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PubMed2001

[Clinical significance and strategies to analyze genetic polymorphisms].

A DNA polymorphism can be defined as a difference in the primary sequence of DNA, and the frequency of the rarer allele among the general population exceeds 1%. Several types of polymorphisms, including minisatellite and microsatellite markers, deletion or insertion of short nucleotide sequences, and single nucleotide polymorphisms(SNPs), are present in human genome, with different frequencies and different distribution patterns. SNPs are very common and clinically important, because they often appear within genes, particularly within coding sequences. The biological significance of a polymorphism differs significantly depending upon its location within the genome. For example, polymorphisms located outside genes usually do not have biological consequences, and will be used merely as markers for genetic linkage. On the other hand, those located within a gene may cause subtle changes in transcription, mRNA stability, or protein conformation if amino acid substitution occurs. These subtle changes in biologically important factors then alter susceptibility to certain disorders. Environmental factors often interact with genes. Relationships between genetic polymorphisms and disease susceptibility have been reported on many kinds of human diseases, including neurological and psychiatric disorders, infectious diseases, endocrine and metabolic disorders, malignancy, as well as cardiovascular diseases. Recent years have seen the progress in novel strategies for rapid genotyping of a large numbers of polymorphisms, and also, for searching unknown SNPs.

Genetic Predisposition to Disease↗
PubMed2004

ADAM33 polymorphisms and phenotype associations in childhood asthma.

BACKGROUND: A disintegrin and metalloproteinase (ADAM) 33 has been implicated as an asthma susceptibility gene by using a positional cloning approach. However, genetic linkage of asthma phenotypes to chromosome 20p13 (the location of ADAM33) has not been observed in most asthma genome scans, and it is unclear whether these associations with ADAM33 are broadly generalizable. OBJECTIVE: To examine whether ADAM33 is associated with asthma in a North American population of childhood asthmatic patients. METHODS: We performed a family-based association study by using 652 nuclear families ascertained through asthmatic subjects enrolled in a large randomized clinical trial. Seventeen ADAM33 single nucleotide polymorphisms (SNPs; including 9 associated with asthma in the initial report) were genotyped by mass spectrometry. Single-SNP and haplotype association analysis was performed. RESULTS: Among white and African American subjects, no single-SNP association with asthma was observed. However, a common 16-SNP haplotype (frequency, 14.6% in white subjects) was associated with asthma (P=.006). Two SNPs in strong linkage disequilibrium (T1 and T+1) were marginally associated with asthma in the Hispanic cohort (P=.04). These data provide marginal support for an asthma locus in the ADAM33 genomic region. However, the magnitudes of the observed associations are modest at best and are inconsistent with the original report. CONCLUSIONS: We conclude that either ADAM33 has only modest effects on asthma susceptibility, and the initial reports of association were a result of analysis in a selected population, or the initial findings were a result of chance. It is also possible that the true asthma susceptibility locus in this genomic region is near, but not at, ADAM33.

ADAM Proteins↗
PubMed2006

Identification of base pairs in single-nucleotide polymorphisms by MutS protein-mediated capillary electrophoresis.

Single-nucleotide polymorphisms (SNPs) are widespread genomic variations, which are associated with serious health disorders and drug resistance. Multiple clinical applications and studies of global population genetics require fast and informative analysis of SNPs. Most of conventional methods sense the presence of the SNP but cannot identify the base pair in it. Here we report simple identification of base pairs in SNPs without DNA sequencing. Our approach is based on the unique ability of MutS protein to bind different single-nucleotide mismatches in DNA with different affinities. Conceptually, the DNA in question is mixed with reference DNA, melted, and reannealed. If the DNA in question has an SNP, the products of reannealing will have two different single-nucleotide mismatches, which provide a base-pair-specific signature of the SNP. The products of reannealing are mixed with MutS, equilibrated, and separated by equilibrium capillary electrophoresis of equilibrium mixtures with MutS in the run buffer. The pattern of migration times of DNAs with mismatches is used for unequivocal identification of the base pair in the SNP. In addition to its ability to identify base pairs in SNPs, the new analytical approach is fast, simple, highly sensitive, and requires no quantitation. It will find applications in studies of heterogeneity of base pairs in known SNPs in large human populations.

