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Results for “Single nucleotide polymorphisms (SNPs)”

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PubMed2001

Characterization of publicly available SNPs in the Korean population.

Single-nucleotide polymorphisms (SNPs) are the most abundant form of genetic variations and have a great potential for mapping studies of complex genetic traits. Currently a great deal of effort is invested in the identification of SNPs, and a large volume of data is already available through public databases (NCBI, NCI, WICGR, HGBASE). For an association mapping study, SNP allele frequencies in the population are critical. As an initial step toward construction of an SNP database of the Korean population, we have determined the allele frequencies of 300 cSNPs selected from the public database in 24 individuals. Among the tested markers, approximately 23% did not show polymorphism in the population. The results suggest that the ethnic and population based differences should be considered in the selection of SNPs for the study of complex diseases with association mapping methods.

Alleles↗
PubMed1999

Identification and characterisation of polymorphisms in human phosphoglucomutase (PGM1).

This study is part of our effort to map recombination hotspots in two regions (site A, 18 kb; site B, 40 kb) of the human phosphoglucomutase PGM1 gene. Twenty-two PCR amplified fragments comprising six groups, covering about 5.2 kb, were screened for single nucleotide polymorphisms (SNPs) using non-isotopic single stranded conformation polymorphism (SSCP) analysis. Fourteen fragments were variable and seven of these showed common polymorphism. Our strategy for screening for polymorphic sites in the PGM1 gene was based on the results of allelic association analysis between each new marker and the sites of the classical isozyme polymorphism (2/1 in exon 4 and +/- in exon 8). Samples from four populations (Caucasian, Chinese, Vietnamese and New Guinean) were typed for each of the seven polymorphic markers. Between two and four common alleles were found in each case, together with a few rare alleles. Co-dominant inheritance patterns were demonstrated by family studies. The molecular basis of each new marker was determined by direct sequencing of the PCR products: most were SNPs except two that were small insertions/deletions. Direct sequence analysis of a 2.1 kb segment in sixteen individuals revealed no additional nucleotide variation indicating a very high level of efficiency of the SSCP screening method used in this study. The overall nucleotide diversity (theta) for PGM1 was estimated as 0.9 x 10(-3) based on 33 segregating sites in a sequence of 5187 nt and a sample size of 614 individuals.

Alleles↗
PubMed2003

Efficient selective screening of haplotype tag SNPs.

UNLABELLED: Haplotypes defined by common single nucleotide polymorphisms (SNPs) have important implications for mapping of disease genes and human traits. Often only a small subset of the SNPs is sufficient to capture the full haplotype information. Such subsets of markers are called haplotype tagging SNPs (htSNPs). Although htSNPs can be identified by eye, efficient computer algorithms and flexible interactive software tools are required for large datasets such as the human genome haplotype map. We describe a java-based program, SNPtagger, which screens for minimal sets of SNP markers to represent given haplotypes according to various user requirements. The program offers several options for inclusion/exclusion of specific markers and presents alternative panels for final selection. AVAILABILITY: The www-based program is available at http://www.well.ox.ac.uk/~xiayi/haplotype/index.html.

Algorithms↗
PubMed2002

[Studies of single nucleotide polymorphism of PPAR gene and its associations with fattiness trait in chicken].

In this experiment, the AA broiler fat traits and three Chinese special breeds (Shiqiza, Beijing youji and Baier) were used to study the effect of PPAR-alpha gene on fat trait. Coding region of the gene was amplified by seven pairs of primers, and then single nucleotide polymorphisms (SNPs) were detected by the technique of single strand conformation polymorphism (SSCP) and finally confirmed by sequencing. One nucleotide variation was found, the result of chi 2 analysis showed that the distribution of three genotypes was very different among different breeds(P < 0.01). The result of variance analysis showed that the birds with BB genotype had a higher abdominal fat weight than the birds with other genotypes (AA and AB). It implied that PPAR-alpha gene could be a candidate locus or linked to a major gene to significantly affect abdominal fat traits in chicken.

