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At least 145 records · Page 8Linked to original sources
PubMed2006

TAMAL: an integrated approach to choosing SNPs for genetic studies of human complex traits.

UNLABELLED: Investigators conducting studies of the molecular genetics of complex traits in humans often need rationally to select a set of single nucleotide polymorphisms (SNPs) from the hundreds or thousands available for a candidate gene. Accomplishing this requires integration of genomic data from distributed databases and is both time-consuming and error-prone. We developed the TAMAL (Technology And Money Are Limiting) web site to help identify promising SNPs for further investigation. For a given list of genes, TAMAL identifies SNPs that meet user-specified criteria (e.g. haplotype tagging SNPs or SNP predicted to lead to amino acid changes) from current versions of online resources (i.e. HapMap, Perlegen, Affymetrix, dbSNP and the UCSC genome browser). AVAILABILITY: TAMAL is a platform independent web-based application available free of charge at http://neoref.ils.unc.edu/tamal. SUPPLEMENTARY INFORMATION: http://neoref.ils.unc.edu/tamal/.

Chromosome Mapping↗
PubMed2006

SNPeffect v2.0: a new step in investigating the molecular phenotypic effects of human non-synonymous SNPs.

UNLABELLED: Single nucleotide polymorphisms (SNPs) constitute the most fundamental type of genetic variation in human populations. About 75 000 of these reported variations cause an amino acid change in the translated protein. An important goal in genomic research is to understand how this variability affects protein function, and whether or not particular SNPs are associated to disease susceptibility. Accordingly, the SNPeffect database uses sequence- and structure-based bioinformatics tools to predict the effect of non-synonymous SNPs on the molecular phenotype of proteins. SNPeffect analyses the effect of SNPs on three categories of functional properties: (1) structural and thermodynamic properties affecting protein dynamics and stability (2) the integrity of functional and binding sites and (3) changes in posttranslational processing and cellular localization of proteins. The search interface of the database can be used to search specifically for polymorphisms that are predicted to cause a change in one of these properties. Now based on the Ensembl human databases, the SNPeffect database has been remodeled to better fit an automatically updatable structure. The current edition holds the molecular phenotype of 74 567 nsSNPs in 23 426 proteins. AVAILABILITY: SNPeffect can be accessed through http://snpeffect.vib.be.

Algorithms↗
PubMed2004

Variation of gene-based SNPs and linkage disequilibrium patterns in the human genome.

A principal goal in human genetics is to provide the tools necessary to enable genome-wide association studies. Extensive information on the distribution of gene-based single-nucleotide polymorphisms (SNPs) and linkage disequilibrium (LD) patterns across the genome is required in order to choose markers for efficient implementation of this approach. To obtain such information, we have genotyped a large Japanese cohort for SNPs identified by systematic resequencing of more than 14 000 autosomal genes. Analysis of these data led to the conclusion that the Japanese population contains approximately 130 000 common autosomal gene haplotypes (frequency >0.05), of which more than 35% are identified in the present study. We also examined allele frequencies and LD patterns according to the position of variants within genes, and their distribution across the genome. We found lower allele variability at exonic SNP sites (both non-synonymous and synonymous) compared with non-exonic SNP sites, and greater average LD between SNPs within exons of the same gene compared with other SNP combinations, both of which could be signals of selection. LD was correlated with the recombination rate per physical distance as estimated from the meiotic map, but the strength of the relationship varied considerably in different regions of the genome. Unique LD patterns, characterized by frequent instances of high LD between non-adjacent SNPs punctuated by blocks of low LD, were found in a 7 Mb region on chromosome 6p that includes the MHC (major histocompatibility complex) locus and many non-MHC genes. These results demonstrate the complexity that must be taken into account when considering SNP variability and LD patterns, while also providing tools necessary for implementation of efficient genome-wide association studies.

Chromosomes, Human, Pair 6↗
PubMed2005

FESD: a Functional Element SNPs Database in human.