Base Pairing↗
PubMed2000

Use of single nucleotide polymorphisms for gene discovery in hypertension.

Genetic susceptibility to common diseases is likely influenced by common DNA variants with small-to-moderate effects, rather than by rare mutations with large effects. The majority of such common variation occurs in the form of single nucleotide polymorphisms (SNPs). DNA sequence variation, including SNPs, is created and maintained by the action of evolutionary forces such as mutation, recombination, and selection. Over time and space, these forces have shaped the relationships between the contemporary organization of the human genome and disease susceptibility in the population at large. Single nucleotide polymorphisms have emerged as valuable new tools to uncover these relationships. In particular, their use in both genome-wide and gene-based association studies holds great promise for the identification of genes and gene variations involved in predisposition to essential hypertension. New advances in biotechnology are making possible large-scale discovery of SNP variation and rapid application of this information to disease gene discovery.

Base Sequence↗
PubMed2001

Association study of polymorphisms in the GluR5 kainate receptor gene (GRIK1) with schizophrenia.

The glutamatergic dysfunction hypothesis suggests genes involved in glutamatergic transmission as candidates for schizophrenia susceptibility genes. We screened single nucleotide polymorphisms (SNPs) in the entire coding sequence of the GluR5 kainate receptor gene, GRIK1, by polymerase chain reaction-single strand conformation polymorphism and direct sequencing. We identified six SNPs including three known ones, 522A/C (174T, synonymous), 1173C/T (391D, synonymous), and 2705C/T (902L/S), as well as three novel ones, 995C/T (332A/V), 2400C/T (800L, synonymous), and 2585A/G (862R/Q). We genotyped Japanese samples of schizophrenia (n = 193-203) and healthy controls (n = 199-215) for three SNPs those were commonly observed in our samples, 522A/C, 1173C/T, and 2705C/T. We observed no significant associations of the SNPs and their haplotypes with schizophrenia. Therefore, we conclude that GRIK1 does not play a major role in schizophrenia pathogenesis in the Japanese population.

Base Sequence↗
PubMed2004

PupaSNP Finder: a web tool for finding SNPs with putative effect at transcriptional level.

We have developed a web tool, PupaSNP Finder (PupaSNP for short), for high-throughput searching for single nucleotide polymorphisms (SNPs) with potential phenotypic effect. PupaSNP takes as its input lists of genes (or generates them from chromosomal coordinates) and retrieves SNPs that could affect the conserved regions that the cellular machinery uses for the correct processing of genes (intron/exon boundaries or exonic splicing enhancers), predicted transcription factor binding sites (TFBS) and changes in amino acids in the proteins. The program uses the mapping of SNPs in the genome provided by Ensembl. Additionally, user-defined SNPs (not yet mapped in the genome) can be easily provided to the program. Also, additional functional information from Gene Ontology, OMIM and homologies in other model organisms is provided. In contrast to other programs already available, which focus only on SNPs with possible effect in the protein, PupaSNP includes SNPs with possible transcriptional effect. PupaSNP will be of significant help in studies of multifactorial disorders, where the use of functional SNPs will increase the sensitivity of identification of the genes responsible for the disease. The PupaSNP web interface is accessible through http://pupasnp.bioinfo.cnio.es.

Amino Acid Substitution↗
PubMed2002

[Linkage disequilibrium analysis of the single nucleotide polymorphisms in the PRKCZ gene].

