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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

Assessment and implications of linkage disequilibrium in genome-wide single-nucleotide polymorphism and microsatellite panels.

Linkage disequilibrium (LD) between markers is more likely to exist in dense genome-wide single-nucleotide polymorphism (SNP) panels than in microsatellite panels. As part of Genetic Analysis Workshop 14 (GAW14), the extent of LD in the Illumina linkage panel III and the Affymetrix Genechip 10 K mapping array was assessed, using data from the Collaborative Study on the Genetics of Alcoholism (COGA). The impact of LD on linkage results was examined in COGA and simulated data, and characteristics of SNPs were assessed for their ability to detect population substructure and predict haplotypes. The authors of the papers summarized here observed greater LD in the Affymetrix than in the Illumina panel, possibly due to increased marker density in the Affymetrix panel, and found greater LD on chromosome X than on the autosomes. Simulation analyses suggest that intermarker LD can cause an upward bias in linkage statistics; however, the impact of LD on linkage analysis depends on the proportion of ungenotyped founders and the extent of LD. No large effect of LD on linkage peaks was observed in COGA analyses. In addition, the papers summarized here found that SNPs with high minor allele frequencies were the most informative compared with microsatellites for the detection of population substructure, and that SNPs in higher LD, and small numbers of SNPs, were the most reliable for haplotype prediction. As ease of genotyping continues to increase, study design and SNP selection for linkage and association studies (including genome-wide association studies) will be improved with consideration of LD in the particular populations studied.

Alcoholism↗
PubMed2005

Simultaneous detection of microsatellite repeats and SNPs in the macrophage migration inhibitory factor (MIF) gene by thin-film biosensor chips and application to rural field studies.

Microsatellite repeat and single nucleotide polymorphisms (SNPs) are abundant sources of genetic variation, but existing methodologies cannot simultaneously detect these variants in a facile or inexpensive way. We describe herein a thin-film biosensor chip based on an allele-discriminating oligonucleotide array that enables genotyping for both microsatellite repeats and SNPs in a single analysis. We validated this methodology for the functionally polymorphic -794 CATT(5-8) repeat and -173 G/C SNP present in the promoter of the human gene for macrophage migration inhibitory factor (MIF). In a comparison of 30 samples collected at a rural hospital in Zambia, we observed a 100% concordance for both the CATT repeat and G/C SNP between the biosensor methodology and the conventional capillary electrophoresis. The biosensor chips are low in cost and once printed, they are robust and require no instrumentation for analysis. When combined with multiple displacement amplification, this methodology can be utilized in primitive settings for the genotyping of nanogram quantities of DNA present in blood, dried and stored on filter paper samples. We applied this methodology to a field study of MIF genotype in children with malaria, and provide first evidence for a potential association between MIF alleles and malaria infection. We also present data supporting significant population stratification of the low- versus high-expression forms of MIF that may bear on the role of this gene in infectious diseases.

Biosensing Techniques↗
PubMed2004

High throughput SNP genotyping with two mini-sequencing assays.

Two mini-sequencing methods, FP-TDI (template-directed dye-terminator incorporation with fluorescence-polarization) and MassArray (matrix assisted laser desorption ionization time of flight detection mass spectrometry), were optimized. A numeric standard was introduced to evaluate the SNP scoring quality of FP-TDI assay, thus made the optimization work easier. At the same time, using multi-PCR technology, 8-plex genotyping of MassArray assay was successfully carried out, some softwares were developed and the data process of MassArray was highly automated. Then these two methods were applied to high throughput SNP genotyping, the accuracy, efficiency and robustness were compared. The result shows FP-TDI is more sensitive to the concentration of SNPprimer and PCR product, as well as extension cycles, the SNPprimer length of FP-TDI should be 24 to 30 bp long, whereas MassArray assay prefers to be as short as only 16 bp. Altogether 6440 SNP sites of human chromosome 3 were genotyped in a sample of 90 individuals, 4792 sites by FP-TDI assay and 1648 sites by MassArray assay, the success rates of FP-TDI and MassArray were 67.7% and 93.6% respectively. The throughput of MassArray was higher than FP-TDI, and the cost of MassArray was lower, MassArray was more suitable for high throughput SNP genotyping.

DNA↗
PubMed2002

Analysis of clinically relevant single-nucleotide polymorphisms by use of microelectronic array technology.