We have created the Functional Element SNPs Database (FESD) that categorizes functional elements in human genic regions and provides a set of single nucleotide polymorphisms (SNPs) located within each area. In the FESD, the human genic regions were divided into 10 different functional elements, such as promoter regions, CpG islands, 5'-untranslated regions (5'-UTRs), translation start sites, splice sites, coding exons, introns, translation stop sites, polyadenylation signals and 3'-UTRs, and subsequently, all the known SNPs were assigned to each functional element at their respective position. With the FESD web interface, users can select a set of SNPs in the specific functional elements and get their flanking sequences for genotyping experiments, which will help in finding mutations that contribute to the common and polygenic diseases. A web interface for the FESD is freely available at http://combio.kribb.re.kr/ksnp/resd/.

Databases, Nucleic Acid↗
PubMed2004

Angiotensin II type I receptor gene and myocardial infarction: tagging SNPs and haplotype based association study. The Beijing atherosclerosis study.

OBJECTIVES: The present study aimed to assess the effect of haplotype variation in angiotensin II type I receptor (AGTR1) gene on the risk of myocardial infarction (MI) in Chinese males. METHODS: We used 48 patients to identify the putative functional polymorphisms in AGTR1 gene by direct sequencing. The program tagSNPs was used to identify an optimal set of tagging single nucleotide polymorphisms (SNPs). These selected SNPs were then genotyped in 419 male patients with MI and 400 age-matched male controls. The program haplo.stats was used to investigate the relationship between the haplotypes and MI. RESULTS: Sixteen polymorphisms in AGTR1 gene were identified. Based on the linkage disequilibrium pattern among these SNPs, six polymorphisms, SNP1, SNP6-SNP7 and SNP13-SNP15, were selected as haplotype tagging SNPs and further genotyped. Single SNP analyses indicated that the SNP1, SNP6 and SNP13 were significantly associated with MI, adjusted for covariates. Haplotype-based association analyses identified the frequency of haplotype AGATAA was lower in cases than in controls (P = 0.006). In comparison, three haplotypes (AAATAA, TAGCAA and AAACAG) were found to significantly increase the risk of MI with adjusted odds ratio equal to 1.33, 1.75 and 2.64, respectively (P = 0.029, 0.026 and 0.015). CONCLUSIONS: Our study suggests that common genetic variations in the AGTR1 gene may affect the risk of MI in Chinese males, and that there might be several functional variants in AGTR1 gene and the combined effect of these variants seemed to have a larger effect on the risk of MI in Chinese males.

Adult↗
PubMed2000

Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene.

A common strategy for genotyping large samples begins with the characterization of human single nucleotide polymorphisms (SNPs) by sequencing candidate regions in a small sample for SNP discovery. This is usually followed by typing in a large sample those sites observed to vary in a smaller sample. We present results from a systematic investigation of variation at the human apolipoprotein E locus (APOE), as well as the evaluation of the two-tiered sampling strategy based on these data. We sequenced 5.5 kb spanning the entire APOE genomic region in a core sample of 72 individuals, including 24 each of African-Americans from Jackson, Mississippi; European-Americans from Rochester, Minnesota; and Europeans from North Karelia, Finland. This sequence survey detected 21 SNPs and 1 multiallelic indel, 14 of which had not been previously reported. Alleles varied in relative frequency among the populations, and 10 sites were polymorphic in only a single population sample. Oligonucleotide ligation assays (OLA) were developed for 20 of these sites (omitting the indel and a closely-linked SNP). These were then scored in 2179 individuals sampled from the same three populations (n = 843, 884, and 452, respectively). Relative allele frequencies were generally consistent with estimates from the core sample, although variation was found in some populations in the larger sample at SNPs that were monomorphic in the corresponding smaller core sample. Site variation in the larger samples showed no systematic deviation from Hardy-Weinberg expectation. The large OLA sample clearly showed that variation in many, but not all, of OLA-typed SNPs is significantly correlated with the classical protein-coding variants, implying that there may be important substructure within the classical epsilon 2, epsilon 3, and epsilon 4 alleles. Comparison of the levels and patterns of polymorphism in the core samples with those estimated for the OLA-typed samples shows how nucleotide diversity is underestimated when only a subset of sites are typed and underscores the importance of adequate population sampling at the polymorphism discovery stage. [The sequence data described in this paper have been submitted to the GenBank data library under accession no. AF261279.]

Alleles↗
PubMed2004

Parallel genotyping of over 10,000 SNPs using a one-primer assay on a high-density oligonucleotide array.