OBJECTIVE: To search for the disease-associated haplotype in the PRKCZ gene, a susceptibility gene for type 2 diabetes in Han population of North China, by case-control study and linkage disequilibrium (LD) analysis using single nucleotide polymorphisms (SNPs). METHODS: SNPs located in the PRKCZ gene were chosen from public SNP domain by bioinformatic methods and single base extension (SBE) method was used to genotype the loci in 173 sporadic type 2 diabetes patients and 152 normal individuals to perform case-control study and LD analysis. Haplotype block were constructed in these populations. RESULTS: Several SNPs in the PRKCZ gene were found to be associated with the disease. The SNPs formed different haplotype block pattern in case and control groups. The frequencies of the haplotypes formed by 5 SNPs were statistically different between the two groups. CONCLUSION: The haplotype formed by 5 SNPs in the PRKCZ gene may be associated with type 2 diabetes in Han population of China, which is confirmed from statistics to be a susceptibility gene for the disease.

Alleles↗
PubMed2005

DNA microarrays on a dendron-modified surface improve significantly the detection of single nucleotide variations in the p53 gene.

Selectivity and sensitivity in the detection of single nucleotide polymorphisms (SNPs) are among most important attributes to determine the performance of DNA microarrays. We previously reported the generation of a novel mesospaced surface prepared by applying dendron molecules on the solid surface. DNA microarrays that were fabricated on the dendron-modified surface exhibited outstanding performance for the detection of single nucleotide variation in the synthetic oligonucleotide DNA. DNA microarrays on the dendron-modified surface were subjected to the detection of single nucleotide variations in the exons 5-8 of the p53 gene in genomic DNAs from cancer cell lines. DNA microarrays on the dendron-modified surface clearly discriminated single nucleotide variations in hotspot codons with high selectivity and sensitivity. The ratio between the fluorescence intensity of perfectly matched duplexes and that of single nucleotide mismatched duplexes was >5-100 without sacrificing signal intensity. Our results showed that the outstanding performance of DNA microarrays fabricated on the dendron-modified surface is strongly related to novel properties of the dendron molecule, which has the conical structure allowing mesospacing between the capture probes. Our microarrays on the dendron-modified surface can reduce the steric hindrance not only between the solid surface and target DNA, but also among immobilized capture probes enabling the hybridization process on the surface to be very effective. Our DNA microarrays on the dendron-modified surface could be applied to various analyses that require accurate detection of SNPs.

Anthracenes↗
PubMed2000

Electrophoretic detection of single-nucleotide polymorphisms.

Single-nucleotide polymorphisms (SNPs) represent the most prevalent class of genetic markers available for linkage disequilibrium or cladistic analyses. PCR primers may be labeled with fluorescent dyes and used to rapidly and accurately differentiate among alleles that are defined by a single-nucleotide differences. Here, we describe the primer-mediated detection of SNPs based on primer mismatch during allele-specific amplification of preamplified target sequences. Primers are labeled with different fluors at their 5' nucleotides, with their 3' termini at the transition mutation that defines allelic variation at the target locus. Each primer perfectly matches one of the two available alleles for each locus. Electrophoretic detection permits characterization of the product both by size and fluor. This report demonstrates some of the capabilities of this assay, including heterozygote determination and multiplexed analysis.

Alleles↗
PubMed2001

Electrospray ionization mass spectrometry-based genotyping: an approach for identification of single nucleotide polymorphisms.