BACKGROUND: Microelectronic DNA chip devices represent an emerging technology for genotyping. We developed methods for detection of single-nucleotide polymorphisms (SNPs) in clinically relevant genes. METHODS: Primer pairs, with one containing a 5'-biotin group, were used to PCR-amplify the region encompassing the SNP to be interrogated. After denaturation, the biotinylated strand was electronically targeted to discrete sites on streptavidin-coated gel pads surfaces by use of a Nanogen Molecular Workstation. Allele-specific dye-labeled oligonucleotide reporters were used for detection of wild-type and variant sequences. Methods were developed for SNPs in genes, including factor VII, beta-globin, and the RET protooncogene. We genotyped 331 samples for five DNA variations in the factor VII gene, >600 samples from patients with beta-thalassemia, and 15 samples for mutations within the RET protooncogene. All samples were previously typed by various methods, including DNA sequence analysis, allele-specific PCR, and/or restriction enzyme digestion of PCR products. RESULTS: Analysis of amplified DNA required 4-6 h. After mismatched DNA was removed, signal-to-noise ratios were >5. More than 940 samples were typed with the microelectronic array platform, and results were totally concordant with results obtained previously by other genotyping methods. CONCLUSIONS: The described protocols detect SNPs of clinical interest with results comparable to those of other genotyping methods.

Factor VII↗
PubMed2001

Cambridge Healthtech Institute's Third Annual Conference on Lab-on-a-Chip and Microarrays. 22-24 January 2001, Zurich, Switzerland.

Cambridge Healthtech Institute's Third Annual Conference on Lab-on-a-Chip and Microarray technology covered the latest advances in this technology and applications in life sciences. Highlights of the meetings are reported briefly with emphasis on applications in genomics, drug discovery and molecular diagnostics. There was an emphasis on microfluidics because of the wide applications in laboratory and drug discovery. The lab-on-a-chip provides the facilities of a complete laboratory in a hand-held miniature device. Several microarray systems have been used for hybridisation and detection techniques. Oligonucleotide scanning arrays provide a versatile tool for the analysis of nucleic acid interactions and provide a platform for improving the array-based methods for investigation of antisense therapeutics. A method for analysing combinatorial DNA arrays using oligonucleotide-modified gold nanoparticle probes and a conventional scanner has considerable potential in molecular diagnostics. Various applications of microarray technology for high-throughput screening in drug discovery and single nucleotide polymorphisms (SNP) analysis were discussed. Protein chips have important applications in proteomics. With the considerable amount of data generated by the different technologies using microarrays, it is obvious that the reading of the information and its interpretation and management through the use of bioinformatics is essential. Various techniques for data analysis were presented. Biochip and microarray technology has an essential role to play in the evolving trends in healthcare, which integrate diagnosis with prevention/treatment and emphasise personalised medicines.

Computational Biology↗
PubMed2006

Analysis of LDLR mutations in familial hypercholesterolemia patients in Greece by use of the NanoChip microelectronic array technology.

BACKGROUND: Three mutations in the low density lipoprotein receptor (LDLR) gene account for 49% of familial hypercholesterolemia (FH) cases in Greece. METHODS: We used the microelectronic array technology of the NanoChip Molecular Biology Workstation to develop a multiplex method to analyze these single-nucleotide polymorphisms (SNPs). Primer pairs amplified the region encompassing each SNP. The biotinylated PCR amplicon was electronically addressed to streptavidin-coated microarray sites. Allele-specific fluorescently labeled oligonucleotide reporters were designed and used for detection of wild-type and SNP sequences. Genotypes were compared to PCR-restriction fragment length polymorphism (PCR-RFLP). RESULTS: We developed three monoplex assays (1 SNP/site) and an optimized multiplex assay (3SNPs/site). We performed 92 Greece II, 100 Genoa, and 98 Afrikaner-2 NanoChip monoplex assays (addressed to duplicate sites and analyzed separately). Of the 580 monoplex genotypings (290 samples), 579 agreed with RFLP. Duplicate sites of one sample were not in agreement with each other. Of the 580 multiplex genotypings, 576 agreed with the monoplex results. Duplicate sites of three samples were not in agreement with each other, indicating requirement for repetition upon which discrepancies were resolved. CONCLUSIONS: The multiplex assay detects common LDLR mutations in Greek FH patients and can be extended to accommodate additional mutations.