Abdomen↗
PubMed2001

High-throughput conformation-sensitive gel electrophoresis for discovery of SNPs.

High-throughput screening for single nucleotide polymorphisms (SNPs) or mutations can be achieved by inexpensive technologies. We modified the original protocols of conformation-sensitive gel electrophoresis (CSGE) to increase throughput several fold to 1.3 samples/min, which is about five times faster than denaturing high-performance liquid chromatography (DHPLC). The modifications include decreasing the gel thickness, increasing the number of lanes to 96, and increasing the number of samples per lane to seven. This high-throughput CSGE method is fast, robust, and as simple as the original protocols. Together with a two-stage strategy for screening homozygotes and the replacement of ethidium bromide with SYBR Gold DNA dye staining, this protocol is a reliable and cost-effective alternative for laboratories that require high-throughput screening.

Heterozygote↗
PubMed2006

Common polymorphisms in the CACNA1H gene associated with childhood absence epilepsy in Chinese Han population.

Variants with a relatively high frequency in the CACNA1H gene have previously been identified in cases of childhood absence epilepsy (CAE) in the Chinese Han population most of which are located in exons 6 to 12. In present study we attempted to further investigate whether the CACNA1H gene is associated with CAE. Exons 6 to 12 of CACNA1H gene were sequenced in samples of 100 CAE trios recruited consecutively, and 191 normal human controls. Single nucleotide polymorphisms (SNPs) were studied in both single locus and haplotype analyses in 218 CAE trios, of which 118 trios were selected from our previous research. Case-control comparisons and the transmission disequilibrium test (TDT) both supported a coding SNP (cSNP) rs9934839 (R603R) in exon 9 as being close related to CAE. The carriers of the G allele of rs9934839 had a 3-fold higher risk of CAE than non-carriers. Moreover, another cSNP rs8044363 was predicted to be connected directly with CAE in a Bayesian network. In addition, two haplotypes consisting of five cSNPs in the region of CACNA1H were statistically associated with CAE. Our research provides new evidence to further support the hypothesis that CACNA1H may be an important susceptibility gene for CAE in the Chinese Han population.

Asian People↗
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↗
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

Typing of Y chromosome single nucleotide polymorphisms in a Japanese population by a multiplexed single nucleotide primer extension reaction.

We have developed a new method for typing single nucleotide polymorphisms (SNPs) on the human Y chromosome based on a multiplexed single nucleotide primer extension. This method has the advantage that several SNPs are typed rapidly and simultaneously. We examined 15 different SNP loci on Y chromosome, M9, M105, M122, M125, M128, M130, SRY465, IMS-JST006241, IMS-JST006841, IMS-JST002611, IMS-JST003305, IMS-JST008425, IMS-JST021354, IMS-JST021355 and IMS-JST055457, in 159 Japanese males. From the typing results of these 15 loci, we found 13 haplotypes. Gene diversity for each locus ranged from 0.025 to 0.486 and the haplotype diversity was estimated to be 0.838. This method could be readily applied for personal identification and paternity testing.

Journal Article↗
PubMed2003

Recipient ctla-4 +49 G/G genotype is associated with reduced incidence of acute rejection after liver transplantation.

The aim of this pilot study was to investigate whether acute rejection after liver transplantation is associated with known single-nucleotide polymorphisms (SNPs) in the CD86- and CTLA-4 genes of liver-transplant donors and recipients. Single nucleotide polymorphisms were determined in 135 liver transplant recipients and in 73 donors. Acute rejection was not associated with CD86 + 1057 G/A genotype distributions in donors and in recipients. In univariate analysis recipient CTLA-4 -318 G/T and + 49 A/G genotype distributions were both weakly associated with acute rejection. Multivariate analysis revealed that the CTLA-4 + 49 SNP, but not the -318 SNP, was independently of other risk factors associated with acute rejection. Only one out of 13 CTLA-4 + 49 G-homozygotes (8%) experienced acute rejection(s) compared with 40% of A/A or A/G recipients. The CTLA-4 + 49 A/G SNP, which results in an amino acid substitution in the signal peptide of the protein, did not, however, affect intracellular expression or trafficking of CTLA-4 in T cells, nor soluble serum CTLA-4 concentrations of the liver transplant recipients. In conclusion, this pilot study suggests that liver transplant recipients homozygous for CTLA-4 + 49 G have a reduced risk of acute rejection.

