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At least 145 records · Page 8Linked to original sources
PubMed2000

Multiplexed single nucleotide polymorphism genotyping by oligonucleotide ligation and flow cytometry.

BACKGROUND: We have developed a rapid, high throughput method for single nucleotide polymorphism (SNP) genotyping that employs an oligonucleotide ligation assay (OLA) and flow cytometric analysis of fluorescent microspheres. METHODS: A fluoresceinated oligonucleotide reporter sequence is added to a "capture" probe by OLA. Capture probes are designed to hybridize both to genomic "targets" amplified by polymerase chain reaction and to a separate complementary DNA sequence that has been coupled to a microsphere. These sequences on the capture probes are called "ZipCodes". The OLA-modified capture probes are hybridized to ZipCode complement-coupled microspheres. The use of microspheres with different ratios of red and orange fluorescence makes a multiplexed format possible where many SNPs may be analyzed in a single tube. Flow cytometric analysis of the microspheres simultaneously identifies both the microsphere type and the fluorescent green signal associated with the SNP genotype. RESULTS: Application of this methodology is demonstrated by the multiplexed genotyping of seven CEPH DNA samples for nine SNP markers located near the ApoE locus on chromosome 19. The microsphere-based SNP analysis agreed with genotyping by sequencing in all cases. CONCLUSIONS: Multiplexed SNP genotyping by OLA with flow cytometric analysis of fluorescent microspheres is an accurate and rapid method for the analysis of SNPs.

Chromosomes, Human, Pair 19↗
PubMed2004

A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism.

Autism is a complex genetic neuropsychiatric condition characterized by deficits in social interaction and language and patterns of repetitive or stereotyped behaviors and restricted interests. Chromosome 15q11.2-q13 is a candidate region for autism susceptibility based on observations of chromosomal duplications in a small percentage of affected individuals and findings of linkage and association. We performed linkage disequilibrium (LD) mapping across a 1-Mb interval containing a cluster of GABA(A) receptor subunit genes (GABRB3, GABRA5, and GABRG3) which are good positional and functional candidates. Intermarker LD was measured for 59 single nucleotide polymorphism (SNP) markers spanning this region, corresponding to an average marker spacing of 17.7 kb(-1). We identified haplotype blocks, and characterized these blocks for common (>5%) haplotypes present in the study population. At this marker resolution, haplotype blocks comprise <50% of the DNA in this region, consistent with a high local recombination rate. Identification of haplotype tag SNPs reduces the overall number of markers necessary to detect all common alleles by only 12%. Individual SNPs and multi-SNP haplotypes were examined for evidence of allelic association to autism, using a dataset of 123 multiplex autism families. Six markers individually, across GABRB3 and GABRA5, and several haplotypes inclusive of those markers, demonstrated nominally significant association. These results are positively correlated with the position of observed linkage. These studies support the existence of one or more autism risk alleles in the GABA(A) receptor subunit cluster on 15q12 and have implications for analysis of LD and association in regions with high local recombination.

Alleles↗
PubMed2003

Genetic diversity of Eurycoma longifolia inferred from single nucleotide polymorphisms.

Eurycoma longifolia Jack. is a treelet that grows in the forests of Southeast Asia and is widely used throughout the region because of its reported medicinal properties. Widespread harvesting of wild-grown trees has led to rapid thinning of natural populations, causing a potential decrease in genetic diversity among E. longifolia. Suitable genetic markers would be very useful for propagation and breeding programs to support conservation of this species, although no such markers currently exist. To meet this need, we have applied a genome complexity reduction strategy to identify a series of single nucleotide polymorphisms (SNPs) within the genomes of several E. longifolia accessions. We have found that the occurrence of these SNPs reflects the geographic origins of individual plants and can distinguish different natural populations. This work demonstrates the rapid development of molecular genetic markers in species for which little or no genomic sequence information is available. The SNP markers that we have developed in this study will also be useful for identifying genetic fingerprints that correlate with other properties of E. longifolia, such as high regenerability or the appearance of bioactive metabolites.

