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Results for “single nucleotide variation”

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PubMed2005

Single nucleotide polymorphisms detection based on DNA microarray technology: HLA as a model.

The significance of DNA variations among individuals, including single nucleotide polymorphisms (SNPs) and/or genome nucleotide mutations as well as to their detection by using new technology, will improve and facilitate the knowledge of each gene sequence. Microarray may provide information about thousands of gene simultaneously, leading to a more rapid and accurate genotyping. In this view, we developed a new methodology as an example for the detection of SNPs based on DNA microarray, using a panel of HLA alleles representative of loci A, B, DRB1. A panel of 180 oligonucleotide probes was selected to identify polymorphic positions located in exons 2 and 3 of HLA-A and B, and in exon 2 of HLA-DRB1 locus. Each oligonucleotide sequence was designed with a nucleotide mismatch located in the same position as the center of the hybridization sequence. Hybridization experiments were carried out with genomic probes constructed with an asymmetric PCR strategy. The amplified DNAs were obtained from bone marrow cells of donors previously typed for transplant. The results obtained were showing that the method was reliable thus providing a feasible technique both for HLA typing and for the investigation of other regions of genetic and clinical interest including polymorphisms correlated with different autoimmune diseases.

Alleles↗

PubMed2006

Analysis of the variations in IL-28RA gene and their association with allergic rhinitis.

IL-28RA is one of the important candidate genes for complex trait of genetic diseases, but there is no published information of the genetic variation in this gene. We scanned the seven exons and their boundary introns sequence of IL-28RA including the promoter regions to analyze genetic variation sites, and identified eighteen single nucleotide polymorphisms (SNPs) and two variation sites. We chose seven SNPs (g.-1193 A>C, g.-30 C>T, g.17654 C>T, g.27798 A>G, g.31265 C>T, g.31911 C>T and g.32349 G>A) of them for large sample size genotyping, and assessed the association of genotype and allele frequencies of these SNPs between allergic rhinitis patients and non-allergic rhinitis controls. We also compared the genotype frequencies between Korean controls and Han Chinese control or Korean Chinese control. We investigated the frequencies of haplotype constructed by these SNPs between allergic rhinitis patients and non-allergic rhinitis controls. Our results suggested that the g.32349 G>A polymorphism of IL-28RA might be associated with susceptibility to allergic rhinitis (P=0.032), but seems to have no relationship with serum total IgE levels. The haplotype frequencies by these SNPs also show significant association between controls and allergic rhinitis patients.

Adult↗

PubMedDate not supplied

Rolling circle amplification for scoring single nucleotide polymorphisms.

The analysis of the genetic basis of phenotypic traits is moving towards the complex diseases prevalent in wealthy populations. There is an increasing requirement for the detection of different types of sequence variation, particularly single-nucleotide polymorphisms (SNPs). SNPs occur about once every 100 to 300 bases. High-density SNP maps will help to identify the multiple genes associated with complex diseases such as cancer, diabetes, vascular disease, and some forms of mental illness.

DNA↗

PubMed2002

Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus.

Psoriasis is a common skin disorder of multifactorial origin. Genomewide scans for disease susceptibility have repeatedly demonstrated the existence of a major locus, PSORS1 (psoriasis susceptibility 1), contained within the major histocompatibility complex (MHC), on chromosome 6p21. Subsequent refinement studies have highlighted linkage disequilibrium (LD) with psoriasis, along a 150-kb segment that includes at least three candidate genes (encoding human leukocyte antigen-C [HLA-C], alpha-helix-coiled-coil-rod homologue, and corneodesmosin), each of which has been shown to harbor disease-associated alleles. However, the boundaries of the minimal PSORS1 region remain poorly defined. Moreover, interpretations of allelic association with psoriasis are compounded by limited insight of LD conservation within MHC class I interval. To address these issues, we have pursued a high-resolution genetic characterization of the PSORS1 locus. We resequenced genomic segments along a 220-kb region at chromosome 6p21 and identified a total of 119 high-frequency SNPs. Using 59 SNPs (18 coding and 41 noncoding SNPs) whose position was representative of the overall marker distribution, we genotyped a data set of 171 independently ascertained parent-affected offspring trios. Family-based association analysis of this cohort highlighted two SNPs (n.7 and n.9) respectively lying 7 and 4 kb proximal to HLA-C. These markers generated highly significant evidence of disease association (P<10-9), several orders of magnitude greater than the observed significance displayed by any other SNP that has previously been associated with disease susceptibility. This observation was replicated in a Gujarati Indian case/control data set. Haplotype-based analysis detected overtransmission of a cluster of chromosomes, which probably originated by ancestral mutation of a common disease-bearing haplotype. The only markers exclusive to the overtransmitted chromosomes are SNPs n.7 and n.9, which define a 10-kb PSORS1 core risk haplotype. These data demonstrate the power of SNP haplotype-based association analyses and provide high-resolution dissection of genetic variation across the PSORS1 interval, the major susceptibility locus for psoriasis.