The analysis of single nucleotide polymorphisms (SNPs) is increasingly utilized to investigate the genetic causes of complex human diseases. Here we present a high-throughput genotyping platform that uses a one-primer assay to genotype over 10,000 SNPs per individual on a single oligonucleotide array. This approach uses restriction digestion to fractionate the genome, followed by amplification of a specific fractionated subset of the genome. The resulting reduction in genome complexity enables allele-specific hybridization to the array. The selection of SNPs was primarily determined by computer-predicted lengths of restriction fragments containing the SNPs, and was further driven by strict empirical measurements of accuracy, reproducibility, and average call rate, which we estimate to be >99.5%, >99.9%, and>95%, respectively [corrected]. With average heterozygosity of 0.38 and genome scan resolution of 0.31 cM, the SNP array is a viable alternative to panels of microsatellites (STRs). As a demonstration of the utility of the genotyping platform in whole-genome scans, we have replicated and refined a linkage region on chromosome 2p for chronic mucocutaneous candidiasis and thyroid disease, previously identified using a panel of microsatellite (STR) markers.

Alleles↗
PubMed2002

In silico model-driven assessment of the effects of single nucleotide polymorphisms (SNPs) on human red blood cell metabolism.

The completion of the human genome project and the construction of single nucleotide polymorphism (SNP) maps have lead to significant efforts to find SNPs that can be linked to pathophysiology. In silico models of complete biochemical reaction networks relate a cell's individual reactions to the function of the entire network. Sequence variations can in turn be related to kinetic properties of individual enzymes, thus allowing an in silico model-driven assessment of the effects of defined SNPs on overall cellular functions. This process is applied to defined SNPs in two key enzymes of human red blood cell metabolism: glucose-6-phosphate dehydrogenase and pyruvate kinase. The results demonstrate the utility of in silico models in providing insight into differences between red cell function in patients with chronic and nonchronic anemia. In silico models of complex cellular processes are thus likely to aid in defining and understanding key SNPs in human pathophysiology.

Computational Biology↗
PubMed2005

SNPs in ecological and conservation studies: a test in the Scandinavian wolf population.

Single nucleotide polymorphisms (SNPs) have the potential to become the genetic marker of choice in studies of the ecology and conservation of natural populations because of their capacity to access variability across the genome. In this study, we provide one of the first demonstrations of SNP discovery in a wild population in order to address typical issues of importance in ecology and conservation in the recolonized Scandinavian and neighbouring Finnish wolf Canis lupus populations. Using end sequence from BAC (bacterial artificial chromosome) clones specific for dogs, we designed assays for 24 SNP loci, 20 sites of which had previously been shown to be polymorphic in domestic dogs and four sites were newly identified as polymorphic in wolves. Of the 24 assayed loci, 22 SNPs were found to be variable within the Scandinavian population and, importantly, these were able to distinguish individual wolves from one another (unbiased probability of identity of 4.33 x 10(-8)), providing equivalent results to that derived from 12 variable microsatellites genotyped in the same population. An assignment test shows differentiation between the Scandinavian and neighbouring Finnish wolf populations, although not all known immigrants are accurately identified. An exploration of the misclassification rates in the identification of relationships shows that neither 22 SNP nor 20 microsatellite loci are able to discriminate across single order relationships. Despite the remaining obstacle of SNP discovery in nonmodel organisms, the use of SNPs in ecological and conservation studies is encouraged by the advent of large scale screening methods. Furthermore, the ability to amplify extremely small fragments makes SNPs of particular use for population monitoring, where faecal and other noninvasive samples are routinely used.

Animals↗
PubMedDate not supplied

A measure of phase ambiguity in pairs of SNPs in the presence of linkage disequilibrium.