Conservation of Natural Resources↗
PubMed2004

Test of linkage and/or association between the estrogen receptor alpha gene with bone mineral density in Caucasian nuclear families.

Extensive studies have been performed on the association between the estrogen receptor alpha (ER-alpha) gene and bone mineral density (BMD). Despite considerable efforts, the studies using limited markers and relatively small sample size have yielded largely inconsistent results. In this study, 1873 Caucasian subjects from 405 nuclear families containing 1512 sib pairs were recruited. BMD at the lumbar spine (LS) and femoral neck (FN) was measured by dual-energy X-ray absorptiometry (DXA). Seven single-nucleotide polymorphisms (SNPs) spanning from exon 1 to 8 in the ER-alpha gene were genotyped. The program QTDT (quantitative transmission disequilibrium test) was applied to test linkage and/or association of the ER-alpha gene and BMD variation using individual SNP markers and reconstructed haplotypes. Linkage disequilibrium (LD) was generally detected for SNPs in the ER-a gene (P < 0.05). Associations were observed between SNP rs932477 and FN BMD (P = 0.028), and between the most predominant three-marker haplotype (GCG) containing SNP rs932477 and FN BMD (P = 0.010). Within-family association (present only with both linkage and association) between SNP rs2228480 (G2014A) and FN BMD (P = 0.015) was observed. The most predominant seven-SNP haplotype (TCGCGGG) was associated with higher LS BMD (P = 0.015). However, after correction for multiple testing, these associations did not reach statistical significance. Denser markers may be necessary to better define the relationship between the ER-alpha gene and BMD variation in our sample.

Absorptiometry, Photon↗
PubMed2005

A comparison in association and linkage genome-wide scans for alcoholism susceptibility genes using single-nucleotide polymorphisms.

We conducted genome-wide linkage scans using both microsatellite and single-nucleotide polymorphism (SNP) markers. Regions showing the strongest evidence of linkage to alcoholism susceptibility genes were identified. Haplotype analyses using a sliding-window approach for SNPs in these regions were performed. In addition, we performed a genome-wide association scan using SNP data. SNPs in these regions with evidence of association (P <or= 0.0001) were identified. We found that the general patterns for nonparametric linkage (NPL) scores from SNP and microsatellite genome scans are fairly consistent; however, the peaks of the NPL scores are mostly higher in the SNP-based scan than those using microsatellite markers, which might be located at different regions. Furthermore, SNPs identified from linkage screens were not so strongly associated with alcoholism (the most significant SNP had a p-value of 0.030) as those identified from association genomic screening (the most significant SNP had a p-value of 2.0 x 10(-8)).

Alcoholism↗
PubMed2006

Genetic and expression analyses of the STOP (MAP6) gene in schizophrenia.

Accumulating evidence suggests that the pathologic lesions of schizophrenia may in part be due to the altered cytoskeletal architecture of neurons. Microtubule-associated proteins (MAPs) that bind to cytoskeletal microtubules to stabilize their assembly are prominently expressed in neurons. Of the MAPs, MAP6 (STOP) has a particular relevance to schizophrenia pathology, since mice deficient in the gene display neuroleptic-responsive behavioral defects. Here we examined the genetic contribution of MAP6 to schizophrenia in a case (n = 570) -control (n = 570) study, using dense single nucleotide polymorphism (SNP) markers. We detected nominal allelic (p = 0.0291) and haplotypic (global p = 0.0343 for 2 SNP-window, global p = 0.0138 for 3 SNP-window) associations between the 3' genomic interval of the gene and schizophrenia. MAP6 transcripts are expressed as two isoforms. A postmortem brain expression study showed up-regulation of mRNA isoform 2 in the prefrontal cortex (Brodmann's area 46) of patients with schizophrenia. These data suggest that the contribution of MAP6 to the processes that lead to schizophrenia should be further investigated.

Adult↗
PubMed2000

Approaches to allele frequency determination.

