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At least 703 records · Page 39Linked to original sources
PubMed2004

The west side story: MEFV haplotype in Spanish FMF patients and controls, and evidence of high LD and a recombination "hot-spot" at the MEFV locus.

Mutations at the MEFV gene cause, with various degrees of penetrance, familial Mediterranean fever (FMF). This disease is more prevalent in the Middle East than elsewhere, and most studies have focused on those populations. However, FMF occurs also in the Western Mediterranean and these populations should be taken into account for a complete view of FMF. We have analyzed intragenic MEFV SNPs in Spanish and Chueta (descendants of converted Jews) FMF patients and controls, and this constitutes the first systematic survey of normal MEFV SNP haplotype structure and variability. Our findings have allowed us to systematize the nomenclature of MEFV haplotypes and show that there is strong linkage disequilibrium (LD) at the MEFV locus and an intragenic recombination hot spot. The high local LD, regardless the recombination hot spot, is responsible for the limited diversity of the MEFV control haplotypes found in the Spanish population and it suggests that it may be a common feature to all Mediterranean populations. The MEFV mutation spectrum in Spain is quite diverse, and similar to those of France and Italy. On the contrary, the Chueta spectrum was poorer and closer to that of North African Jews, suggesting a direct connection with the Jewish diaspora.

Case-Control Studies↗
PubMed2004

[Study on the optic neuropathy induced response protein gene mutation in Chinese patients with primary open-angle glaucoma].

OBJECTIVE: To screen the mutation loci of optic neuropathy induced response protein (OPTN) gene in Chinese with primary open-angle glaucoma (POAG) and to investigate the association between OPTN genotype and phenotype of POAG. METHODS: Specimens of peripheral blood were collected from Chinese 118 patients with POAG and 150 sex- and aged-matched subjects without POAG. Polymerase chain reaction (PCR) was used to analyze the coding sequence of OPTN gene consisting of thirteen exons. The abnormal strands by SSCP were evaluated by bi-directional sequencing. RESULTS: Eleven sequence changes were identified, 6 of which had been reported before (T34T, T49T, M98K, IVS6-SC-->T, IVS6-10G-->A, and R545Q), and 5 of which were novel (IVS6-9C-->T, IVS6-14G-->A, IVS7 + 36G-->A, IVS8-51T-->C, and K435R) Only K435R was found in patient with POAG, whereas IVS6-9C-->T and IVS6-14G-->A were present in control subjects. IVS6-5C-->T and IVS6-10G-->A showed significant association with POAG. The patients with IVS6-5C-->T sequence abnormality were aged 23 to 73 with an average intraocular pressure of 23.14 mm Hg (1 mm Hg =0. 133 kPa) and a mean defect of visual field 0.2 to 28. 2dB. The patients with IVS6-10C-->T sequence abnormality were aged 20 to 74 with an average intraocular pressure of 20.19 mm Hg and a mean defect of visual field from 0.9 to 26. 5dB. CONCLUSION: The single nucleotide polymorphism (SNP) of OPTN gene may contribute to the pathogenesis of glaucoma in Chinese.

Adolescent↗
PubMed2006

SNP-PHAGE--High throughput SNP discovery pipeline.

BACKGROUND: Single nucleotide polymorphisms (SNPs) as defined here are single base sequence changes or short insertion/deletions between or within individuals of a given species. As a result of their abundance and the availability of high throughput analysis technologies SNP markers have begun to replace other traditional markers such as restriction fragment length polymorphisms (RFLPs), amplified fragment length polymorphisms (AFLPs) and simple sequence repeats (SSRs or microsatellite) markers for fine mapping and association studies in several species. For SNP discovery from chromatogram data, several bioinformatics programs have to be combined to generate an analysis pipeline. Results have to be stored in a relational database to facilitate interrogation through queries or to generate data for further analyses such as determination of linkage disequilibrium and identification of common haplotypes. Although these tasks are routinely performed by several groups, an integrated open source SNP discovery pipeline that can be easily adapted by new groups interested in SNP marker development is currently unavailable. RESULTS: We developed SNP-PHAGE (SNP discovery Pipeline with additional features for identification of common haplotypes within a sequence tagged site (Haplotype Analysis) and GenBank (-dbSNP) submissions. This tool was applied for analyzing sequence traces from diverse soybean genotypes to discover over 10,000 SNPs. This package was developed on UNIX/Linux platform, written in Perl and uses a MySQL database. Scripts to generate a user-friendly web interface are also provided with common queries for preliminary data analysis. A machine learning tool developed by this group for increasing the efficiency of SNP discovery is integrated as a part of this package as an optional feature. The SNP-PHAGE package is being made available open source at http://bfgl.anri.barc.usda.gov/ML/snp-phage/. CONCLUSION: SNP-PHAGE provides a bioinformatics solution for high throughput SNP discovery, identification of common haplotypes within an amplicon, and GenBank (dbSNP) submissions. SNP selection and visualization are aided through a user-friendly web interface. This tool is useful for analyzing sequence tagged sites (STSs) of genomic sequences, and this software can serve as a starting point for groups interested in developing SNP markers.