Adult↗
PubMed2006

Predicting deleterious nsSNPs: an analysis of sequence and structural attributes.

BACKGROUND: There has been an explosion in the number of single nucleotide polymorphisms (SNPs) within public databases. In this study we focused on non-synonymous protein coding single nucleotide polymorphisms (nsSNPs), some associated with disease and others which are thought to be neutral. We describe the distribution of both types of nsSNPs using structural and sequence based features and assess the relative value of these attributes as predictors of function using machine learning methods. We also address the common problem of balance within machine learning methods and show the effect of imbalance on nsSNP function prediction. We show that nsSNP function prediction can be significantly improved by 100% undersampling of the majority class. The learnt rules were then applied to make predictions of function on all nsSNPs within Ensembl. RESULTS: The measure of prediction success is greatly affected by the level of imbalance in the training dataset. We found the balanced dataset that included all attributes produced the best prediction. The performance as measured by the Matthews correlation coefficient (MCC) varied between 0.49 and 0.25 depending on the imbalance. As previously observed, the degree of sequence conservation at the nsSNP position is the single most useful attribute. In addition to conservation, structural predictions made using a balanced dataset can be of value. CONCLUSION: The predictions for all nsSNPs within Ensembl, based on a balanced dataset using all attributes, are available as a DAS annotation. Instructions for adding the track to Ensembl are at http://www.brightstudy.ac.uk/das_help.html.

Algorithms↗
PubMed2002

Genetic analysis in human hypertension.

Hypertension is considered to be a complex trait to which genetic, environmental, and demographic factors contribute interactively. Recently, molecular genetic studies have achieved remarkable success in the elucidation of causative mutations in several Mendelian hypertensive disorders in which single nucleotide polymorphisms (SNPs) disrupt the function of single genes, thereby leading to unambiguous phenotypes. It seems unlikely, however, that such a simple base-substitution is the primary mechanism in cases of essential hypertension, even if SNPs modify the relevant gene function to some extent. Despite the enormous efforts made to date, no consistent association between any of the candidate genes and essential hypertension has been established. One plausible explanation is that because individual genes play a modest role in the pathogenesis of hypertension, confounding variables, whether individual (sex, ethnic origin, etc.) or environmental, may decrease the chance of identifying a causative relation between the genes and hypertension, depending on the populations studied. Several approaches can be proposed to overcome this problem, including long-term follow-up of clinical events collected to attain sufficient phenotypic information and statistical power. With the recent advances in high-throughput genotyping techniques and bioinformatic strategies, it has become possible to perform even SNP-based genome-wide screening. At present, however, the need for identification of susceptibility genes for hypertension still poses a great and unanswered challenge. Nonetheless, we believe that a precise understanding of the manner in which genetic variations affect hypertension can be achieved, and that clarification of the associated phenotypes will lead to the development of effective preventive and treatment strategies.

Angiotensinogen↗
PubMed2003

Association studies in candidate genes: strategies to select SNPs to be tested.