The high frequency of single nucleotide polymorphisms (SNPs) in the human genome makes them ideal genetic markers for mapping, diagnosing disease-related alleles, and identifying SNPs that contribute to drug response differences between individuals. Here we report a novel assay utilizing a single nucleotide primer extension (SNuPE) and electrospray ionization mass spectrometry (ESI-MS) detection for the analysis of SNPs. In contrast to most SNuPE genotyping technologies that detect the extended primer product, the novel Survivor assay detects the unreacted dideoxynucleotides (ddNTPs) remaining or surviving in solution following a SNuPE. This assay involves a simple analysis of the same four ddNTP analytes, regardless of the SNP being investigated, and either single or double-stranded DNA can be used to genotype a SNP, without any labeling requirements of the ddNTPs or oligonucleotide primers. We have tested and blindly validated the Survivor assay by genotyping the C/T SNP at -857 of the human TNFalpha promoter gene. The results obtained are in agreement with the control sequencing data. The results demonstrate that the homogeneous Survivor assay with ESI-MS detection offers advantages in simplicity, accuracy, specificity, and sensitivity. Additional advantages of the method include enhanced hybridization efficiencies in this solution-phase assay and the elimination of immobilized primers for the isolation of single-stranded DNA. With a one-well reaction and an automation platform being developed, the Survivor assay provides a powerful new tool for large-scale SNP analysis and screening.

Base Sequence↗
PubMed2002

Detection rates for genotyping errors in SNPs using the trio design.

One well-known approach for the analysis of transmission-disequilibrium is the investigation of single nucleotide polymorphisms (SNPs) in trios consisting of an affected child and its parents. Results may be biased by erroneously given genotypes. Various reasons, among them sample swap or wrong pedigree structure, represent a possible source for biased results. As these can be partly ruled out by good study conditions together with checks for correct pedigree structure by a series of independent markers, the remaining main cause for errors is genotyping errors. Some of the errors can be detected by Mendelian checks whilst others are compatible with the pedigree structure. The extent of genotyping errors can be estimated by investigating the rate of detected genotyping errors by Mendelian checks. In many studies only one SNP of a specific genomic region is investigated by TDT which leaves Mendelian checks as the only tool to control genotyping errors. From the rate of detected errors the true error rate can be estimated. Gordon et al. [Hum Hered 1999;49:65-70] considered the case of genotyping errors that occur randomly and independently with some fixed probability for the wrong ascertainment of an allele. In practice, instead of single alleles, SNP genotypes are determined. Therefore, we study the proportion of detected errors (detection rate) based on genotypes. In contrast to Gordon et al., who reported detection rates between 25 and 30%, we obtain higher detection rates ranging from 39 up to 61% considering likely error structures in the data. We conclude that detection rates are probably substantially higher than those reported by Gordon et al.

Genotype↗
PubMed2003

Genotyping single nucleotide polymorphisms directly from genomic DNA by invasive cleavage reaction on microspheres.

Here we report proof-of-principle for a microsphere-based genotyping assay that detects single nucleotide polymorphisms (SNPs) directly from human genomic DNA samples. This assay is based on a structure-specific cleavage reaction that achieves single base discrimination with a 5'-nuclease which recognizes a tripartite substrate formed upon hybridization of target DNA with probe and upstream oligonucleotides. The assay is simple with two easy steps: a cleavage reaction, which generates fluorescent signal on microsphere surfaces, followed by flow cytometry analysis of the microspheres. Genomic DNA samples were genotyped for the SNP in the Apolipoprotein E gene at amino acid position 158. The assay successfully scored wild type, heterozygous and homozygous mutants. To our knowledge, this is the first report of a solid-support assay for detection of SNPs directly from genomic DNA without PCR amplification of the target.

Apolipoproteins E↗
PubMed2005

Carriers of three polymorphisms of cholesteryl ester transfer protein gene are at increased risk to coronary heart disease in a Chinese population.