Base Sequence↗
PubMed2005

Identification of disease causing loci using an array-based genotyping approach on pooled DNA.

BACKGROUND: Pooling genomic DNA samples within clinical classes of disease followed by genotyping on whole-genome SNP microarrays, allows for rapid and inexpensive genome-wide association studies. Key to the success of these studies is the accuracy of the allelic frequency calculations, the ability to identify false-positives arising from assay variability and the ability to better resolve association signals through analysis of neighbouring SNPs. RESULTS: We report the accuracy of allelic frequency measurements on pooled genomic DNA samples by comparing these measurements to the known allelic frequencies as determined by individual genotyping. We describe modifications to the calculation of k-correction factors from relative allele signal (RAS) values that remove biases and result in more accurate allelic frequency predictions. Our results show that the least accurate SNPs, those most likely to give false-positives in an association study, are identifiable by comparing their frequencies to both those from a known database of individual genotypes and those of the pooled replicates. In a disease with a previously identified genetic mutation, we demonstrate that one can identify the disease locus through the comparison of the predicted allelic frequencies in case and control pools. Furthermore, we demonstrate improved resolution of association signals using the mean of individual test-statistics for consecutive SNPs windowed across the genome. A database of k-correction factors for predicting allelic frequencies for each SNP, derived from several thousand individually genotyped samples, is provided. Lastly, a Perl script for calculating RAS values for the Affymetrix platform is provided. CONCLUSION: Our results illustrate that pooling of DNA samples is an effective initial strategy to identify a genetic locus. However, it is important to eliminate inaccurate SNPs prior to analysis by comparing them to a database of individually genotyped samples as well as by comparing them to replicates of the pool. Lastly, detection of association signals can be improved by incorporating data from neighbouring SNPs.

Alleles↗
PubMed2004

Nitric oxide activates Rap1 and Ral in a Ras-independent manner.

Rap1 and Ral, the small GTPases belonging to the Ras superfamily, have recently attracted much attention; Ral because of Ral-specific guanine nucleotide exchange factors which are regulated by direct binding to Ras and Rap1 because of its proposed role as an antagonist of Ras signaling. We have previously demonstrated that nitric oxide (NO) activates Ras and proposed the structural basis of interaction between NO and Ras. In the present study we have shown that NO activates Rap1 and Ral in a time- and concentration-dependent manner. Using activation-specific probes for Rap1 and Ral, it was found that the NO-generating compounds SNP and SNAP could activate both Rap1 and Ral in Jurkat and PC12 cell lines. To investigate the involvement of Ras in NO mediated activation of Rap1 and Ral, we used PC12 cell lines expressing either the Ras mutant C118S (Cys118 mutated to Ser) or N17 (GDP-locked and inactive). We had previously shown that NO fails to activate Ras in these mutant cell lines. However, here it was found that Rap1 and Ral were activated by NO in these cell lines. The evidence presented in this study unambiguously demonstrates the existence of Ras-independent pathways for NO mediated activation of Rap1 and Ral.

Amino Acid Substitution↗
PubMed2001

High-throughput identification, database storage and analysis of SNPs in EST sequences.

