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PubMed2004

Single nucleotide polymorphisms: aging and diseases.

Differences of more than 3 million nucleotides can bee seen comparing the genomes of two individuals as a result of single nucleotide polymorphism (SNP). More and more SNPs can be identified and it seems that these alterations are behind of several biological phenomena. Personal differences in these nucleotides result for example in elevated disease susceptibilities, that is, certain nucleotides are more frequent in patients suffering from different diseases comparing to the healthy population. SNPs may cause substantial alterations in the cells, e.g. the enzyme activity of the respective gene changes, but in other cases the effects of the SNPs are not so pronounced. Later results indicate that SNPs can be rendered to individuals living a longer life than the average. Perhaps these results will not directly lead to the lengthening of the maximal life span; however, genes that play an important role in the aging process could be identified. In this respect SNPs are important factors in determining the information level of the cells of individuals which determines the maximal life span (I. Semsei On the nature of aging. Mech. Ageing Dev . 2000; 117: 93-108), in turn SNP is one of the factors that determine the aging process. Since there are certain age-related diseases, the discovery and the description of the SNPs as a function of age and diseases may result in a better understanding of the common roots of aging and those diseases.

Aging↗

PubMed2006

A nonsynonymous single-nucleotide polymorphism in the PDZ-Rho guanine nucleotide exchange factor (Ser1416Gly) modulates the risk of lung cancer in Mexican Americans.

BACKGROUND: Based on in vitro studies, Rho guanine nucleotide exchange factors (RhoGEFs) are key regulators of mitogenic and transforming pathways. At least 1 family member, PDZ-RhoGEF, also integrates signaling between monomeric Rho G proteins and heterotrimeric G proteins through a so-called regulator of G-protein signaling (RGS) domain. Recently, the authors reported that 3 single-nucleotide polymorphisms (SNPs) in 2 members of the RGS family were associated with significant reductions in the risk of cancer. METHODS: For the current report, the authors studied the risk of lung cancer associated with a nonsynonymous SNP (rs868188; Ser1416Gly) in PDZ-RhoGEF in a large lung cancer case-control study of 2260 Caucasians and 369 Mexican Americans. RESULTS: Compared with individuals who had the wild-type genotype (AA), Mexican Americans with the variant genotypes (AG and GG) had a significantly reduced risk for lung cancer (odds ratio [OR], 0.57; 95% confidence interval [95%CI], 0.34-0.94). The protective effect appeared to be more evident in younger individuals (OR, 0.42; 95%CI, 0.20-0.91), men (OR, 0.36; 95%CI, 0.18-0.71), and ever smokers (OR, 0.50; 95%CI, 0.29-0.88). A joint effect was observed between Ser1416Gly and polymorphisms in 2 cell-cycle control genes: p53 (intron 3) and cyclin D1 (CCND1). Tallying the variant alleles of the 4 RGS gene SNPs, a gene-dosage effect was apparent. Compared with individuals who had < 3 variant alleles, patients with > or = 3 variant alleles had a 51% reduction in lung cancer risk (OR, 0.49; 95%CI, 0.28-0.88). CONCLUSIONS: To the authors' knowledge, this is the first epidemiological study to link PDZ-RhoGEF polymorphisms with cancer risk. The results suggest that there are interactions between RGS2, RGS6, and PDZ-RhoGEF and validate this family of proteins as key regulators of tumorigenesis.

Aged↗

PubMed2004

Identification of two novel single nucleotide polymorphisms in the promoter of the human interleukin-18 receptor alpha.

Single-strand conformational polymorphism (SSCP) was used to identify single nucleotide polymorphisms (SNPs) in the promoter region of the human interleukin-18 receptor alpha (IL-18Ralpha). Two SNPs were identified at positions -69 and -638 relative to the transcriptional start site. Two-way comparison of the two SNPs revealed strong linkage disequilibrium (chi2 = 63.45, P < 0.001). Three haplotypes were identified, namely C-69C-638, T-69C-638 and C-69T-638, with frequencies of 0.26, 0.39 and 0.35, respectively.

Alleles↗

PubMed2006

Multiplex single-nucleotide polymorphism detection by combinatorial fluorescence energy transfer tags and molecular affinity.

Combinatorial fluorescence energy transfer (CFET) tags, constructed by exploiting fluorescence energy transfer and combinatorial synthesis to generate a large number of unique fluorescence emission signatures from a limited number of fluorophores, allow multiple biological targets to be identified simultaneously. All of the CFET tags can be excited by a single wavelength of 488 nm and analyzed by a simple optical system. In genetic analysis, the CFET tags are coupled with solid phase capture for multiplex single-nucleotide polymorphism (SNP) detection. The design, synthesis, purification of CFET tags, and the methods to use the CFET tags and molecular affinity for SNP detection in the retinoblastoma tumor suppressor gene are described.