OBJECTIVE: When numerous single nucleotide polymorphisms (SNPs) have been identified in a candidate gene, a relevant and still unanswered question is to determine how many and which of these SNPs should be optimally tested to detect an association with the disease. Testing them all is expensive and often unnecessary. Alleles at different SNPs may be associated in the population because of the existence of linkage disequilibrium, so that knowing the alleles carried at one SNP could provide exact or partial knowledge of alleles carried at a second SNP. We present here a method to select the most appropriate subset of SNPs in a candidate gene based on the pairwise linkage disequilibrium between the different SNPs. METHOD: The best subset is identified through power computations performed under different genetic models, assuming that one of the SNPs identified is the disease susceptibility variant. RESULTS: We applied the method on two data sets, an empirical study of the APOE gene region and a simulated study concerning one of the major genes (MG1) from the Genetic Analysis Workshop 12. For these two genes, the sets of SNPs selected were compared to the ones obtained using two other methods that need the reconstruction of multilocus haplotypes in order to identify haplotype-tag SNPs (htSNPs). We showed that with both data sets, our method performed better than the other selection methods.

Algorithms↗
PubMed2005

The molecular genetics of blood group polymorphism.

Nearly 300 blood group specificities on red cells are known, many of which are polymorphic. The molecular mechanisms responsible for these polymorphisms are diverse, though the majority represent single nucleotide polymorphisms (SNPs) encoding amino acid substitutions. Other mechanisms include the following: gene deletion; single nucleotide deletion and sequence duplication, which introduce reading-frame shifts; nonsense mutation; intergenic recombination between closely-linked genes, giving rise to hybrid genes and hybrid proteins; and a SNP in the promoter region of a blood group gene. Examples of these genetic mechanisms are taken from the ABO, Rh, Kell, and Duffy blood group systems. Null phenotypes, in which no antigens of a blood group system are expressed, are not generally polymorphic, but provide good examples of the effect of inactivating mutations on blood group expression. As natural human 'knock-outs' they provide useful clues to the functions of blood group antigens. Knowledge of the molecular bases to blood group polymorphisms provides a means to predict blood group phenotype from genomic DNA with a high degree of accuracy. This currently has two main applications in transfusion medicine: for determining fetal blood groups to assess whether the fetus is at risk from haemolytic disease; and to determine blood group phenotypes in multiply transfused, transfusion-dependent patients, where serological tests are precluded by the presence of donor red cells. Other applications are being developed for the future.

Blood Group Antigens↗
PubMed2003

Genotyping African haplotypes in ATM using a co-spotted single-base extension assay.

Human genetic analysis, including population genetic studies, increasingly calls for cost-effective, high-throughput methods for the rapid screening of single nucleotide polymorphisms (SNPs) across many individuals. The modified single-base extension assay described here (arrayed SBE) is a highly accurate and robust method for SNP genotyping that can deliver genotypes at 3.5 cents each, following PCR. Specifically, amino-modified probe/target pairs were prehybridized, then co-spotted in a microarray format prior to enzymatic addition of allele-specific nucleotides. Probe/target identity was determined solely by its physical location on the array rather than by hybridization to a complementary target, resulting in a call rate of 99-100%. These innovations result in an inexpensive, accurate assay with exceptional signal-to-noise ratios, depending on the glass surface employed. Comparison of glass slides from three different manufacturers indicated that aldehyde-based Zyomyx slides provided superior performance for this assay. Arrayed SBE was applied to study the geographic distribution of three African-specific haplotypes in the human ATM gene. Four selectively neutral markers, which define the haplotypes H5, H6, and H7, were screened in a total of 415 individuals. Region-specific haplotype frequencies were consistent with patterns of human migration across and outside of Africa, suggesting a possible haplotype origin in East Africa. Arrayed SBE was a robust tool for this analysis that could be applied to any situation requiring the genotyping of a few SNPs in many individuals.

Africa, Eastern↗
PubMed2006

Association of TNF-alpha genetic polymorphism with HLA DPB1*0301.