Single nucleotide polymorphisms (SNPs) are the most frequent form of DNA variation and disease-causing mutations in many genes. Due to their abundance and slow mutation rate within generations, they are thought to be the next generation of genetic markers that can be used in a myriad of important biological, genetic, pharmacological, and medical applications. There are several strategies both experimental, and in-silico for SNP discovery and mapping. Experimental SNP discovery consists of a number of labourious steps that make this process complex and expensive. In-silico discovery has been proposed as an alternative discovery method that makes use and takes advantage of large data sets with potential SNP information that have been generated with other purposes and have not been used as a SNP information source yet. However, in order to successfully apply the in-silico method to large data sets, the following challenges need to be addressed: First it is necessary to build an integrated SNP pipeline that handles data processing steps smoothly from the beginning (collecting sequence information) to end (SNPs in the database). Also, SNP detection tool parameters have to be optimized to satisfy specific goals of the project. Finally, SNP data could not be fully used until the in-silico method is validated experimentally. In this paper we present a design and implementation of an in-silico SNP detection software pipeline that exploits the existence of large EST (expressed sequence tag) data sets and effectively addresses the above challenges. First, the pipeline allows for smooth data transition between its different components by implementing data interfaces that translate the data formats of the different tools in the different stages. Second, we optimized PolyBayes parameters for SNP detection in maize EST. Finally, we implemented a user interface that along with the database structure created allows the scientist to perform preliminary analysis of the data and to perform basic statistics on the SNP data prior to experimental validation. The pipeline works with two different types of sequence assemblers (PHRAP (http://www.phrap.org/) and CAT from DoubleTwist (http://www.doubletwist.com/). It uses a Bayesian engine for SNP detection (PolyBayes), selects relevant polymorphism information which is then uploaded into a database. We detected 2439 SNPs and 822 insertion deletions (INDELs) with a PolyBayes probability higher than 0.99 on the public set of 68,000 maize ESTs. The user interface allowed us analyzing the polymorphism information right after discovery in several ways that allowed us to gain insight into the distribution and significance of the newly acquired data.

Animals↗
PubMedDate not supplied

Association of a missense mutation in the bovine leptin gene with carcass fat content and leptin mRNA levels.

Previously, we have shown that alleles of the BM1500 microsatellite, located 3.6 kb downstream of the leptin gene in cattle, were associated with carcass fat measures in a population of 154 unrelated beef bulls. Subsequently, a cytosine (C) to thymine (T) transition that encoded an amino acid change of an arginine to a cysteine was identified in exon 2 of the leptin gene. A PCR-RFLP was designed and allele frequencies in four beef breeds were correlated with levels of carcass fat. The T allele was associated with fatter carcasses and the C allele with leaner carcasses. The frequencies of the SNP alleles among breeds indicated that British breeds have a higher frequency of the T allele whereas the continental breeds have a higher occurrence of the C allele. A ribonuclease protection assay was developed to quantify leptin mRNA in a separate group of animals selected by genotype. Animals homozygous for thymine expressed higher levels of leptin mRNA. This may suggest that the T allele, which adds an extra cysteine to the protein, imparts a partial loss of biological function and hence could be the causative mutation.

Adipose Tissue↗
PubMed2005

The T-786C NOS3 polymorphism in Alzheimer's disease: association and influence on gene expression.

A common single nucleotide polymorphism (SNP), consisting in a T-->C transition (T-786C) in endothelial nitric oxide synthase (NOS3), has been reported to be associated with vascular pathologies, but no information are available on a possible association with AD. T-786C genotype was determined by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) assay in an Italian population of 432 AD patients compared with 360 healthy controls, matched for ethnic background, age and gender. Peripheral blood mononuclear cells (PBMC) from 22 subjects (11 AD and 11 controls) carrying different genotypes were isolated. Total RNA was extracted and analyzed by real-time PCR. No significant differences either in allelic or genotypic frequencies of the T-786C polymorphism between AD and normal population were observed, even stratifying AD patients by age at onset, gender, or ApoE status. However, expression of NOS3 in PBMC seems to be influenced by the presence of the C mutated allele, as demonstrated by a tendency towards a decrease in mRNA levels in C carriers, assessed by real-time PCR assay. This effect was observed both in patients and controls, independently from the cognitive impairment, and is likely to be dose-dependent, being mostly evident in CC homozygous. In conclusion, the T-786C SNP does not seem to be a risk factor for sporadic AD, but its presence correlates with a trend toward lower NOS3 expression rate, possibly exerting a beneficial effect in AD by contributing to lower oxidative damage.

Alzheimer Disease↗
PubMed2004

Analysis of the allele-specific expression of the mismatch repair gene MLH1 using a simple DHPLC-Based Method.