Combinatorial Chemistry Techniques↗

PubMedDate not supplied

Discovery and assay of single-nucleotide polymorphisms in barley (Hordeum vulgare).

The least ambiguous genetic markers are those based on completely characterized DNA sequence polymorphisms. Unfortunately, assaying allele states by allele sequencing is slow and cumbersome. The most desirable type of genetic marker would be unambiguous, inexpensive to assay and would be assayable singly or in parallel with hundreds of other markers (multiplexable). In this report we sequenced alleles at 54 barley (Hordeum vulgare ssp. vulgare) loci, 38 of which contained single-nucleotide polymorphisms (SNPs). Many of these 38 loci contained multiple polymorphisms, and a total of 112 polymorphisms were scored in five barley genotypes. The polymorphism data set was analyzed both by using the individual mutations as cladistic characters and by reducing data for each locus to haplotypes. We compared the informativeness of these two approaches by consensus tree construction and bootstrap analysis. Both approaches provided similar results. Since some of the loci sequenced contained insertion/deletion events and multiple point mutations, we thought that these multiple-mutated loci might represent old alleles that predated the divergence of barley from H. spontaneum. We evaluated sequences from a sample of H. spontaneum accessions from the Eastern Mediterranean, and observed similar alleles present in both cultivated barley and H. spontaneum, suggesting either multiple domestication events or multiple transfers of genes between barley and its wild ancestor.

Base Sequence↗

PubMed2003

Single-nucleotide polymorphism analysis by allele-specific extension of fluorescently labeled nucleotides in a microfluidic flow-through device.

We describe a microfluidic approach for allele-specific extension of fluorescently labeled nucleotides for scoring of single-nucleotide polymorphism (SNP). The method takes advantage of the fact that the reaction kinetics differs between matched and mismatched configurations of allele-specific primers hybridized to DNA template. A microfluidic flow-through device for biochemical reactions on beads was used to take advantage of the reaction kinetics to increase the sequence specificity of the DNA polymerase, discriminating mismatched configurations from matched. The volume of the reaction chamber was 12.5 nL. All three possible variants of an SNP site at codon 72 of the p53 gene were scored using our approach. This work demonstrates the possibility of scoring SNP by allele-specific extension of fluorescently labeled nucleotides in a microfluidic flow-through device. The sensitive detection system and easy microfabrication of the microfluidic device enable further miniaturization and production of an array format of microfluidic devices for high-throughput SNP analysis.

Alleles↗

PubMed2002

Single nucleotide polymorphism genotyping using short, fluorescently labeled locked nucleic acid (LNA) probes and fluorescence polarization detection.

Locked nucleic acids (LNAs) are synthetic nucleic acid analogs that bind to complementary target molecules (DNA, RNA or LNA) with very high affinity. At the same time, this binding affinity is decreased substantially when the hybrids thus formed contain even a single mismatched base pair. We have exploited these properties of LNA probes to develop a new method for single nucleotide polymorphism genotyping. In this method, very short (hexamer or heptamer) LNA probes are labeled with either rhodamine or hexachlorofluorescein (HEX), and their hybridization to target DNAs is followed by measuring the fluorescence polarization (FP) of the dyes. The formation of perfectly complementary double-stranded hybrids gives rise to significant FP increases, whereas the presence of single mismatches results in very small or no changes of this parameter. Multiplexing of the assay can be achieved by using differentially labeled wild-type and mutant specific probes in the same solution. The method is homogeneous, and because of the use of extremely short LNA probes, the generation of a universal set of genotyping reagents is possible.

Base Composition↗

PubMed2005

Hydrogen bond-mediated binding of ligands to a nucleobase at a gap site in a DNA duplex and its use for fluorescence detection of single-nucleotide polymorphisms.

Here we report on the strong and selective binding of a hydrogen bond-forming ligand, 2-amino-7-methyl-1,8-naphthyridine (AMND), to a nucleobase at a gap site in DNA duplexes. In solutions buffered to pH 7.0 (at 20 degrees C, I = 0.11 M), AMND is found to selectively recognize cytosine (C) base over other nucleotides, and the 1:1 association constant reaches 3.2x10(5) M(-1) when binding to C. The ligand-nucleotide interaction results in significant fluorescence quenching of AMND, which is highly selective to C. These sensing functions of AMND at the gap site are utilized for the development of ligand-based fluorescence assay for SNPs (single-nucleotide polymorphisms) typing.