Hundreds of thousands of candidate single nucleotide polymorphisms (SNPs) are being identified as part of the human genome project. For these markers to be useful in any study their allele frequencies in the study population must be known, or much effort will be wasted when markers with the wrong characteristics are selected for studies involving large-scale genotyping of SNP markers. Because allele frequency estimations by genotyping a representative sample of a population is a costly endeavour, an obvious strategy to reduce the cost is to identify accurate and efficient approaches to allele frequency estimation using DNA pools. There are several allele frequency estimation approaches currently in use, including PCR-RFLP analysis, DNA sequencing, the Taqman assay and kinetic PCR. All these approaches give reasonably good allele frequency estimates. Accurate and efficient allele frequency estimation in DNA pools will reduce the cost and effort needed in genetic and association studies and opens up ways to perform pharmacogenomic and evolutionary studies efficiently.

Alleles↗
PubMed2004

Comparative informativeness for linkage of multiple SNPs and single microsatellites.

Single nucleotide polymorphisms (SNPs), or biallelic markers, are popular in genetic linkage studies due to their abundance in the genome, stability, and ease of scoring. We determined the 'information ratio' (IR) of closely spaced SNPs in simulated nuclear families and affected sib pairs (ASPs). (The IR is the ratio of actual average maximum lod score to the maximum lod score attainable if the marker were fully informative.) The nuclear families included parental information, whereas the ASPs did not. We analyzed these SNPs in two ways: (1) using multipoint analysis, and (2) treating the SNPs as 'composite markers' (i.e., haplotypes, as assigned by GENEHUNTER). (3) We also calculated the IR of a single microsatellite marker with multiple alleles and compared with the IR from the SNPs. For each set of input conditions, we simulated 1000 nuclear families, of 2, 3, 4, or 5 children each, as well as 1000 ASPs. We generated SNP marker data for strings of k = 1, 2, 3, 5, 7, and 10 SNP loci, with no recombination (theta = 0) and no linkage disequilibrium among the SNPs. The MAF (minor allele frequency) was either 0.5 or 0.25, and allele frequencies were the same for all k loci in any analysis. We also generated marker data for one single-locus microsatellite marker, with m = 3, 4, 5, 6, 7, and 9 equally frequent alleles. In all simulations, the disease was fully penetrant dominant, and there was no recombination or linkage disequilibrium among markers or between marker and disease. When multipoint analysis was used, we found that 5-7 closely spaced SNPs were usually enough to yield an IR of approximately 100%, for nuclear families of any size. However, for the ASPs, even 7-10 SNPs yielded an IR of only 70-80%. A microsatellite with 9 equally frequent alleles yielded about the same IR (86-88%) as a string of 4-5 SNPs, in nuclear families. SNPs analyzed as 'composite markers' analyses performed worse, due to the inherent ambiguity of SNP haplotyping.

Alleles↗
PubMed2001

Comparison of novel and existing methods for detection of linkage disequilibrium using parent-child trios in the GAW12 genetic isolate simulated data.

A novel method for joint detection of association caused by linkage disequilibrium (LD) and estimation of both recombination fraction and linkage disequilibrium parameters was compared to several existing implementations of the transmission/disequilibrium test (TDT) and modifications of the TDT in the simulated genetic isolate data from Genetic Analysis Workshop 12. The first completely genotyped trio of affected child and parents was selected from each family in each replicate so that the TDT tests are valid tests of linkage and association, rather than being only valid as tests for linkage. In general, power to detect LD using the genome-wide scan markers was inadequate in the individual replicate samples, but the power was better when analyzing several SNP markers in candidate gene 1.

Adult↗
PubMed2004

MaGIC: a program to generate targeted marker sets for genome-wide association studies.