Case-Control Studies↗

PubMed2003

Clines and adaptive evolution in the methuselah gene region in Drosophila melanogaster.

In an effort to characterize further the patterns of selection and adaptive evolution at the methuselah locus in Drosophila species, we extended an analysis of geographical variation to include single nucleotide polymorphisms (SNPs) in adjacent genes on either side of the mth locus, and examined the molecular variation in a neighbouring methuselah paralogue (mth2). An analysis of 13 SNPs spanning a region of nearly 19 kilobases surrounding the mth locus demonstrated that a clinal pattern associated with the most common mth haplotype does not extend to adjacent gene loci, providing compelling evidence that the clinal pattern results from selection on as yet unidentified sites associated with the functional mth locus. mth2 exhibited a significant pattern of adaptive divergence among D. melanogaster, D. simulans and D. yakuba similar to that seen at mth. However, Ka : Ks ratios indicate a difference in levels of functional constraint at the two methuselah, loci with mth2 exhibiting a five- to six-fold reduction in levels of amino acid divergence relative to mth.

Amino Acid Sequence↗

PubMed2006

Single nucleotide polymorphisms (SNPs) in human lactoferrin gene.

The lactoferrin protein possesses antimicrobial and antiviral activities. It is also involved in the modulation of the immune response. In a normal healthy individual, lactoferrin plays a role in the front-line host defense against infection and in immune and inflammatory responses. Whether genomic variations, such as single nucleotide polymorphisms (SNPs), have an effect on the structure and function of lactoferrin protein and whether these variations contribute to the different susceptibility of individuals in response to environmental insults are interesting health-related issues. In this study, the lactoferrin gene was resequenced as part of the Environmental Genome Project of the National Institute of Environmental Health Sciences, which operates within the National Institutes of Health. Ninety-one healthy donors of different ethnicities were used to establish common SNPs in the exons of the lactoferrin gene in the general population. The data will serve as a basis from which study the association of lactoferrin polymorphism and disease.

Ethnicity↗

PubMed2002

Evaluation of single-nucleotide polymorphisms in CAPN1 for association with meat tenderness in cattle.

Micromolar calcium activated neutral protease (CAPN1) was evaluated as a candidate gene for a quantitative trait locus (QTL) on BTA29 affecting meat tenderness by characterization of nucleotide sequence variation in the gene. Single-nucleotide polymorphisms (SNP) were identified by sequencing all 22 exons and 19 of the 21 introns in two sires (Piedmontese x Angus located at the U.S. Meat Animal Research Center in Clay Center, NE; Jersey x Limousin located at AgResearch in New Zealand) of independent resource populations previously shown to be segregating meat tenderness QTL on BTA29. The majority of the 38 SNP were found in introns or were synonymous substitutions in the coding regions, with two exceptions. Exons 14 and 9 contained SNP that were predicted to alter the protein sequence by the substitution of isoleucine for valine in Domain III of the protein, and alanine for glycine in Domain II of the protein. The resource populations were genotyped for these two SNP in addition to six intronic polymorphisms and two silent substitutions. Analysis of genotypes and shear force values in both populations revealed a difference between paternal CAPN1 alleles in which the allele encoding isoleucine at position 530 and glycine at position 316 associated with decreased meat tenderness (increased shear force values) relative to the allele encoding valine at position 530 and alanine at position 316 (P < 0.05). The association of maternal alleles with meat tenderness phenotypes is consistent with the hypothesis of CAPN1 as the gene underlying the QTL effect in two independent resource populations and presents the possibility of using these markers for selective breeding to reduce the numbers of animals with unfavorable meat tenderness traits.

