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At least 433 records · Page 24Linked to original sources
PubMed2005

A Pyrosequencing assay for rapid recognition of SNPs in Mycobacterium tuberculosis embB306 region.

Ethambutol (EMB) is in use worldwide as a first-line anti-tuberculosis drug and substitutions in codon 306 of the embB gene are the most common mutations found in EMB resistant Mycobacterium tuberculosis (MTB) strains. Pyrosequencing is a real time sequencing method able to rapidly detect mutations in a large number of samples. Using this technique we analyzed, in parallel with conventional sequencing, a 24 bp region of the embB gene of 28 MTB clinical isolates. Pyrosequencing efficiently identified all embB306 mutations, detecting three different single-base substitutions leading to 2 amino acid changes (Met to Val or Ile). Mutated embB alleles were detected in 2 multidrug-resistant (MDR) EMB-susceptible strains. Overall, our results demonstrated that the Pyrosequencing method efficiently recognizes mutations in embB in a very short time and represents a valid molecular method to detect mutations in the MTB embB306 region.

Antitubercular Agents↗
PubMed2005

Gene SNPs and mutations in clinical genetic testing: haplotype-based testing and analysis.

Haplotype-based analysis using high-density single nucleotide polymorphism (SNP) markers have gained increasing attention in evaluating candidate genes in various clinical situations. For example, haplotype information is useful for predicting the severity and prognosis of certain genetic disorders. The intragenic cis-interactions between the common polymorphisms and the pathogenic mutations of prion protein (PRNP) and cystic fibrosis transmembrane conductance regulator (CFTR) genes greatly influence the phenotypes and the disease penetrance of hereditary Creutzfeldt-Jakob disease and cystic fibrosis. Merits of haplotype study are more evident in the fine mapping of complex diseases and in identifying genetic variations that influence individual's response to drugs. Knowledge-based approaches and/or linkage analyses using SNP tagged haplotypes are effective tools in detecting genetic associations. For example, haplotype studies in the inflammatory bowel disease susceptibility loci revealed diverse cis and trans gene-gene interactions, which can affect the clinical outcomes. Although currently, we have very limited knowledge on haplotype-phenotypic characterizations of most genes, these examples demonstrate that increased understanding of the clinically relevant haplotypes will provide better results in the diagnosis and possibly in the treatment of both monogenic and polygenic diseases.

Amyloid↗
PubMed2004

Three SNPs in the GSTO1, GSTO2 and PRSS11 genes on chromosome 10 are not associated with age-at-onset of Alzheimer's disease.

Linkage studies suggest the presence of putative risk and/or age-at-onset genes for Alzheimer's disease on Chromosome 10. Recently, a genomic converging approach using a combination of linkage, expression and association studies has reported significant associations of the glutathione S-transferase omega 1 and 2 (GSTO1 and GSTO2) genes and possibly the protease serine 11 (PRSS11) gene on chromosome 10 with age-at-onset, but not risk, for Alzheimer's disease (AD) and Parkinson disease. We investigated the association of the reported three polymorphisms in 990 sporadic late-onset AD cases (26% autopsy confirmed) and 735 controls. In our sample, we found no association either with age-at-onset in AD cases or with disease risk in the case-control cohort. However, haplotype analysis revealed a modest association of one haplotype with AD risk (p = 0.04). Additional markers in these genes need to be screened to explore their role in the etiology of AD.

Adult↗
PubMed2005

The usefulness of single nucleotide polymorphisms (SNPs) for genetic epidemiological investigation of complex psychiatric diseases.

The genetic epidemiology of complex psychiatric diseases has become a much studied and very prospering field. It is widely believed that many genetic factors contribute to the various phenotypes and diseases, with overall contributions of a single factor being comparatively minor. The study of choice in such settings is the investigation of allelic association, which may be performed in a variety of ways. Here single nucleotide polymorphisms are an indispensable tool.

Gene Frequency↗
PubMed2005

No association of haplotype-tagging SNPs in TRAR4 with schizophrenia in Japanese patients.

Recent study of linkage disequilibrium mapping showed one of the trace amine receptor (TRAR) genes, TRAR4, was associated with schizophrenia. We conducted a replication study of TRAR4 with schizophrenia in Japanese patients. We used two large independent sets of samples in a first-set analysis (cases=405, controls=401) and second-set analysis (cases=503, controls=440). In the first-set analysis, one Marker (Marker5) showed a significant association, but this significance was not seen in the second-set analysis. Our results indicate that TRAR4 may not play a major role in Japanese schizophrenia patients, and that it is important to examine the possibility of false positives in genetic association analysis.

Adult↗
PubMed2004

Linkage disequilibrium maps constructed with common SNPs are useful for first-pass disease association screens.

To develop an efficient strategy for mapping genetic factors associated with common diseases, we constructed linkage disequilibrium (LD) maps of human chromosomes 5, 7, 17, and X. These maps consist of common single nucleotide polymorphisms at an average intermarker distance of 100 kb. The genotype data from these markers in a panel of American samples of European descent were analyzed to produce blocks of markers in strong pair-wise LD. Power calculations were used to guide block definitions and predicted that high-level LD maps would be useful in initial genome scans for susceptibility alleles in case-control association studies of complex diseases. As anticipated, LD blocks on the X chromosome were larger and covered more of the chromosome than those found on the autosomes.

Black or African American↗
PubMedDate not supplied

Mutations and promoter SNPs in RUNX2, a transcriptional regulator of bone formation.

Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal malformation syndrome with high penetrance and variable expressivity. It is caused by loss of function mutations in the RUNX2 gene that encodes for a transcription factor essential for osteoblast differentiation and chondrocyte maturation. To identify new pathogenic mutations associated with CCD we screened 38 CCD patients for mutations in the RUNX2 coding sequence. We also report the mutation screening of the "bone-related" RUNX2 promoter in CCD patients without mutation in the RUNX2 coding region. We identify eight new and three previously described mutations in the RUNX2 gene. Additionally, a total of five sequence variants in the RUNX2 promoter were detected. Three of them occur within putative zinc finger transcription factor binding sites. DHPLC analysis of chromosomes from the control population and CCD patients showed that two promoter sequence variants were unique for CCD families. Electrophoretic mobility shift assay (EMSA) with protein extracts from ROS17/2.8 and C3H10T1/2 cell lines demonstrated that the promoter sequence variants altered DNA-protein binding specificity. Moreover, one of the variants significantly decreased the expression of a RUNX2 reporter gene in osteoblastic ROS17/2.8 cells, but not in multipotent, mesenchymal C3H10T1/2 cells. Interestingly, one of these sites bound the TRPS1 transcription factor and we demonstrated that TRPS1 is able to repress the RUNX2 promoter. The in vitro functional studies in conjunction with analysis of clinical phenotype of CCD patients suggest that these promoter sequence variants may affect transcriptional activity of the RUNX2 gene. Analysis of the promoter variants and RUNX2-interacting proteins may help to identify important cis-elements and trans-factors that regulate the RUNX2 transcriptional network and identify new susceptibility markers for more common bone disorders.

Animals↗
PubMed2002

Can mutation or fixation biases explain the allele frequency distribution of human single nucleotide polymorphisms (SNPs)?

One of the most abiding controversies in evolutionary biology concerns the role of neutral processes in molecular evolution. A main focus of the debate has been the evolution of isochores, the strong and systematic variation of base composition in mammalian genomes. One set of hypotheses argue that regions of similar GC are owing to localised mutational biases coupled with neutral evolution. The alternatives point to either selection or biased gene conversion as mechanisms to preferentially remove A or T bases, favouring G and C instead. Using a novel method, we compare models including such fixation biases to models based on mutation bias alone, under the assumption that non-coding, non-repetitive human DNA is at compositional equilibrium. While failing to fully explain the allele frequency distributions of recent single nucleotide polymorphism data, we show that the data are best fitted if the mutation bias is assumed to be constant across the genome, while fixation bias varies with GC content. We also attempt to estimate the strength of fixation bias, which increases linearly with increasing GC. Our approximation suggests that this force exists within the necessary parameter range: it is not so weak as to be drowned by random drift, but not so strong as to lead to exclusive use of G and C alone. Together these results demonstrate that mutation bias fails to explain the evolution of isochores, and suggest that either selection or biased gene conversion are involved.

Alleles↗
PubMed2002

Gene repair and mutagenesis mediated by chimeric RNA-DNA oligonucleotides: chimeraplasty for gene therapy and conversion of single nucleotide polymorphisms (SNPs).

Gene augmentation is an attractive and viable approach in treatment of inherited diseases, despite its limitations, such as the eliciting of host immune response, and the sustainability of gene expression. Therefore, alternative therapeutic approaches are being investigated, such as the use of chimeric RNA-DNA oligonucleotides (chimeraplasts), in which a mutated allele that already exists in an affected individual can be corrected. Although the only gene defects that can be corrected by chimeraplasty are point mutations, and the correction frequencies are variable, it has been observed that intracellular delivery of oligonucleotides is likely to be more efficient than that of plasmid DNA or viral vectors. Furthermore, corrected genes are expressed from their autologous promoters, thus ensuring correct spatial and temporal expression. Here we report on the recent progress made in the field of chimeraplasty, and the problems encountered.

Anemia, Sickle Cell↗
PubMed2002

A bias-ed assessment of the use of SNPs in human complex traits.

Although many biotechnological advancements have been made in the past decade, there has been very limited success in unraveling the genetic component of complex traits. Heavily invested research has been initiated based on etiological models of unrealistic simplicity and conducted under poor experimental designs, on data sets of insufficient size, leading to an overestimation of the effect sizes of genetic variants and the quantity and quality of linkage disequilibrium (LD). Arguments about whether families or unrelated individuals provide more power for gene mapping have been erroneously debated as issues of whether linkage or LD are more detectable sorts of correlation. Although the latter issue may be subject to debate, there is no doubt that family-based analysis is more powerful for detecting linkage and/or LD. If the recent advances in biotechnology are to be exploited effectively, vastly improved study designs will be imperative, as the reasons for the lack of success to date have much more to do with biology than technology, an issue that has become increasingly clear with the findings of the past years.

Bias↗
PubMed2001

The heart SNPs a beat: polymorphisms in candidate genes for cardiovascular disease.

Several environmental risk factors of cardiovascular disease are well established, but genetic risk alleles contributing to the disease in the general population are hotly debated. New strategies focusing on polymorphism discovery in candidate disease genes followed by tests of association to genes across the genome offer a pioneering approach to identifying risk alleles. Several hundred candidate genes for cardiovascular disease have been screened for common polymorphisms and these variants may provide susceptibility alleles which largely contribute to risk of cardiovascular disease in the general population. However, the impact of common susceptibility alleles for disease management will depend on many years of future investigation.

Cardiovascular Diseases↗