The extent of haplotype ambiguity in a string of single-nucleotide polymorphisms (SNPs) was quantified by Hodge et al. [Nat Genet 1999;21:360]. In their measure, the level of ambiguity increases with increasing numbers of loci and as loci become more polymorphic. That work assumed linkage equilibrium (LE). However, linkage disequilibrium (LD) provides additional information about the haplotypes at a site, thereby diluting the level of ambiguity. The ambiguity vanishes altogether when LD reaches its maximum value. Here, we introduce the ambiguity measure, Phi, to allow for LD (between pairs of SNPs). We derive the formula Phi = 4x(2)x(3) for ambiguity in individuals, where x(1), x(2), x(3) and x(4) are the probabilities of the A(1)A(2), A(1)B(2), B(1)A(2) and B(1)B(2) haplotypes, respectively, and w.l.o.g. x(1)x(4) > or = x(2)x(3). Alternatively, Phi can be expressed in terms of the allele frequencies and the LD parameter delta. We also extend the formula to triads of two parents plus one child. We estimate our measure Phi for relevant SNPs in the published lipoprotein lipase (LPL) gene dataset [Clark et al., Am J Hum Genet 1998;63:595; Nickerson et al., Nat Genet 1998;19:233], obtaining values ranging from a low of 0 to a high of 0.11 among adjacent pairs of sites. In genome-wide LD studies to map common disease genes, a dense map of SNPs may be utilized to detect association between a marker and disease. Therefore, the measurement of ambiguity can potentially help investigators to determine a more efficient map, designed to minimize ambiguity and subsequent information loss.

Algorithms↗
PubMed2004

Selecting tagging SNPs for association studies using power calculations from genotype data.

Recent studies have indicated that linkage disequilibrium (LD) between single nucleotide polymorphism (SNP) markers can be used to derive a reduced set of tagging SNPs (tSNPs) for genetic association studies. Previous strategies for identifying tSNPs have focused on LD measures or haplotype diversity, but the statistical power to detect disease-associated variants using tSNPs in genetic studies has not been fully characterized. We propose a new approach of selecting tSNPs based on determining the set of SNPs with the highest power to detect association. Two-locus genotype frequencies are used in the power calculations. To show utility, we applied this power method to a large number of SNPs that had been genotyped in Caucasian samples. We demonstrate that a significant reduction in genotyping efforts can be achieved although the reduction depends on genotypic relative risk, inheritance mode and the prevalence of disease in the human population. The tSNP sets identified by our method are remarkably robust to changes in the disease model when small relative risk and additive mode of inheritance are employed. We have also evaluated the ability of the method to detect unidentified SNPs. Our findings have important implications in applying tSNPs from different data sources in association studies.

Algorithms↗
PubMed2005

Transforming growth factor-beta1 SNPs: genetic and phenotypic correlations in progressive kidney insufficiency.

Associations have been described between polymorphisms of cytokine and growth factor genes and susceptibility to, or progression of, an increasing number of diseases. TGF-beta1 plays an important role in the pathogenesis of experimental and clinical glomerulosclerosis and tubulointerstitial fibrosis. In this study, single nucleotide polymorphisms (SNPs) in the TGFbeta1 gene were investigated as possible markers for the progression of chronic kidney failure (CKF). 145 Caucasian patients with CKF were screened for four TGFbeta1 SNPs: T-509C in the promoter region; Arg25Pro and Leu10Pro in exon 1 and Thr263Ile in exon 5. There were significant differences between CKF patients and controls in allele frequencies of two of the SNPs, Leu10Pro (p = 0.038) and C-509T (p = 0.02) and in haplotype distributions (p = 0.0175), indicating an association with susceptibility to CKF. We also observed a significant association between progression of CKF and homozygosity for Arg25 (odds ratio 3.77, 95% confidence interval 1.57-9.04, p = 0.002). Homozygosity for Arg25 was also associated with severity of proteinuria at diagnosis (p = 0.038), plasma TGF-beta1 protein levels (p = 0.01), and severity of glomerulosclerosis (p = 0.04). Homozygosity for -509T was associated with severity of proteinuria at diagnosis (p = 0.0017), level of renal tubular TGF-beta1 immunostaining (p = 0.0006) and with severity of renal interstitial inflammatory cellular infiltration (p = 0.01). Tubular TGF-beta1 immunostaining was significantly higher in biopsies with inflammatory cellular infiltration compared those without inflammation (p = 0.0048). There was a significant difference in haplotype distributions between CKF patients with progressive, as opposed to non-progressive disease (p = 0.0484). TGFbeta1 SNPs may be useful prognostic indicators for the progression of CKF.