Alleles↗

PubMed2001

[The impact of calpain-10 gene combined-SNP variation on type 2 diabetes mellitus and its related metabolic traits].

OBJECTIVE: To investigate the impact of calpain-10 gene (CAPN-10) combined single nucleotide polymorphism (SNP) variation on type 2 diabetes mellitus (T2DM) and its related clinical metabolic traits in Chinese. METHODS: The study population consisted of 268 Chinese residents in Shanghai. Among them, 144 were subjects with normal glucose tolerance (NGT) and 124, with T2DM. Plasma glucose (PG), insulin (INS), c-peptide (CP) and free fatty acids (FFA) levels were measured at fasting and 30, 60, 120, and 180 minutes after oral 75 g glucose challenge. The islet beta-cell insulin secretion and tissue insulin sensitivity were assessed. CAPN-10 UCSNP44,-43,-19 and -63 were genotyped. RESULTS: (1) In Chinese NGT subjects, the major allele of UCSNP-44 was allele T (frequency=91%), of UCSNP43 was G(89%), of UCSNP-19 was I (3 repeats of a 32 bp sequence) (67%) and of UCSNP-63 was C allele (79%). Significant differences were observed in comparison of these allele frequencies in Chinese to those in other ethnic groups reported in the literature. (2) 14 genotype combinations of these four SNPs were observed in Chinese NGT subjects. 69% of the NGT population was composed of four genotype combinations, in the order of UCSNP44,-43,-19 and -63, i.e., combination A:TT-GG-DI-CC(haplotype combination was 1121/1111) (frequency=10%), combination B:TT-GA-II-CC(1121/1221)(10%), combination C:TT-GG-II-CC(1121/1121)(26%) and combination D:TT-GG-DI-CT(1121/1112)(22%).(3) The frequencies of the above mentioned SNP in single or in combinations were not different significantly between NGT and T2DM groups. (4) The variation of clinical metabolic parameter levels shifted from completely normal towards abnormal glucose intolerance among genotype combination subgroups. In comparison between combination A and combination D, subjects in the former subgroups had: higher PG levels with delayed peak after glucose challenge; less and lower decrement of FFA levels after challenge with no rising in late stage; higher insulin levels with delayed peak after challenge; and the tendency of decreased insulin sensitivity. More than half of the comparisons remained statistically significant after adjusted with age, gender, body mass index and waist circumference. CONCLUSION: The variation of calpain-10 gene has impact on the variation of clinical metabolic parameter levels related to type 2 diabetes mellitus. Such impact depends upon the haplotypes as well as the haplotype combination of calpain-10 gene variations.

Alleles↗

PubMed2006

Prospecting for pig single nucleotide polymorphisms in the human genome: have we struck gold?

Gene-to-gene variation in the frequency of single nucleotide polymorphisms (SNPs) has been observed in humans, mice, rats, primates and pigs, but a relationship across species in this variation has not been described. Here, the frequency of porcine coding SNPs (cSNPs) identified by in silico methods, and the frequency of murine cSNPs, were compared with the frequency of human cSNPs across homologous genes. From 150,000 porcine expressed sequence tag (EST) sequences, a total of 452 SNP-containing sequence clusters were found, totalling 1394 putative SNPs. All the clustered porcine EST annotations and SNP data have been made publicly available at http://sputnik.btk.fi/project?name=swine. Human and murine cSNPs were identified from dbSNP and were characterized as either validated or total number of cSNPs (validated plus non-validated) for comparison purposes. The correlation between in silico pig cSNP and validated human cSNP densities was found to be 0.77 (p < 0.00001) for a set of 25 homologous genes, while a correlation of 0.48 (p < 0.0005) was found for a primarily random sample of 50 homologous human and mouse genes. This is the first evidence of conserved gene-to-gene variability in cSNP frequency across species and indicates that site-directed screening of porcine genes that are homologous to cSNP-rich human genes may rapidly advance cSNP discovery in pigs.