BACKGROUND: We speculated TNF-alpha can be one of candidate gene for aspirin-intolerant asthma (AIA) because TNF-alpha is pro-inflammatory cytokine and known to be increased level in asthmatic airways. In addition, genetic interaction between TNF-alpha and human antigen leucocyte (HLA) DPB1*0301, which is a strong genetic marker for AIA, was examined for its close location within chromosome 6. METHOD: To investigate genetic association of TNF-alpha with an AIA phenotype, three study groups (163 patients with AIA, 197 patients with aspirin-tolerant asthma (ATA), 257 normal control subjects) were enrolled. Single nucleotide polymorphisms (SNPs) were genotyped using a single-base extension method and HLA DPB1 genotyping was determined by high-throughput sequencing method. RESULTS: All five SNPs of TNF-alpha were tested; there were no significant differences in allele and genotype frequencies among the three groups. However, significant association between TNF-alpha-308G>A polymorphism and atopy status was noted (P<0.05). Gene to gene interaction between TNF-alpha-1031T>C (or -863C>A or -857C>A) and HLA DPB1*0301could synergistically increase the susceptibility to AIA with odds ratio (OR) to 7.738 (or OR=8.184 for -863C>A, OR=7.500 for -857C>T, P<0.001, respectively). CONCLUSION: TNF-alpha promoter polymorphism may significantly increase susceptibility to AIA by gene-to-gene interaction with HLA DPB1*0301.

Adult↗
PubMed2005

Association of interleukin 18 (IL18) polymorphisms with specific IgE levels to mite allergens among asthmatic patients.

BACKGROUND: Allergy is regarded as a multifactorial condition. Its onset and severity are influenced by both genetic and environmental factors. Identification of genetic factors involved in asthma development and related phenotypes is a major task in understanding the genetic background of asthma. The possible involvement of IL18 polymorphisms in asthma was examined in a Korean asthma cohort. METHODS: Direct sequencing was performed to discover single-nucleotide polymorphisms (SNPs) in the IL18 gene. Single-base extension (SBE) method was employed for genotyping. Genotypic influence of IL18 was analysed using logistic and multiple-regression models. RESULTS: Although no polymorphisms in the IL18 gene showed significant association with the risk of asthma development, analyses of the association with specific serum IgE levels to Dermatophagoides farinae (D.f.) and D. pteronyssinus (D.p.) among asthmatic patients revealed significant associations with two completely linked SNPs, i.e. -148G>C and +13925A>C(Ser35Ser) (P = 0.01-0.11 for D.f. and P = 0.005-0.11 for D.p.). Both C allele of -148G>C and C allele of +13925A>C showed gene dose-dependent effects on the levels of specific IgE. The lowest IgE levels in homozygotes of minor alleles (1.13 and 1.22 of D.f.; 1.38 and 1.33 of D.p., respectively), intermediate IgE levels in heterozygotes (1.60 and 1.70 of D.f.; 1.84 and 1.92 of D.p., respectively), and the highest levels in homozygotes for major allele (1.93 and 1.93 of D.f.; 2.24 and 2.24 of D.p., respectively), were found. CONCLUSION: The genetic relevance of IL18 to specific IgE might offer an important step in understanding the genetic background of allergic diseases.

Adolescent↗
PubMed2004

Mass spectrometry provides accurate characterization of two genetic marker types in Bacillus anthracis.

Epidemiological and forensic analyses of bioterrorism events involving Bacillus anthracis could be improved if both variable number tandem repeats (VNTRs) and single nucleotide polymorphisms (SNPs) could be combined on a single analysis platform. Here we present the use of electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) to characterize 24 alleles from 6 VNTR loci and 11 alleles from 7 SNP loci in B. anthracis. The results obtained with ESI-FTICR-MS were consistent with independent results obtained from traditional approaches using electrophoretic detection of fluorescent products. However, ESI-FTICR-MS improves on the traditional approaches because it does not require fluorescent labeling of PCR products, minimizes post-PCR processing, obviates electrophoresis, and provides unambiguous base composition of both SNP and VNTR PCR products. In addition, ESI-FTICR-MS allows both marker types to be examined simultaneously and at a rate of approximately 1 sample per min. This technology represents a significant advance in our ability to rapidly characterize B. anthracis isolates using VNTR and SNP loci.

Alleles↗