Cytosine↗

PubMed2006

Characterization of 37 breed-specific single-nucleotide polymorphisms in sheep.

We identified 37 single-nucleotide polymorphisms (SNPs) in sheep and screened 16 individuals from 8 different sheep breeds selected throughout Europe. Population genetic measures based on the genotyping of about 30 sheep from the same 8 breeds are reported. To date, there are no sheep SNPs documented in the National Center for Biotechnology Information dbSNP database. Therefore, the markers presented here contribute significantly to those currently available.

Animals↗

PubMed2002

Assessing allele frequencies of single nucleotide polymorphisms in DNA pools by pyrosequencing technology.

Single nucleotide polymorphism (SNP) association studies searching for differences in allele frequencies between cases and controls have been widely used for genetic analysis. Individual genotyping is prohibitively expensive in large sample sizes. Pooling of samples provides the obvious advantage of higher throughput and lower cost. Here we report our results with the analysis of SNP allele frequencies in DNA pools using Pyrosequencing technology. For seven different SNPs, we observed a mean difference of 1.1 +/- 0.6% between allele frequencies determined in two different DNA pools (n = 150 cases and 150 controls) compared to individually genotyped samples.

Diabetes Mellitus, Type 2↗

PubMed2000

An analysis of strategies for discovery of single-nucleotide polymorphisms.

Strategies for the discovery of single-nucleotide polymorphisms (SNPs) can be characterized by the number of individuals in the discovery sample, and by the minimal required number of observations of each allele. We examine the effect of different strategies on two key properties of the resulting SNP collection: (1) the probability that a SNP with a given population allele frequency is detected; and (2) the allele-frequency distribution of the discovered SNPs. We show that strategies that accept all polymorphic sites lead to collections with a high fraction of SNPs with rare minor alleles, particularly in expanded populations. Such SNPs have a low probability of replication in a second sample. We discuss how to tailor a discovery strategy to the desired properties of a SNP collection.

Alleles↗

PubMed2004

Genotyping of single nucleotide polymorphism using model-based clustering.

MOTIVATION: Single nucleotide polymorphisms have been investigated as biological markers and the representative high-throughput genotyping method is a combination of the Invader assay and a statistical clustering method. A typical statistical clustering method is the k-means method, but it often fails because of the lack of flexibility. An alternative fast and reliable method is therefore desirable. RESULTS: This paper proposes a model-based clustering method using a normal mixture model and a well-conceived penalized likelihood. The proposed method can judge unclear genotypings to be re-examined and also work well even when the number of clusters is unknown. Some results are illustrated and then satisfactory genotypings are shown. Even when the conventional maximum likelihood method and the typical k-means clustering method failed, the proposed method succeeded.

Algorithms↗

PubMed2002

LNA-enhanced detection of single nucleotide polymorphisms in the apolipoprotein E.

Genotyping of single nucleotide polymorphisms (SNPs) in large populations presents a great challenge, especially if the SNPs are embedded in GC-rich regions, such as the codon 112 SNP in the human apolipoprotein E (apoE). In the present study, we have used immobilized locked nucleic acid (LNA) capture probes combined with LNA-enhancer oligonucleotides to obtain efficient and specific interrogation of SNPs in the apoE codons 112 and 158, respectively. The results demonstrate the usefulness of LNA oligonucleotide capture probes combined with LNA enhancers in mismatch discrimination. The assay was applied to a panel of patient samples with simultaneous genotyping of the patients by DNA sequencing. The apoE genotyping assays for the codons 112 and 158 SNPs resulted in unambiguous results for all patient samples, concurring with those obtained by DNA sequencing.

Apolipoproteins E↗

PubMed2003

An exponential dispersion model for the distribution of human single nucleotide polymorphisms.

An analysis of 1.42 million human single nucleotide polymorphisms (SNPs), mapped by the International SNP Map Working Group, revealed an apparent power function relationship between the estimated variance and mean number of SNPs per sample bin. This relationship could be explained by the assumption that a scale invariant Poisson gamma (PG) exponential dispersion model could describe the distribution of SNPs within the bins. In this model the sample bins would contain random (Poisson distributed) numbers of identical by descent genomic segments, each with independently distributed and gamma distributed numbers of SNPs. This model was both qualitatively and quantitatively consistent with the conventional coalescent model. It agreed with the empirical cumulative distribution functions derived from the SNP maps as well as with simulated data. The model was used to estimate the heterozygosity pi, and the mean number and size of haplotype blocks for each chromosome. These estimates were consistent with measurements from conventional studies. This PG model thus provides an alternative to Monte Carlo simulation for description of the distribution of SNPs.

