus. 9.5%, P = 0.04) and at follow up: need for surgery (39.5% versus. 12.8%, P = 0.0002) jejunal involvement (50% versus. 18.4%, P = 0.01) jejunal and ileal involvement (50% versus. 10.7%, P = 0.009), raised CRP (57.1% and 12.8%, P = 0.0009), lower weight/height centile (75.0% versus. 20.2%, P = 0.03, 50.0% versus. 16.0%, P = 0.001 respectively) and stricturing disease (45.5% versus. 19.4%, P < 0.05). Multifactorial analysis demonstrated carriage was associated with need for surgery (P = 0.004, OR 4.9 [1.5-14.7]).</AbstractText>These NOD2/CARD 15 variants in the Scottish early onset CD population have a definite, albeit relatively small contribution to CD susceptibility (PAR 7.9%) but a major impact on phenotype. In particular NOD2/CARD15 variants are strongly associated with several markers of disease severity in pediatric CD, notably need for surgery.</AbstractText>
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2,336,490 |
Heterozygosity mapping by quantitative fluorescent PCR reveals an interstitial deletion in Xq26.2-q28 associated with ovarian dysfunction.
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Deletions of Xq chromosome are reported for a number of familial conditions exhibiting premature ovarian failure (POF) and early menopause (EM).</AbstractText>We describe the inheritance of an interstitial deletion of the long arm of the X chromosome associated with either POF or EM in the same family. Cytogenetic studies and heterozygosity mapping by quantitative fluorescent PCR revealed a 46,X,del(X)(q26.2-q28) karyotype in a POF female, in her EM mother, and also in her aborted fetus with severe cardiopathy. Applying a microsatellite approach, we have narrowed the extension of an identical interstitial deletion located between DXS1187 and DXS1073. These data, in line with other mapped deletions, single out the proximal Xq28 as the region most frequently involved in ovarian failure. We also propose that other factors may influence the phenotypic effect of this alteration. Indeed, skewed X inactivation has been ascertained in EM and POF to be associated with different X haplotypes.</AbstractText>Our analysis indicates that Xq26.2-q28 deletion is responsible for gonad dysgenesis in a family with EM/POF. The dissimilar deletion penetrance may be due to epigenetic modifications of other X genes that can contribute to human reproduction, highlighting that ovarian failure should be considered as a multifactorial disease.</AbstractText>
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2,336,491 |
Atopic dermatitis, extrinsic atopic dermatitis and the hygiene hypothesis: results from a cross-sectional study.
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Atopic Dermatitis (AD), hayfever and asthma are commonly summarized as atopic diseases. The spatial distribution of AD differs from that of asthma and hayfever, suggesting that AD might follow a different risk pattern than these diseases. AD can be differentiated into an allergic extrinsic form (EAD) and a non-allergic intrinsic form (IAD). Only EAD might follow the distribution and risk pattern that have been ascribed to asthma and hayfever.</AbstractText>To investigate the distribution and risk factor profile of AD and EAD focusing on environmental factors relating to the hygiene hypothesis.</AbstractText>Population-based cross-sectional study on 12,601 children aged 5-7 and 9-11 years from Dresden (Eastern Germany) and Munich (Western Germany). Information was obtained by International Study of Asthma and Allergic Childhood questionnaires, dermatological examinations and skin prick testing. AD-diagnosis ever, current AD-symptoms and visible eczema were investigated with their respective extrinsic forms.</AbstractText>Maternal and paternal history of AD were equally strong determinants of the child's AD status. Factors related to the hygiene hypothesis like day-care attendance and number of older siblings were not associated with a decreased risk of AD. The proportion of EAD within AD was higher in Eastern than in Western Germany. The determinants of the diseases appeared to be similar for both EAD and IAD.</AbstractText>There was no evidence of the hygiene hypothesis holding true for AD or EAD. AD might be a separate entity than respiratory atopic diseases. Little is known about the risk factors of AD and factors different from those of respiratory allergic diseases should be considered in future research.</AbstractText>
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2,336,492 |
Transmission of Campylobacter spp. to chickens during transport to slaughter.
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To determine the prevalence of Campylobacter-contaminated transport crates and to determine whether contaminated crates represent a risk for contamination of chickens during transport to slaughter.</AbstractText>Samples were collected from cleaned transport crates before they were dispatched to the farms. Chicken groups were sampled within 24 h before transport to slaughter and at the slaughterhouse. Campylobacter spp. were isolated from 69 of 122 (57%) sampled batches of transport crates. Twenty-six slaughter groups, negative at farm level, were transported in batches of crates from which Campylobacter spp. had been isolated. In 11 (42%) of these 26 slaughter groups, Campylobacter spp. were found in samples taken at slaughter. The corresponding figure for at-farm-negative slaughter groups transported in negative crates was four (15%) testing positive at slaughterhouse of 27 slaughter groups [relative risk (RR) = 2.9, 95% CI 1.1-7.3]. In four of 11 slaughter groups, genetic subtyping by pulsed-field gel electrophoresis was able to support the hypothesis of contamination from crates to chickens during transport to slaughter.</AbstractText>Despite washing and disinfection, crates were frequently contaminated with Campylobacter and it could have contaminated chickens during transport to slaughter.</AbstractText>Campylobacter-positive crates are a risk factor for chickens testing campylobacter-positive at slaughter.</AbstractText>
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2,336,493 |
[Prophylactic surgery of mammary and ovarian carcinoma].