Genetic Testing↗
PubMed2004

Towards optimally multiplexed applications of universal arrays.

We study a design and optimization problem that occurs, for example, when single nucleotide polymorphisms (SNPs) are to be genotyped using a universal DNA tag array. The problem of optimizing the universal array to avoid disruptive cross-hybridization between universal components of the system was addressed in previous work. Cross-hybridization can, however, also occur assay specifically, due to unwanted complementarity involving assay-specific components. Here we examine the problem of identifying the most economic experimental configuration of the assay-specific components that avoids cross-hybridization. Our formalization translates this problem into the problem of covering the vertices of one side of a bipartite graph by a minimum number of balanced subgraphs of maximum degree 1. We show that the general problem is NP-complete. However, in the real biological setting, the vertices that need to be covered have degrees bounded by d. We exploit this restriction and develop an O(d)-approximation algorithm for the problem. We also give an O(d)-approximation for a variant of the problem in which the covering subgraphs are required to be vertex disjoint. In addition, we propose a stochastic model for the input data and use it to prove a lower bound on the cover size. We complement our theoretical analysis by implementing two heuristic approaches and testing their performance on synthetic data as well as on simulated SNP data.

Algorithms↗
PubMed2004

Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays.

We present a genotyping method for simultaneously scoring 116,204 SNPs using oligonucleotide arrays. At call rates >99%, reproducibility is >99.97% and accuracy, as measured by inheritance in trios and concordance with the HapMap Project, is >99.7%. Average intermarker distance is 23.6 kb, and 92% of the genome is within 100 kb of a SNP marker. Average heterozygosity is 0.30, with 105,511 SNPs having minor allele frequencies >5%.

Algorithms↗
PubMed2004

High-resolution analysis of DNA copy number using oligonucleotide microarrays.

Genomic copy number alterations are a feature of many human diseases including cancer. We have evaluated the effectiveness of an oligonucleotide array, originally designed to detect single-nucleotide polymorphisms, to assess DNA copy number. We first showed that fluorescent signal from the oligonucleotide array varies in proportion to both decreases and increases in copy number. Subsequently we applied the system to a series of 20 cancer cell lines. All of the putative homozygous deletions (10) and high-level amplifications (12; putative copy number >4) tested were confirmed by PCR (either qPCR or normal PCR) analysis. Low-level copy number changes for two of the lines under analysis were compared with BAC array CGH; 77% (n = 44) of the autosomal chromosomes used in the comparison showed consistent patterns of LOH (loss of heterozygosity) and low-level amplification. Of the remaining 10 comparisons that were discordant, eight were caused by low SNP densities and failed in both lines. The studies demonstrate that combining the genotype and copy number analyses gives greater insight into the underlying genetic alterations in cancer cells with identification of complex events including loss and reduplication of loci.

Cell Line↗
PubMed2005

Competitive enzymatic reaction to control allele-specific extensions.

Here, we present a novel method for SNP genotyping based on protease-mediated allele-specific primer extension (PrASE), where the two allele-specific extension primers only differ in their 3'-positions. As reported previously [Ahmadian,A., Gharizadeh,B., O'Meara,D., Odeberg,J. and Lundeberg,J. (2001), Nucleic Acids Res., 29, e121], the kinetics of perfectly matched primer extension is faster than mismatched primer extension. In this study, we have utilized this difference in kinetics by adding protease, a protein-degrading enzyme, to discriminate between the extension reactions. The competition between the polymerase activity and the enzymatic degradation yields extension of the perfectly matched primer, while the slower extension of mismatched primer is eliminated. To allow multiplex and simultaneous detection of the investigated single nucleotide polymorphisms (SNPs), each extension primer was given a unique signature tag sequence on its 5' end, complementary to a tag on a generic array. A multiplex nested PCR with 13 SNPs was performed in a total of 36 individuals and their alleles were scored. To demonstrate the improvements in scoring SNPs by PrASE, we also genotyped the individuals without inclusion of protease in the extension. We conclude that the developed assay is highly allele-specific, with excellent multiplex SNP capabilities.

Alleles↗
PubMed2005

Analysis of SNP profiles in patients with major depressive disorder.