High-throughput genotyping technologies such as DNA pooling and DNA microarrays mean that whole-genome screens are now practical for complex disease gene discovery using association studies. Because it is currently impractical to use all available markers, a subset is typically selected on the basis of required saturation density. Restricting markers to those within annotated genomic features of interest (e.g., genes or exons) or within feature-rich regions, reduces workload and cost while retaining much information. We have designed a program (MaGIC) that exploits genome assembly data to create lists of markers correlated with other genomic features. Marker lists are generated at a user-defined spacing and can target features with a user-defined density. Maps are in base pairs or linkage disequilibrium units (LDUs) as derived from the International HapMap data, which is useful for association studies and fine-mapping. Markers may be selected on the basis of heterozygosity and source database, and single nucleotide polymorphism (SNP) markers may additionally be selected on the basis of validation status. The import function means the method can be used for any genomic features such as housekeeping genes, long interspersed elements (LINES), or Alu repeats in humans, and is also functional for other species with equivalent data. The program and source code is freely available at http://cogent.iop.kcl.ac.uk/MaGIC.cogx.

Algorithms↗
PubMed2006

Role of large sequence polymorphisms (LSPs) in generating genomic diversity among clinical isolates of Mycobacterium tuberculosis and the utility of LSPs in phylogenetic analysis.

Mycobacterium tuberculosis strains contain different genomic insertions or deletions called large sequence polymorphisms (LSPs). Distinguishing between LSPs that occur one time versus ones that occur repeatedly in a genomic region may provide insights into the biological roles of LSPs and identify useful phylogenetic markers. We analyzed 163 clinical M. tuberculosis isolates for 17 LSPs identified in a genomic comparison of M. tuberculosis strains H37Rv and CDC1551. LSPs were mapped onto a single-nucleotide polymorphism (SNP)-based phylogenetic tree created using nine novel SNP markers that were found to reproduce a 212-SNP-based phylogeny. Four LSPs (group A) mapped to a single SNP tree segment. Two LSPs (group B) and 11 LSPs (group C) were inferred to have arisen independently in the same genomic region either two or more than two times, respectively. None of the group A LSPs but one group B LSP and five group C LSPs were flanked by IS6110 sequences in the references strains. Genes encoding members of the proline-glutamic acid or proline-proline-glutamic acid protein families were present only in group B or C LSPs. SNP- versus LSP-based phylogenies were also compared. We classified each isolate into 58 LSP types by using a separate LSP-based phylogenetic analysis and mapped the LSP types onto the SNP tree. LSPs often assigned isolates to the correct phylogenetic lineage; however, significant mistakes occurred for 6/58 (10%) of the LSP types. In conclusion, most LSPs occur in genomic regions that are prone to repeated insertion/deletion events and were responsible for an unexpectedly high degree of genomic variation in clinical M. tuberculosis. Group B and C LSPs may represent polymorphisms that occur due to selective pressure and affect the phenotype of the organism, while group A LSPs are preferable phylogenetic markers.

Gene Deletion↗
PubMed2026

Development of a 10K breeder-friendly SNP chip for faba bean.

INTRODUCTION: Faba bean breeding and genomics have seen steady progress in recent years, supported by genome sequences and high-density genotyping platforms. These tools have been valuable for trait mapping, diversity assessment, and genomic research, but they have limited routine use in breeding programs due to their relatively high cost. Recent progress in establishing an optimized, cost-efficient genotyping-by-sequencing protocol tailored to the large and complex faba bean genome has created the foundation for a more accessible genotyping solution. METHODS: Using this approach, we explored the genetic diversity of faba bean germplasm from various panels, providing a comprehensive representation of the crop's genetic landscape. From this dataset, we identified and selected a high-quality set of informative SNP markers that are evenly distributed across the genome. Building on these resources, we designed a breeder-friendly 10K SNP chip. RESULTS: The 10K SNP chip delivers high accuracy, broad genomic coverage, and affordability. The chip was validated across diverse germplasm panels, demonstrating strong clustering performance, high reproducibility, and applicability to breeding-relevant germplasm. DISCUSSION: This platform offers a cost-effective alternative to higher-density arrays, enabling its integration into genomic selection, marker-assisted breeding, and diversity monitoring, ultimately supporting accelerated genetic gain and the delivery of improved varieties to farmers.

SNP chip↗
PubMed2005

Investigation of altering single-nucleotide polymorphism density on the power to detect trait loci and frequency of false positive in nonparametric linkage analyses of qualitative traits.