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New insights into the genetic basis of carcinogenesis have been obtained by modern molecular biological techniques. Several susceptibility genes are known. The hereditary breast and ovarian cancer syndrome (germline mutations in BRCA1 and BRCA2) and endometrial cancer in the context of the hereditary non-polyposis colorectal cancer syndrome (HNPCC), germline mutations in mismatch-repair genes, are the most frequent hereditary cancer syndromes in gynaecology. Mutations in TP53 (Li-Fraumeni syndrome) and PTEN (Cowden's disease), associated with increased risk of breast cancer, are responsible for a smaller portion of familial breast cancer. The risk of inheritance and disease can be identified and defined by investigating family history, risk calculation programs, and genetic testing. Afterwards, options of primary, secondary, and tertiary prevention can be formulated. Presently, prophylactic surgery is the only option proven by clinical trials that can reduce the mortality of hereditary breast and ovarian cancer.
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2,336,494 |
Assay validation for identification of hereditary nonpolyposis colon cancer-causing mutations in mismatch repair genes MLH1, MSH2, and MSH6.
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Hereditary nonpolyposis colon cancer (HNPCC, Online Mendelian Inheritance in Man (OMIM) 114500) is an autosomal dominant disorder that is genetically heterogeneous because of underlying mutations in mismatch repair genes, primarily MLH1, MSH2, and MSH6. One challenge to correctly diagnosing HNPCC is that the large size of the causative genes makes identification of mutations both labor intensive and expensive. We evaluated the usefulness of denaturing high performance liquid chromatography (DHPLC) for scanning mismatch repair genes (MLH1, MSH2, and MSH6) for point mutations, small deletions, and insertions. Our assay consisted of 51 sets of primers designed to amplify all exons of these genes. All polymerase chain reaction reactions were amplified simultaneously using the same reaction conditions in a 96-well format. The amplified products were analyzed by DHPLC across a range of optimum temperatures for partial fragment denaturation based on the melting profile of each specific fragment. DNA specimens from 23 previously studied HNPCC patients were analyzed by DHPLC, and all mutations were correctly identified and confirmed by sequence analysis. Here, we present our validation studies of the DHPLC platform for HNPCC mutation analysis and compare its merits with other scanning technologies. This approach provides greater sensitivity and more directed molecular analysis for clinical testing in HNPCC.
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2,336,495 |
A novel multiplexing, polymerase chain reaction-based assay for the analysis of chromosome 18q status in colorectal cancer.
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Chromosome 18q allelic loss has been reported to have prognostic significance in stage II colorectal carcinoma. We have developed a fluorescent multiplex polymerase chain reaction assay to analyze five microsatellite markers (D18S55, D18S58, D18S61, D18S64, and D18S69) for allelic loss at the long arm of chromosome 18. Amplicon detection and evaluation was accomplished by capillary electrophoresis using an ABI 310 genetic analyzer. Robustness of the assay when performed on DNA extracted from formalin-fixed, paraffin-embedded tissue sections was confirmed by analyzing its repeatability and reproducibility. Allelic loss was assessed in 61 stage II colorectal tumors and was detected in 58% (31 of 53) of tumors not showing instability. As part of the study, results of 207 previous polymerase chain reaction/polyacrylamide-based assays were re-evaluated by two independent observers to determine the degree of concordance of visual evaluation. In the case of stage II colorectal tumors, when electropherogram results were compared with those obtained from visual evaluation of the same markers after polyacrylamide gel electrophoresis, discrepancies between observers were detected in 16.4% of determinations. In conclusion, we have developed a robust and reliable assay for multiplexed loss of heterozygosity determination that improves assessment of chromosome 18q allelic loss in colorectal tumors processed as routine formalin-fixed, paraffin-embedded specimens.
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2,336,496 |
Tumor microsatellite instability in early onset gastric cancer.
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Gastric cancer (GC) remains a leading cause of cancer mortality worldwide. Genetic factors are implicated, including DNA mismatch repair (MMR) deficiency manifested as tumor microsatellite instability (MSI). However, a standardized panel of markers and a definition of low-versus-high level MSI in GC are lacking. We examined a population-based cohort of early onset (<or=50 yrs) gastric cancer. We identified 211 cases of early onset gastric cancer in Central-East Ontario from 1989 to 1993, with archival material available for 139 cases. Testing included a six-mononucleotide marker panel and a three-MMR immunohistochemical panel. Overall, 30% (41 of 139) of GC were MSI+, with allelic shifts at one to eight markers. An unexpected discordance between the BAT-25, BAT-26, and BAT-40 markers was observed in the MSI+ cases. Six cases showing multiple loci instability (>or=3 markers MSI+/MSI-high) demonstrated MMR protein deficiency. Three novel hMLH1 mutations (two germline frameshift and one somatic nonsense) were also found. The only significant clinicopathological associations were increased tumor size in MSI+ cases (P=0.04) and Lauren histotype (P=0.006) and tumor grade (P=0.007) in MSI-high cases. Tumor size, location, depth, nodal status, and Ming subtype were significant prognostic variables. Therefore, we propose a new definition of high-level MSI based on unifying characteristics of instability of more than or equal to three of six mononucleotide markers and loss of MMR protein expression.