Adult↗
PubMed2006

SNP-RFLPing: restriction enzyme mining for SNPs in genomes.

BACKGROUND: The restriction fragment length polymorphism (RFLP) is a common laboratory method for the genotyping of single nucleotide polymorphisms (SNPs). Here, we describe a web-based software, named SNP-RFLPing, which provides the restriction enzyme for RFLP assays on a batch of SNPs and genes from the human, rat, and mouse genomes. RESULTS: Three user-friendly inputs are included: 1) NCBI dbSNP "rs" or "ss" IDs; 2) NCBI Entrez gene ID and HUGO gene name; 3) any formats of SNP-in-sequence, are allowed to perform the SNP-RFLPing assay. These inputs are auto-programmed to SNP-containing sequences and their complementary sequences for the selection of restriction enzymes. All SNPs with available RFLP restriction enzymes of each input genes are provided even if many SNPs exist. The SNP-RFLPing analysis provides the SNP contig position, heterozygosity, function, protein residue, and amino acid position for cSNPs, as well as commercial and non-commercial restriction enzymes. CONCLUSION: This web-based software solves the input format problems in similar softwares and greatly simplifies the procedure for providing the RFLP enzyme. Mixed free forms of input data are friendly to users who perform the SNP-RFLPing assay. SNP-RFLPing offers a time-saving application for association studies in personalized medicine and is freely available at http://bio.kuas.edu.tw/snp-rflp/.

Animals↗
PubMed2005

Common variation in EMSY and risk of breast and ovarian cancer: a case-control study using HapMap tagging SNPs.

BACKGROUND: EMSY could be involved in low-level susceptibility to breast and ovarian cancer. Gene amplification is seen in a proportion of breast and ovarian tumours and correlates with poor prognosis in breast cancer patients. Furthermore, the EMSY protein silences a transcription activation domain in BRCA2 exon 3. METHODS: We used a genetic association study design to determine if common genetic variation (frequency > or = 5%) in EMSY was associated with breast or ovarian cancer risk in the British population. Haplotype tagging single-nucleotide polymorphisms (htSNPs) were selected from the HapMap database and genotyped using Taqman in two large study sets of white British women (n [breast set] = 2343 cases and 2284 controls, n [ovarian set] = 864 cases and 864 controls). HapMap data might be insufficient to tag genetic variation in EMSY comprehensively. We therefore screened the gene promoter and coding sequences with denaturing high performance liquid chromatography in order to identify additional SNPs that are most likely to be functional. RESULTS: HapMap data on 22 SNPs show that 4 htSNPs tag 4 common haplotypes: rs2282611 (5'up t > g), rs4245443 (IVS7 g > a), rs2513511 (IVS16 a > g), rs2155220 (3'down c > t). We observed no association between any of the genotypes or associated haplotypes and breast or ovarian cancer risk. Seventeen out of the 18 remaining HapMap polymorphisms (94%) were well tagged by the 4 selected htSNPs (r2s > 0.8). Genotype frequencies for two further SNPs identified by screening and located near exon-intron boundaries, rs2508740 (IVS9 a > g) and rs11600501 (IVS10 c > t), were also similar in cases and controls. In order to simulate unidentified SNPs, we performed the leave-one-out cross-validation procedure on the HapMap data; over 95% of the common genetic variation was well represented by tagging polymorphisms. We are therefore likely to have tagged any common, functional variants present in our population. CONCLUSION: We found no association between common genetic variation in EMSY and risk of breast or ovarian cancer in two large study sets of white British women.

Adolescent↗
PubMed2002

Genotyping of Snps in a polyploid genome by pyrosequencing.

Single-nucleotide polymorphisms (SNPs) are the most frequent DNA sequence variations, and they have become increasingly popular markers for association studies. Allelic discrimination of the mostly binary SNPs has been reported for diploid species, mainly the human, but not for polyploid genomes such as the agriculturally important crops. In the present study, we analyzed the applicability of pyrosequencing to genotyping SNPs in tetraploid potatoes. Out of 94 polymorphic loci tested, 76 (81%) proved to be amenable to allelic discrimination by pyrosequencing. An additional locus could be genotyped by the addition of an ssDNA binding protein to the pyrosequencing reaction. Of the remaining 17 loci, two failed because of the presence of paralogs in the genome, while in the other cases, self-annealing of the primer or template at the low reaction temperature (28 degrees C) employed in pyrosequencing rendered allelic discrimination impossible. The quantitative precision ofpyrosequencing was found to be similar to that of conventional dideoxy sequencing and single-nucleotide primer extension. Exceptfor some sequencespecific limitations, pyrosequencing appears to be an appropriate method for genotying SNPs in polyploid species because it is possible to distinguish not only between homoand heterozygosity but also between the different heterozygous states.