Genome-wide linkage analysis using microsatellite markers has been successful in the identification of numerous Mendelian and complex disease loci. The recent availability of high-density single-nucleotide polymorphism (SNP) maps provides a potentially more powerful option. Using the simulated and Collaborative Study on the Genetics of Alcoholism (COGA) datasets from the Genetics Analysis Workshop 14 (GAW14), we examined how altering the density of SNP marker sets impacted the overall information content, the power to detect trait loci, and the number of false positive results. For the simulated data we used SNP maps with density of 0.3 cM, 1 cM, 2 cM, and 3 cM. For the COGA data we combined the marker sets from Illumina and Affymetrix to create a map with average density of 0.25 cM and then, using a sub-sample of these markers, created maps with density of 0.3 cM, 0.6 cM, 1 cM, 2 cM, and 3 cM. For each marker set, multipoint linkage analysis using MERLIN was performed for both dominant and recessive traits derived from marker loci. Our results showed that information content increased with increased map density. For the homogeneous, completely penetrant traits we created, there was only a modest difference in ability to detect trait loci. Additionally, as map density increased there was only a slight increase in the number of false positive results when there was linkage disequilibrium (LD) between markers. The presence of LD between markers may have led to an increased number of false positive regions but no clear relationship between regions of high LD and locations of false positive linkage signals was observed.

Alcoholism↗
PubMed2005

ARTS: a web-based tool for the set-up of high-throughput genome-wide mapping panels for the SNP genotyping of mouse mutants.

Genome-wide mapping in the identification of novel candidate genes has always been the standard method in genetics and genomics to correlate a clinically interesting phenotypic trait with a genotype. However, the performance of a mapping experiment using classical microsatellite approaches can be very time consuming. The high-throughput analysis of single-nucleotide polymorphisms (SNPs) has the potential of being the successor of microsatellite analysis routinely used for these mapping approaches, where one of the major obstacles is the design of the appropriate SNP marker set itself. Here we report on ARTS, an advanced retrieval tool for SNPs, which allows researchers to comb freely the public mouse dbSNP database for multiple reference and test strains. Several filters can be applied in order to improve the sensitivity and the specificity of the search results. By employing the panel generator function of this program, it is possible to abbreviate the extraction of reliable sequence data for a large marker panel including several different mouse strains from days to minutes. The concept of ARTS is easily adaptable to other species for which SNP databases are available, making it a versatile tool for the use of SNPs as markers for genotyping. The web interface is accessible at http://andromeda.gsf.de/arts.

Animals↗
PubMed2005

Comparison of the power between microsatellite and single-nucleotide polymorphism markers for linkage and linkage disequilibrium mapping of an electrophysiological phenotype.

We performed linkage and linkage disequilibrium (LD) mapping analyses to compare the power between microsatellite and single nucleotide polymorphism (SNP) markers. Chromosome-wide analyses were performed for a quantitative electrophysiological phenotype, ttth1, on chromosome 7. Multipoint analysis of microsatellite markers using the variance component (VC) method showed the highest LOD score of 4.20 at 162 cM, near D7S509 (163.7 cM). Two-point analysis of SNPs using the VC method yielded the highest LOD score of 3.98 in the Illumina SNP data and 3.45 in the Affymetrix SNP data around 152-153 cM. In family-based single SNP and SNP haplotype LD analysis, we identified seven SNPs associated with ttth1. We searched for any potential candidate genes in the location of the seven SNPs. The SNPs rs1476640 and rs768055 are located in the FLJ40852 gene (a hypothetical protein), and SNP rs1859646 is located in the TAS2R5 gene (a taste receptor). The other four SNPs are not located in any known or annotated genes. We found the high density SNP scan to be superior to microsatellites because it is effective in downstream fine mapping due to a better defined linkage region. Our study proves the utility of high density SNP in genome-wide mapping studies.

Aging↗
PubMed2005

Association of the NuMA region on chromosome 11q13 with breast cancer susceptibility.