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2,336,497 |
Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation.
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The SCN8A gene on chromosome 12q13 encodes the voltage gated sodium channel Na(v)1.6, which is widely expressed in neurons of the CNS and PNS. Mutations in the mouse ortholog of SCN8A result in ataxia and other movement disorders.</AbstractText>We screened the 26 coding exons of SCN8A in 151 patients with inherited or sporadic ataxia.</AbstractText>A 2 bp deletion in exon 24 was identified in a 9 year old boy with mental retardation, pancerebellar atrophy, and ataxia. This mutation, Pro1719ArgfsX6, introduces a translation termination codon into the pore loop of domain 4, resulting in removal of the C-terminal cytoplasmic domain and predicted loss of channel function. Three additional heterozygotes in the family exhibit milder cognitive and behavioural deficits including attention deficit hyperactivity disorder (ADHD). No additional occurrences of this mutation were observed in 625 unrelated DNA samples (1250 chromosomes).</AbstractText>The phenotypes of the heterozygous individuals suggest that mutations in SCN8A may result in motor and cognitive deficits of variable expressivity, but the study was limited by lack of segregation in the small pedigree and incomplete information about family members. Identification of additional families will be required to confirm the contribution of the SCN8A mutation to the clinical features in ataxia, cognition and behaviour disorders.</AbstractText>
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2,336,498 |
Localization of a mutant p53 response element on the tissue inhibitor of metalloproteinase-3 promoter: mutant p53 activities are distinct from wild-type.
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Missense mutations in the p53 gene have been observed in greater than 60% of all human tumors. Recent evidence indicates that some mutations in p53 arise as the cancer progresses from a benign tumor to a metastatic tumor and that these mutations in p53 actively contribute to the process of cancer progression. Previously, we reported that the expression of the gene encoding the tissue inhibitor of metalloproteinase-3 (TIMP-3) is repressed in cells expressing codons 248 and 281 mutant p53 alleles. The ability of tumor-derived p53 mutants to inhibit TIMP-3 expression provides a novel mechanism for understanding how p53 mutations might contribute to tumorigenesis. Since mutant p53 is often expressed at elevated levels in a variety of cancers, the generation of cells in a tumor carrying certain mutations in p53 would cause inappropriately reduced expression of TIMP-3 and lead to elevated matrix metalloproteinase activity. We present the results of experiments that begin to determine the mechanism by which mutant p53 represses TIMP-3 gene expression. By generating deletion derivatives of the TIMP-3 promoter and testing them for expression and by performing DNA protein binding assays on the regions determined to be required for repression, we have identified elements that are essential for mutant p53-mediated transcriptional repression. These elements respond specifically to mutant but not wild type p53. While mutant p53 itself does not bind to the TIMP-3 promoter, we provide evidence for the presence of DNA binding proteins whose activity is enhanced in the presence of mutant p53.
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2,336,499 |
Assessing the power of tag SNPs in the mapping of quantitative trait loci (QTL) with extremal and random samples.
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Recent studies have indicated that the human genome could be divided into regions with low haplotype diversity interspersed with regions of high haplotype diversity. In regions of low haplotype diversity, a small fraction of SNPs (tag SNPs) are sufficient to account for most of the haplotype diversity of the human genome. These tag SNPs can be extremely useful for testing the association of a marker locus with a qualitative or quantitative trait locus in that it may not be necessary to genotype all the SNPs. When tag SNPs are used to reduce the genotyping effort in association studies, it is important to know how much power is lost. It is also important to know how much power is gained when tag SNPs instead of the same number of randomly chosen SNPs are used.</AbstractText>We design a simulation study to tackle these problems for a variety of quantitative association tests using either case-parent samples or unrelated population samples. First, the samples are generated based on the quantitative trait model with the assumption of either an extremal sampling scheme or a random sampling scheme. Second, a small number of samples are selected to determine the haplotype blocks and the tag SNPs. Third, the statistical power of the tests is evaluated using four kinds of data: (1) all the SNPs and the corresponding haplotypes, (2) the tag SNPs and the corresponding haplotypes, (3) the same number of evenly spaced SNPs with minor allele frequency greater than a threshold and the corresponding haplotypes, (4) the same number of randomly chosen SNPs and their corresponding haplotypes.</AbstractText>Our results suggest that in most situations genotyping efforts can be significantly reduced by using tag SNPs for mapping the QTL in association studies without much loss of power, which is consistent with previous studies on association mapping of qualitative traits. For all situations considered, two-locus haplotype analysis using tag SNPs are more powerful than those using the same number of randomly selected SNPs, but the degree of such power differences depends upon the sampling scheme and the population history.</AbstractText>
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