Quantitative measures of allele-specific gene expression allow the indirect detection of mutations or sequence variants in regulatory elements or in other non-coding regions that may result in significant physiological or pathological changes of gene expression and may contribute to Mendelian or multifactorial disorders. We have devised a simple method, based on RT-PCR and single nucleotide primer extension (SNuPE) with unlabelled dideoxynucleotides, followed by DHPLC (denaturing high performance liquid chromatography). We established optimal conditions for separation of the extended products corresponding to the alleles of the c.655A>G (p.Ile219Val) SNP, which is the most frequent exonic polymorphism of MLH1. We then genotyped 99 unrelated control subjects and measured the allele-specific MLH1 expression in the 40 heterozygous controls found in this group. This method allowed us to define a narrow range of normal biallelic expression of MLH1, each allele contributing between 44.7% and 55.3% of the total expression. We then measured the allele-specific expression in hereditary nonpolyposis colorectal cancer (HNPCC) patients with MLH1 mRNAs bearing different stop-codon or frame-shift mutations, or in-frame deletions, in order to detect the effects of nonsense-mediated mRNA decay (NMD). Defects that induce mRNA instability were identified unambiguously and the data were consistent with current models of NMD. This study provides a sensitive tool to identify indirectly MLH1 defects that may escape detection in genomic DNA screenings but result in a quantitative change at the mRNA level.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Association of the PIM3 allele of the alpha-1-antitrypsin gene with chronic obstructive pulmonary disease.

OBJECTIVE: The study investigated the association of genetic polymorphism of the alpha1AT gene with COPD. DESIGN AND METHODS: The mutations and polymorphism of alpha1AT gene were investigated by DNA sequence analysis using polymerase chain reaction. RESULTS: The frequency of the PIM3 allele in COPD patients was found to be significantly higher than the controls (P < 0.0001). Five SNPs, including a novel SNP (24_25insA), were observed near the junction of exon-intron I. The occurrence of these SNPs didn't show any association with COPD. However, the PIM3 allele of the alpha1AT gene was found to be associated with COPD. CONCLUSION: The PIM3 allele of the alpha1AT gene is found to have an association with the pathogenesis of COPD in the Indian population.

Adult↗
PubMed2005

Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility.

Ath1 is a quantitative trait locus on mouse chromosome 1 that renders C57BL/6 mice susceptible and C3H/He mice resistant to diet-induced atherosclerosis. The quantitative trait locus region encompasses 11 known genes, including Tnfsf4 (also called Ox40l or Cd134l), which encodes OX40 ligand. Here we report that mice with targeted mutations of Tnfsf4 had significantly (P <or= 0.05) smaller atherosclerotic lesions than did control mice. In addition, mice overexpressing Tnfsf4 had significantly (P <or= 0.05) larger atherosclerotic lesions than did control mice. In two independent human populations, the less common allele of SNP rs3850641 in TNFSF4 was significantly more frequent (P <or= 0.05) in individuals with myocardial infarction than in controls. We therefore conclude that Tnfsf4 underlies Ath1 in mice and that polymorphisms in its human homolog TNFSF4 increase the risk of myocardial infarction in humans.

Aged↗
PubMed2005

USF1 and dyslipidemias: converging evidence for a functional intronic variant.

Upstream transcription factor 1 (USF1), the first gene associated with familial combined hyperlipidemia (FCHL), regulates numerous genes of glucose and lipid metabolism. Phenotypic overlap between FCHL, type 2 diabetes and the metabolic syndrome makes this gene an intriguing candidate in the disease process of these traits as well. As no disease-associated mutations in the coding region of USF1 have been identified, we addressed the functional role of intronic single nucleotide polymorphisms (SNPs) which define the FCHL-risk alleles of USF1, and identified that a 20 bp DNA sequence, containing the critical intronic SNP, binds nuclear protein(s), representing a likely transcriptional regulatory element. This functional role is further supported by the differential expression of USF1-regulated genes in fat biopsy between individuals carrying different allelic variants of USF1. Importantly, apolipoprotein E (APOE) is the most downregulated gene in the risk individuals, linking the potential risk alleles of USF1 with the impaired APOE-dependent catabolism of atherogenic lipoprotein particles.

Animals↗
PubMed2005

Single nucleotide polymorphisms of the gonadotrophin-regulated testicular helicase (GRTH) gene may be associated with the human spermatogenesis impairment.