Computer Simulation↗

PubMed2005

Multiplex amplified product-length polymorphism analysis of 36 mitochondrial single-nucleotide polymorphisms for haplogrouping of East Asian populations.

We present a reliable, rapid, and economical multiplex amplified product-length polymorphism (APLP) method for analyzing the haplogroup-diagnostic mitochondrial single-nucleotide polymorphisms (mtSNPs) in East Asian populations. By examining only 36 haplogroup-specific mtSNPs in the coding region by using four 9-multiplex polymerase chain reaction (PCR) and subsequent electrophoresis, we could safely assign 1815 individuals from 8 populations of Japanese, Korean, Chinese, and Germans to 45 relevant haplogroups. This multiplex APLP analysis of coding-region mtSNPs for haplogrouping is especially useful not only for molecular phylogenetic studies but also for large-scale association studies due to its rapid and economical nature. This is the first panel of mtSNPs in the coding region to be used for haplogrouping of East Asian populations.

Asian People↗

PubMed2002

Efficient discovery of single-nucleotide polymorphisms in coding regions of human genes.

Single nucleotide polymorphisms in protein coding regions (cSNPs) are of great interest for their effects on phenotype and potential for mapping disease genes. We have identified 5,400 novel exonic SNPs from alignments of public EST data to the draft human genome sequence, and approximately 12,000 more novel exonic SNPs from EST cluster alignments. We found 82% of the genomic-aligned SNPs and 63% of the EST-only SNPs to be detectably polymorphic in 20 Finnish DNA samples. 37% of the SNPs mapped to known protein coding regions, yielding 6,500 distinct, novel cSNPs from the two datasets. These data reveal selection against mutations that alter protein structure, and distinct classes of genes under strongly positive vs. negative pressure from natural selection for amino acid replacement (detected by K(A)/K(S)ratio). We have searched these cSNPs for compatibility with the amino acid profile at each site and structural impact on protein core stability.

Chromosome Mapping↗

PubMed2006

[Single nucleotide polymorphism (SNP) and its application in rice].

Single nucleotide polymorphisms (SNPs) distribute numerously and high-density throughout rice (Oryza sativa L.) genome. A total of 80,127 SNP sites were identified in rice genome, and one SNP every 154 bp was found between two rice subspecies indica and japonica. The SNP rate is 0.65%. SNPs also are very considerable among within-subspecies cultivars, even it can be found between closely related cultivars, in which it has been difficult to find polymorphic sites by conventional methods. The frequency of SNPs in rice genome varied between chromosomes, moreover it showed uneven distribution of polymorphism-rich and -poor regions along each chromosome. Several routes have been used for identification of SNP in rice, such as sequencing PCR products of DNA samples, screening SNPs in SSR fragments, and searching for SNPs through the rice genome sequences and EST database. A number of genotyping systems have been developed to identify SNPs in rice genome. High automation in SNPs identification has become a very convenient operation by the automatized systems. SNPs can be converted to CAPS (cleaved amplified polymorphic sequence) or dCAPS (derived-CAPS), and allele-specific PCR markers. SNP has shown huge potential in establishing rice genetic maps, genes cloning and functional genomics, MAS (marker assisted selection) in rice breeding, and studying on classification and evolution of germplasm.

Breeding↗

PubMed2004

Chicken single nucleotide polymorphism identification and selection for genetic mapping.

Single nucleotide polymorphisms (SNP) are the ideal markers for high-density genome wide mapping. A total of 327,000 expressed sequence tag (EST) sequences, obtained from the ChickEST project, were examined for the presence of SNP. A total of 32,268 potential chicken SNP were identified and stored in a customized Microsoft Access database and evaluated in silico for their usability for a high-density genetic map. Based on a minimum of 3 for the minor allele occurrence and a minimum of 30% for the minor allele frequency, 5,332 reliable SNP were selected, of which both SNP alleles were present in the database at a high frequency. To test the usefulness of the in silico SNP identification, 24 SNP affecting a BglII site were used for a genotyping study. A functional PCR assay could be designed for 21 of the 24 SNP. It was possible to validate 90% of this marker subset (21 SNP) by BglII restriction analysis. The high percentage of validated markers demonstrates the reliability of the 5,332 chicken SNP markers. Furthermore, the limited number of genomic DNA samples necessary to validate 90% of the SNP markers confirmed the prediction of the high frequency at which both alleles of the selected SNP were present in the tested chicken populations.

Animals↗