BACKGROUND: The cholesteryl ester transfer protein (CETP) is a key participant in the reverse transport of cholesterol from the peripheral tissue to the liver and the polymorphism in the CETP gene may therefore alter the susceptibility to coronary heart disease (CHD). The aim of the present study was to screen the CETP gene for new single nucleotide polymorphisms (SNPs) and to determine whether SNPs at important cholesterol metabolism gene loci might exert effects on the risk to CHD in Chinese. METHODS: Genomic DNA samples were collected from 203 Chinese patients with CHD and 209 age- and gender-matched controls. The coding region, adjacent intronic sequences and promoter region (totally 5501 bp) of the CETP gene were screened based on a combination of polymerase chain reaction, denaturing high performance liquid chromatography and DNA sequencing. The association of individual single nucleotide polymorphisms with CHD was assessed by univariate, multivariate analysis and haplotype analysis. RESULTS: Fifteen SNPs were identified in the CETP gene including 12 novel ones, of which, 3 were in promoter region, 1 in exon 10, and other 9 in introns. The frequencies of -644C, +13054T, 296Q, and 442G alleles were considerably higher, while the frequency of +9907A allele lower, in CHD patients than those in controls (p=0.016, p=0.043, p=0.006, p=0.006, and p=0.029, respectively). The results of individual polymorphism analyses were confirmed by haplotype analysis for the combination of these 5 SNPs. The -644A/C, L296Q, and D442G polymorphisms were found to be associated with CHD in this Chinese population by multivariate analysis (p=0.009, p=0.024, and p=0.007, respectively). The adjusted odds ratio for the development of CHD for the -644C allele carriers was 1.63 compared with -644AA genotype (95% CI 1.05-2.78; p<0.01), 1.71 for the 296Q allele carriers relative to 296LL genotype (95% CI 1.10-2.89; p<0.05), and 1.31 for the 442G allele carriers relative to 442DD genotype (95% CI 1.02-2.56; p<0.01), respectively. CONCLUSIONS: There is a significant relation between the polymorphisms in the CETP gene and the development of CHD, and individuals homozygous or heterozygous for the -644C, 296Q, and 442G alleles of the CETP gene are at increased risk to develop CHD in this Chinese population.

Asian People↗
PubMed2006

Lack of association of two chromosome 10q24 SNPs with Alzheimer's disease.

Several groups have reported evidence of linkage on chromosome 10 to late-onset Alzheimer's disease (LOAD). In a recent scan of single nucleotide polymorphisms (SNPs) on chromosome 10, significant associations between the rs498055 and rs4417206 SNPs and risk of LOAD were observed. We examined the association of these two SNPs with LOAD risk in a large Caucasian American cohort comprising about 2000 cases and controls. Neither SNP revealed significant association with LOAD risk or age-at-onset.

Alzheimer Disease↗
PubMed2006

Identification of single-nucleotide polymorphisms in 5' end and exons of the PRKAG3 gene in Hubbard White broiler, Leghorn layer, and three Chinese indigenous chicken breeds.

5'-AMP-activated protein kinase plays an important role in regulating the level of ATP in the presence of metabolic stress. Previous studies revealed that polymorphisms in 5'-AMP-activated protein kinase gamma 3 subunit (PRKAG3) gene are associated with meat quality in pigs. In the present study, single-nucleotide polymorphisms (SNPs) in the 5'-end and exons of chicken PRKAG3 gene were identified with the method of single-strand conformation polymorphism in Hubbard ISA White broiler, Leghorn layer, and three Chinese indigenous chicken breeds, Tibet Chicken, Shouguang Chicken and Beijing Yellow Chicken. Two SNPs in the 5'-end of the gene and 10 SNPs in exons 3, 4, 9 and 11, of which three caused amino acid substitutions, were identified in the PRKAG3 gene of the five chicken breeds. The results will facilitate further study on the association between the mutations of PRKAG3 and chicken meat quality.

5' Flanking Region↗
PubMed1999

High throughput fluorescent CE-SSCP SNP genotyping.

Large numbers of single nucleotide polymorphisms (SNPs) are being identified by several laboratories for the purpose of developing dense genetic maps. Single-strand conformation polymorphism (SSCP) analysis has been widely used as a method for detecting novel sequence variations in PCR products. Differences in migration of single-stranded DNA can be used not only to find mutations, but to genotype SNPs in large sample populations. Using PCR with fluorescent labeling and automated capillary electrophoresis SSCP (CE-SSCP), we have developed a panel of 15 functional candidate SNPs. With an automated single capillary instrument, relatively rapid and low cost CE-SSCP SNP genotyping using currently available technology is feasible for 135 000 genotypes per year. With parallel multiple array capillary electrophoresis, more genotypes per year may be attainable.