BACKGROUND: Gonadotropin-regulated testicular RNA helicase (GRTH) is a testis-specific RNA helicase that is essential for completion of spermatogenesis and is involved in pathogenesis of impaired spermatogenesis in mouse. It is therefore reasonable to postulate that human GRTH gene may also play a role in impaired spermatogenesis in humans. To test this hypothesis, we investigated the possible association between the variations of the GRTH gene and human spermatogenesis impairment. METHODS: Mutation screening of exons and intron/exon boundaries of GRTH gene was carried out by denaturing high-performance liquid chromatography (DHPLC) in 347 infertile patients with idiopathic azoospermia and severe oligozoospermia as well as 201 fertile men. RESULTS: Four single nucleotide polymorphisms (SNP), namely IVS6+55G-->T, ISV8+10A-->C, c.852C-->T and c.927G-->A, were identified. Among them, significant differences in polymorphism frequencies were observed at the polymorphic IVS6+55G-->T and c.852C-->T loci between the patients and controls, and a significant association between haplotypes of these two loci and male infertility with impaired spermatogenesis was detected. CONCLUSIONS: Results of the present study indicate that SNP IVS6+55G-->T and c.852C-->T of GRTH gene may be associated with male infertility with azoospermia or severe oligozoospermia, suggesting that variations in GRTH gene may contribute to susceptibility to spermatogenic impairment in humans.

Base Sequence↗
PubMed2002

BeadArray technology: enabling an accurate, cost-effective approach to high-throughput genotyping.

The Human Genome Project has opened the door to personalized medicine, provided that human genetic diversity can be analyzed in a high-throughput and cost-effective way Illumina has developed a genotyping system that combines very high throughput and accuracy with low cost per SNP analysis. The system uses our BeadArray platform, a high level of multiplexing, and modular, scalable automation to meet the requirements for cost-effective, genome-wide linkage disequilibrium studies. As implemented in a high-throughput genotyping service facility at Illumina, the system has a current capacity of one million SNP assays per day and is easily expandable. Each SNP call is associated with a quality score that correlates with accuracy

Cost-Benefit Analysis↗
PubMed2000

High-throughput SNP detection by using DNA pooling and denaturing high performance liquid chromatography (DHPLC).

One of the critical steps in the positional cloning of a complex disease gene involves association analysis between a phenotype and a set of densely spaced diallelic markers, typically single nucleotide repeats (SNPs), covering the region of interest. However, the effort and cost of detecting sufficient numbers of SNPs across relatively large physical distances represents a significant rate-limiting step. We have explored DNA pooling, in conjunction with denaturing high performance liquid chromatography (DHPLC), as a possible strategy for augmenting the efficiency, economy, and throughput of SNP detection. DHPLC is traditionally used to detect variants in polymerase chain reaction products containing both allelic forms of a polymorphism (e.g., heterozygotes or a 1:1 mix of both alleles) via heteroduplex separation and thereby requires separate analyses of multiple individual test samples. We have adapted this technology to identify variants in pooled DNA. To evaluate the utility and sensitivity of this approach, we constructed DNA pools comprised of 20 previously genotyped individuals with a frequency representation of 0%-50% for the variant allele. Mutation detection was performed by using temperature-modulated heteroduplex formation/DHPLC and dye-terminator sequencing. Using DHPLC, we could consistently detect SNPs at lower than 5% frequency, corresponding to the detection of one variant allele in a pool of 20 alleles. In contrast, fluorescent sequencing detected variants in the same pools only if the frequency of the less common allele was at least 10%. We conclude that DNA pooling of samples for DHPLC analysis is an effective way to increase throughput efficiency of SNP detection.

Alleles↗
PubMed2005

Neighboring-nucleotide effects on the mutation patterns of the rice genome.

DNA composition dynamics across genomes of diverse taxonomy is a major subject of genome analyses. DNA composition changes are characteristics of both replication and repair machineries. We investigated 3,611,007 single nucleotide polymorphisms (SNPs) generated by comparing two sequenced rice genomes from distant inbred lines (subspecies), including those from 242,811 introns and 45,462 protein-coding sequences (CDSs). Neighboring-nucleotide effects (NNEs) of these SNPs are diverse, depending on structural content-based classifications (genome-wide, intronic, and CDS) and sequence context-based categories (A/C, A/G, A/T, C/G, C/T, and G/T substitutions) of the analyzed SNPs. Strong and evident NNEs and nucleotide proportion biases surrounding the analyzed SNPs were observed in 1-3 bp sequences on both sides of an SNP. Strong biases were observed around neighboring nucleotides of protein-coding SNPs, which exhibit a periodicity of three in nucleotide content, constrained by a combined effect of codon-related rules and DNA repair mechanisms. Unlike a previous finding in the human genome, we found negative correlation between GC contents of chromosomes and the magnitude of corresponding bias of nucleotide C at -1 site and G at +1 site. These results will further our understanding of the mutation mechanism in rice as well as its evolutionary implications.

Base Composition↗