The development of breast cancer is a complex process that involves multiple genes at many stages, from initial cell cycle dysregulation to disease progression. To identify genetic variations that influence this process, we conducted a large-scale association study using a collection of German cases and controls and >25,000 SNPs located within 16,000 genes. One of the loci identified was located on chromosome 11q13 [odds ratio (OR)=1.85, P=0.017]. The initial association was subsequently tested in two independent breast cancer collections. In both sample sets, the frequency of the susceptibility allele was increased in the cases (OR=1.6, P=0.01). The susceptibility allele was also associated with an increase in cancer family history (P=0.1). Fine mapping showed that the region of association extends approximately 300 kb and spans several genes, including the gene encoding the nuclear mitotic apparatus protein (NuMA). A nonsynonymous SNP (A794G) in NuMA was identified that showed a stronger association with breast cancer risk than the initial marker SNP (OR=2.8, P=0.005 initial sample; OR=2.1, P=0.002 combined). NuMA is a cell cycle-related protein essential for normal mitosis that is degraded in early apoptosis. NuMA-retinoic acid receptor alpha fusion proteins have been described in acute promyelocytic leukemia. Although the potential functional relevance of the A794G variation requires further biological validation, we conclude that variations in the NuMA gene are likely responsible for the observed increased breast cancer risk.

Adult↗
PubMed2001

Estimation of DNA sequence diversity in bovine cytokine genes.

DNA sequence variation provides the fundamental material for improving livestock through selection. In cattle, single nucleotide polymorphisms and small insertions/deletions (collectively referred to here as SNPs) have been identified in cytokine genes and scored in a reference population to determine linkage map positions. The aim of the present study was twofold: first, to estimate the SNP frequency in a reference population of beef cattle, and second, to determine cytokine haplotypes in a group of sires from commercial populations. Forty-five SNP markers in DNA segments from nine cytokine gene loci were analyzed in 26 reference parents. Comparison of all 52 haploid genomes at each PCR amplicon locus revealed an average of one SNP per 143 bp of sequence, whereas comparison of any two chromosomes identified heterozygous sites, on average, every 443 bp. The combination of these 45 SNP genotypes was sufficient to uniquely identify each of the 26 animals. The average number of haplotype alleles (4.4) per PCR amplicon (688 bp) and the percentage heterozygosity among founding parents (50%) were similar to those for microsatellite markers in the same population. For 49 sires from seven common breeds of beef cattle, SNP genotypes (1,225 total) were obtained by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) at three amplicon loci. All three of the amplicon haplotypes were correctly deduced for each sire without the use of parent or progeny genotypes. The latter allows a wide range of genetic studies in commercial populations of cattle where genotypic information from relatives may not be available.

Alleles↗
PubMed2001

Use of an artificial neural network to detect association between a disease and multiple marker genotypes.

Single nucleotide polymorphisms (SNPs) are very common throughout the genome and hence are potentially valuable for mapping disease susceptibility loci by detecting association between SNP markers and disease. However as SNPs are biallelic they may have relatively little power in association studies compared with the information that would be obtainable if marker haplotypes were available and could be used efficiently. Modelling the evolutionary events leading to linkage disequilibrium is very complex and many methods that seek to use information from multiple markers simultaneously need to make simplifying assumptions and may only be applicable when marker haplotypes, rather than genotypes, are available for analysis. We explore the properties of a simple application of a standard artificial neural network to this problem. The pattern-recognition properties of the network are used in the hope that marker haplotypes implicit in the genotypes will differ between cases and controls in a way which will lead to the network being able to classify the subjects correctly, according to their marker genotype. This method makes no assumptions at all regarding population history or the marker map, and can be applied to genotypes, as would be available from a simple case-control sample, without any need to determine haplotypes. Through application to data simulated under a very wide range of assumptions we show that such an analysis produces a useful augmentation in power above that which would be achieved by testing each marker individually, in particular when more than one mutation has occurred in a disease gene at different points in evolution. The application of neural networks to such problems shows considerable promise and further work could usefully be directed towards optimising the design and implementation of such networks.

Alleles↗