Animals↗

PubMed2002

A catalog of 106 single-nucleotide polymorphisms (SNPs) and 11 other types of variations in genes for transforming growth factor-beta1 (TGF-beta1) and its signaling pathway.

Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine that is produced in the platelet, bone, placenta, and other tissues. It acts as a growth inhibitor in many types of cells, and also mediates extracellular matrix production and immunosuppression. Mutations in the specific domain of its gene ( TGFB1) cause Camurati-Engelmann disease, a bone-sclerosing disorder, and those in other domains may be associated with osteoporosis. We identified 106 single-nucleotide polymorphisms and 11 other types of variations in TGFB1and six other genes. These genes were TGF-beta type I receptor gene (TGFBR1), TGF-beta type II receptor gene (TGFBR2), SMAD2 gene (SMAD2), SMAD3 gene (SMAD3), SMAD4 gene (SMAD4), and SMAD7 gene (SMAD7), all of which compose the TGF-beta1 signaling pathway. We also estimated allele frequencies of these DNA polymorphisms among 48 Japanese individuals. Our data will provide a useful resource for the study of disease susceptibility.

DNA Primers↗

PubMed2006

Pharmacogenomics in inflammatory bowel disease.

Inherited variations in the nucleotide sequence of genes influence how individual patients respond to drugs. Most commonly, clinically significant genetic variations consist of single nucleotide polymorphisms (SNPs) within genes that affect drug disposition or drug targets. Up to now, relatively few clinically important examples of inherited traits that affect drug responses have been studied in detail. However, one of the well-characterized examples is highly relevant to inflammatory bowel disease therapeutics, that of thiopurine methyltransferase pharmacogenetics. Individuals with 2 normal alleles of the gene encoding thiopurine methyltransferase metabolize and clear thiopurines such as azathioprine and 6-mercaptopurine rapidly. Individuals with 1 normal and 1 variant allele are intermediate, whereas those with 2 variant alleles clear thiopurines very slowly. Intermediate and slow metabolizers are predisposed to have high active thiopurine drug levels and develop bone marrow suppression. Genomic era technology permits determination of large numbers of SNPs in large numbers of individuals. This capability is allowing the field of pharmacogenomics to become one of the most productive interfaces in translational biomedical research at present. By using high-throughput SNP genotyping, combined with careful phenotypic characterization of disease, pharmacogenomic research carries the potential of identifying individual biomarkers that predict the relative likelihood of benefit or risk from a therapeutic intervention. If this promise can be realized, pharmacogenomics will deliver the opportunity for personalized medicine.

Anti-Inflammatory Agents↗

PubMed2004

Haplotype reconstruction from genotype data using Imperfect Phylogeny.

UNLABELLED: Critical to the understanding of the genetic basis for complex diseases is the modeling of human variation. Most of this variation can be characterized by single nucleotide polymorphisms (SNPs) which are mutations at a single nucleotide position. To characterize the genetic variation between different people, we must determine an individual's haplotype or which nucleotide base occurs at each position of these common SNPs for each chromosome. In this paper, we present results for a highly accurate method for haplotype resolution from genotype data. Our method leverages a new insight into the underlying structure of haplotypes that shows that SNPs are organized in highly correlated 'blocks'. In a few recent studies, considerable parts of the human genome were partitioned into blocks, such that the majority of the sequenced genotypes have one of about four common haplotypes in each block. Our method partitions the SNPs into blocks, and for each block, we predict the common haplotypes and each individual's haplotype. We evaluate our method over biological data. Our method predicts the common haplotypes perfectly and has a very low error rate (<2% over the data) when taking into account the predictions for the uncommon haplotypes. Our method is extremely efficient compared with previous methods such as PHASE and HAPLOTYPER. Its efficiency allows us to find the block partition of the haplotypes, to cope with missing data and to work with large datasets. AVAILABILITY: The algorithm is available via a Web server at http://www.calit2.net/compbio/hap/

Algorithms↗

PubMed2004

Surface amplification of invasive cleavage products.