Automation↗
PubMed2002

Homozygosity for multiple contiguous single-nucleotide polymorphisms as an indicator of large heterozygous deletions: identification of a novel heterozygous 8-kb intragenic deletion (IVS7-19 to IVS15-17) in a patient with glycogen storage disease type II.

Current methods for detection of mutations by polymerase chain reaction (PCR) and sequence analysis frequently are not able to detect heterozygous large deletions. We report the successful use of a novel approach to identify such deletions, based on detection of apparent homozygosity of contiguous single-nucleotide polymorphisms (SNPs). The sequence analysis of genomic DNA PCR products containing all coding exons and flanking introns identified only a single heterozygous mutation (IVS18+2t-->a) in a patient with classic infantile-onset autosomal recessive glycogen storage disease type II (GSDII). Apparent homozygosity for multiple contiguous SNPs detected by this sequencing suggested presence of a large deletion as the second mutation; primers flanking the region of homozygous SNPs permitted identification and characterization by PCR of a large genomic deletion (8.26 kb) extending from IVS7 to IVS15. The data clearly demonstrate the utility of SNPs as markers for large deletions in autosomal recessive diseases when only a single mutation is found, thus complementing currently standard DNA PCR sequence methods for identifying the molecular basis of disease.

Amino Acid Sequence↗
PubMed2026

Adaptation to Plant Defence in an Agricultural Insect Pest: Integrating Genome Scans and Gene Expression in the Soybean Aphid Reveals Multi-Genic Pathways.

In agroecosystems, intense selection pressures cause species to adapt and spread, often leading to the evolution and persistence of pests. Understanding how pests rapidly adapt can help develop sustainable strategies for their management and improve agroecosystem health. Pest adaptation involves stable variations in DNA sequence, as well as dynamic shifts in gene expression, often mediated by non-coding regulatory elements. We examined adaptation to plant defences in the soybean aphid, Aphis glycines, in which virulent aphids have overcome plant defences and avirulent aphids have not. Previous data with laboratory colonies suggested that virulent aphids have higher overall gene expression, including transposable elements, some of which influence gene regulation. However, we lack information on how genetic variation in natural populations impacts adaptation and potentially gene regulation. We integrated population genome scans of field-collected, soybean aphid populations with gene expression profiles of virulent and avirulent laboratory colonies to uncover connections between genetic differentiation and gene regulation for virulence. Genome scan methods found 2144 single nucleotide polymorphisms (SNPs) with significant genetic differentiation (i.e., outliers) in field-collected populations. These SNPs were near 1004 genes, representing 5.16% of the effective number of genes. Based on previous RNA-Seq data with laboratory colonies, we found 3160 genes and 147 long non-coding RNAs (lncRNAs) with differential expression among virulent and avirulent biotypes. By integrating both data sets, we identified 16 genes and 5 long non-coding RNAs with differential expression and that were associated with an outlier SNP (within 10&#x2009;kbp). We validated SNPs with additional field collected aphids and found an aphid clone with stronger virulence than our laboratory virulent colony, surviving on 2 different aphid-resistant soybean varieties. This new virulent clone had fixed allele differences at 9 SNPs compared to our avirulent and other virulent colony. Field collected soybean aphids matching the phenotype of this new virulent clone had significant genetic differentiation with 3 outlier SNPs near genes related to zinc transport and lachesin compared to field collected avirulent aphids. Our entire data reinforced the importance of a potential multi-genetic response to overcome plant defence and generates new insights into complex genetic and regulatory mechanisms involved in insect-plant interactions.

Animals↗