Apyrase↗
PubMed2002

SNPCEQer: detecting SNPs in sequences generated by the Beckman CEQ2000 DNA Analysis System.

SNPCEQer identifies and reports SNPs in sequences obtained from the Beckman CEQ2000 DNA Analysis System. SNPCEQer aligns sequences obtained using CEQ2000 heterozygote detection analysis and reports discrepancies between individual sequences and the consensus sequence it generates from this set as SNPs when the individual base calls have high-quality values. SNPCEQer reported comparable numbers of SNPs to the UNIX-based PolyPhred (148 vs. 165, respectively) in regions amplified from eight genes. A total of 21 different SNPs was discovered. Each gene region was analyzed in 96-306 samples. SNPCEQer was designed to operate from Windows NT, making SNP detection more accessible to users without UNIX systems. SNPCEQer is available free of charge at http://innovation.swmed.edu.

Base Sequence↗
PubMed2004

Influence of template DNA degradation on the genotyping of SNPs and STR polymorphisms from forensic materials by PCR.

Detection of single nucleotide polymorphisms (SNPs) and short tandem repeat (STR) polymorphisms by PCR is widely used to analyze degraded DNAs in forensic science. The success of DNA analysis from human remains largely depends on the quality of the template DNA. We examined two SNPs (HLA-DQA1 and ABO) and two STR polymorphisms (VWA and CD4) by SSCP gel or denaturing gel electrophoresis, using two kinds of degraded DNA samples (165 teeth and blood stains contaminated with saliva) derived from the same person and investigated the influence of template DNA degradation on genotyping. As the degradation of DNA proceeds, unbalanced amplification of alleles occurred in the analysis of both SNPs and STRs, followed by allele drop, and further by loss of amplification. Non-target allelic products of STRs were amplified from highly degraded DNA samples; however, false allelic products of SNPs were not amplified from them. Amplification efficiency increased in proportion to the decrease of PCR target size, but reduction of the PCR target sizes also increased the chances of amplifying contaminating DNA, especially in highly degraded DNA specimens. The present results will help investigators to evaluate the genotyping of highly degraded DNA samples in forensic casework.

ABO Blood-Group System↗
PubMed2002

Generation and mapping of AFLP, SSRs and SNPs in Lycopersicon esculentum.

Amplified Fragment Length Polymorphism (AFLP), Simple Sequence Repeat (SSR) and Single Nucleotide Polymorphism (SNP), were applied to the tomato genome for assessment of polymorphism and for mapping. The polymorphism of AFLP was studied in twenty-one commercial tomato (L. esculentum) varieties. Four AFLP primer combinations produced 298 clear bands; an average of 75 bands per combination. SSR markers were generated from two sources: (1) size-selected genomic libraries screened with (AT)n, (CT)n, (GT)n, (ATT)n and (CTT)n probes. (2) GeneBank database. Primers were designed for 114 loci and used for genotyping 13 tomato varieties and three Lycopersicon species. Eighteen markers were used to evaluate the polymorphism among the commercial cultivars and were found to be a useful tool for cultivar identification. In-silico comparison of DNA sequences (ESTs and genes) of L. pennellii and L. esculentum, yielded 312 SNPs. Ten L. pennelli genomic fragments were sequenced and the comparison with L. esculentum yielded 22 SNPs. Another 19 SNPs were discovered by sequencing and comparing L. pennellii genomic DNA to L. esculentum DNA fragments containing SSRs. The average SNP frequency was found to be one in a few tens of base pairs. A total of 52 microsatellites, 159 polymorphic AFLP markers and six SNPs were mapped using the Introgression Lines generated by [1]. Map location and markers' distribution are presented.

Alleles↗