A major focus of current efforts in genomics is to elucidate the genetic variations extent within the human population, and to study the effects of these variations upon the human system. The most common type of genetic variations are the single nucleotide polymorphisms (SNPs), which occur every 500-1000 nt in the genome. Large-scale population association studies to study the biological or medical significance of such variations may require the analysis of hundreds of thousands of SNPs on thousands of individuals. We are pursuing development of an approach to large-scale SNP analysis that combines the specificity of invasive cleavage reactions with the parallelism of high density DNA arrays. A surface-immobilized probe oligonucleotide is specifically cleaved in the presence of a complementary target sequence in unamplified human genomic DNA, yielding a 5' phosphate group. High sensitivity detection of this reaction product on the surface is achieved by the use of rolling circle amplification, with an approximate concentration detection limit of 10 fM target DNA. This combination of very specific surface cleavage and highly sensitive surface detection will make possible the rapid and parallel analysis of genetic variations across large populations.

DNA↗

PubMed2006

Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder.

The genetics of schizophrenia has been approached utilizing a variety of methods. One emerging strategy is the use of endophenotypes in order to understand and identify the functional importance of genetically transmitted, brain-based deficits across schizophrenia kindreds. The endophenotype strategy is a topic of this issue of Schizophrenia Bulletin. Endophenotypes are quantitative, heritable, trait-related deficits typically assessed by laboratory-based methods rather than clinical observation. Endophenotypes are seen as closer to genetic variation than are clinical symptoms of schizophrenia, and are therefore closely linked to heritable risk factors. There has been a broad expansion of opportunities available to psychiatric neuroscientists who use the endophenotype strategy to understand the genetic basis of schizophrenia. In this context, genetic variation such as single nucleotide polymorphisms (SNPs) induces abnormalities in endophenotypic domains such as neurocognition, neurodevelopment, metabolism, and neurophysiology. This article discusses the challenges that abound in genetic research of schizophrenia, including issues in ascertainment, epistasis, ethnic diversity, and the potentially normalizing effects of second-generation antipsychotic medications on neurocognitive and neurophysiological measures. Robust strategies for meeting these challenges are discussed in this review and the subsequent articles in this issue. This article summarizes conceptual advances and progress in the measurement and use of endophenotypes in schizophrenia that form the basis of the multisite National Institute of Mental Health Consortium on the Genetics of Schizophrenia. The endophenotype strategy offers powerful and exciting opportunities to understand the genetically conferred neurobiological vulnerabilities and possible new strong inference and molecularly based treatments for schizophrenia.

Antipsychotic Agents↗

PubMed2000

Determination of single-nucleotide polymorphisms by real-time pyrophosphate DNA sequencing.

The characterization of naturally occurring variations in the human genome has evoked an immense interest during recent years. Variations known as biallelic Single-Nucleotide Polymorphisms (SNPs) have become increasingly popular markers in molecular genetics because of their wide application both in evolutionary relationship studies and in the identification of susceptibility to common diseases. We have addressed the issue of SNP genotype determination by investigating variations within the Renin-Angiotensin-Aldosterone System (RAAS) using pyrosequencing, a real-time pyrophosphate detection technology. The method is based on indirect luminometric quantification of the pyrophosphate that is released as a result of nucleotide incorporation onto an amplified template. The technical platform employed comprises a highly automated sequencing instrument that allows the analysis of 96 samples within 10 to 20 minutes. In addition to each studied polymorphic position, 5-10 downstream bases were sequenced for acquisition of reference signals. Evaluation of pyrogram data was accomplished by comparison of peak heights, which are proportional to the number of incorporated nucleotides. Analysis of the pyrograms that resulted from alternate allelic configurations for each addressed SNP revealed a highly discriminating pattern. Homozygous samples produced clear-cut single base peaks in the expected position, whereas heterozygous counterparts were characterized by distinct half-height peaks representing both allelic positions. Whenever any of the allelic bases of an SNP formed a homopolymer with adjacent bases, the nonallelic signal was added to those of the SNP. This feature did not, however, influence SNP readability. Furthermore, the multibase reading capacity of the described system provides extensive flexibility in regard to the positioning of sequencing primers and allows the determination of several closely located SNPs in a single run.

Alleles↗

PubMed2004

Linkage and association with the NOS2A locus on chromosome 17q11 in multiple sclerosis.

A large body of research supports a multifactorial cause in multiple sclerosis (MS), with an underlying genetic susceptibility likely acting in concert with undefined environmental exposures. Here, we used a highly efficient multilocus genotyping assay to study single nucleotide polymorphisms representing variation in 34 genes from inflammatory pathways in a well-characterized MS familial data set. Evidence of transmission distortion was present for several polymorphisms. Results for the NOS2A locus (exon 10 C/T, D346D) on chromosome 17q11 remained significant after correction for multiple testing and were reproduced in a second independent African American MS data set. In addition, linkage to a NOS2A promoter region polymorphism, (CCTTT)(n), was present in a third data set of multicase MS families. Our results provide strong evidence for linkage and association to a new candidate disease gene on chromosome 17q11 in MS and suggest that variation within NOS2A or a nearby locus contributes to disease susceptibility.

Adult↗

PubMed1999

Single-nucleotide polymorphisms can cause different structural folds of mRNA.

Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variation in man. Genes containing one or more SNPs can give rise to two or more allelic forms of mRNAs. These mRNA variants may possess different biological functions as a result of differences in primary or higher order structures that interact with other cellular components. Here we report the observation of marked differences in mRNA secondary structure associated with SNPs in the coding regions of two human mRNAs: alanyl tRNA synthetase and replication protein A, 70-kDa subunit (RPA70). Enzymatic probing of SNP-containing allelic fragments of the mRNAs revealed pronounced allelic differences in cleavage pattern at sites 14 or 18 nt away from the SNP, suggesting that a single-nucleotide variation can give rise to different mRNA folds. By using phosphorothioate oligodeoxyribonucleotides complementary to the region of different allelic structures in the RPA70 mRNA, but not extending to the SNP itself, we find that the SNP exerts an allele-specific effect on the accessibility of its flanking site in the endogenous human RPA70 mRNA. This further supports the allele-specific structural features identified by enzymatic probing. These results demonstrate the contribution of common genetic variation to structural diversity of mRNA and suggest a broader role than previously thought for the effects of SNPs on mRNA structure and, ultimately, biological function.

Alanine-tRNA Ligase↗

PubMed2004

Genetic variation in the corticotrophin-releasing factor receptors: identification of single-nucleotide polymorphisms and association studies with obesity in UK Caucasians.

OBJECTIVE: To investigate whether genetic variation at the loci encoding the corticotropin-releasing factor receptors-1 and -2 (CRF-R1 and CRF-R2) contributes to human obesity. DESIGN: The coding region of the CRF-R1 and CRF-R2 genes was screened in 51 severely obese children (body mass index (BMI)>4 kg/m(2) standard deviations above the age-related mean) using denaturing high-performance liquid chromatography and direct nucleotide sequencing. Common polymorphisms that were identified were typed from a UK Caucasian population-based cohort by a PCR-based forced restriction digestion. A repeated measures analysis was used to determine associations between the C861T and G1047A genotypes and anthropometric and biochemical indices relevant to obesity. RESULTS: In subjects with extreme early-onset obesity, four missense mutations were found, each in a single individual: CRF-R1 (Val161Met) and CRF-R2 (Glu220Asp, Val240Ile and Val411Met). However, none of these missense mutations clearly cosegregated with obesity in family studies. Two common single-nucleotide polymorphisms, C861T (Cys287Cys) in CRF-R1 and G1047A (Ser349Ser) in CRF-R2, were also detected. G1047A did not associate with any obesity-related phenotype. In contrast, carriers of the CRF-R1 polymorphism, C861T, had a significantly higher body mass index (BMI). CONCLUSION: Mutations in the coding sequence of the CRF-R1 and CRF-R2 genes are unlikely to be a common monogenic cause of early-onset obesity. In an adult UK Caucasian population, the CRF-R1 C861T polymorphism is associated with increased BMI.

Age of Onset↗