The present study focused on 91 single-nucleotide polymorphisms (SNPs) in 21 candidate genes to find associations with major depressive disorder (MDD). In total, 160 healthy controls and 177 patients with MDD were studied. We applied arrayed primer extension (APEX) based genotyping technology followed by association and haplotype analysis. SNPs in CCKAR, DRD1, DRD2, and HTR2C genes showed nominally significant associations with MDD. None of these associations remained significant after adjustment for multiple testing. Haplotype analysis revealed CCKAR haplotypes to be associated with MDD (global p=0.004). More precisely, we found the GAGT haplotype to be associated with increased risk for MDD (OR 7.42, 95% CI 2.13-25.85, p=0.002). This haplotype effect remained significant after Bonferroni correction (p=0.04 after Bonferroni's adjustment). Altogether we were able to find some nominal associations, but due to small sample size these results should be taken as exploratory. However, the effect of GAGT haplotype on the CCKAR gene may be considered as increasing the risk for MDD.

Adolescent↗
PubMed2005

2SNP: scalable phasing based on 2-SNP haplotypes.

2SNP software package implements a new very fast scalable algorithm for haplotype inference based on genotype statistics collected only for pairs of SNPs. This software can be used for comparatively accurate phasing of large number of long genome sequences, e.g. obtained from DNA arrays. As an input 2SNP takes genotype matrix and outputs the corresponding haplotype matrix. On datasets across 79 regions from HapMap 2SNP is several orders of magnitude faster than GERBIL and PHASE while matching them in quality measured by the number of correctly phased genotypes, single-site and switching errors. For example, 2SNP requires 41 s on Pentium 4 2 Ghz processor to phase 30 genotypes with 1381 SNPs (ENm010.7p15:2 data from HapMap) versus GERBIL and PHASE requiring more than a week and admitting no less errors than 2SNP.

Algorithms↗
PubMed2003

Quantitative evaluation by minisequencing and microarrays reveals accurate multiplexed SNP genotyping of whole genome amplified DNA.

Whole genome amplification (WGA) procedures such as primer extension preamplification (PEP) or multiple displacement amplification (MDA) have the potential to provide an unlimited source of DNA for large-scale genetic studies. We have performed a quantitative evaluation of PEP and MDA for genotyping single nucleotide polymorphisms (SNPs) using multiplex, four-color fluorescent minisequencing in a microarray format. Forty-five SNPs were genotyped and the WGA methods were evaluated with respect to genotyping success, signal-to-noise ratios, power of genotype discrimination, yield and imbalanced amplification of alleles in the MDA product. Both PEP and MDA products provided genotyping results with a high concordance to genomic DNA. For PEP products the power of genotype discrimination was lower than for MDA due to a 2-fold lower signal-to-noise ratio. MDA products were indistinguishable from genomic DNA in all aspects studied. To obtain faithful representation of the SNP alleles at least 0.3 ng DNA should be used per MDA reaction. We conclude that the use of WGA, and MDA in particular, is a highly promising procedure for producing DNA in sufficient amounts even for genome wide SNP mapping studies.

Alleles↗
PubMed2000

Flow cytometry-based minisequencing: a new platform for high-throughput single-nucleotide polymorphism scoring.

Single-nucleotide polymorphisms (SNPs) are the most abundant type of human genetic variation. These variable sites are present at high density in the genome, making them powerful tools for mapping and diagnosing disease-related alleles. We have developed a sensitive and rapid flow cytometry-based assay for the multiplexed analysis of SNPs based on polymerase-mediated primer extension, or minisequencing, using microspheres as solid supports. The new method involves subnanomolar concentrations of sample in small volumes ( approximately 10 microl) which can be analyzed at rates of one sample per minute or faster, without a wash step. Further, genomic analysis using multiplexing microsphere arrays (GAMMArrays), enables the simultaneous analysis of dozens, and potentially hundreds of SNPs per sample. We have tested the new method by genotyping the Glu69 variant from the HLA DPB1 locus, a SNP associated with chronic beryllium disease, as well as HLA DPA1 alleles using the multiplexed method. The results demonstrate the sensitivity and accuracy of flow cytometry-based minisequencing, a powerful new tool for genome- and global-scale SNP analysis.

Base Sequence↗
PubMed2006

Historical development of analysing large-scale changes in the human genome.

A widely held belief today is that genomics really only started with the DNA sequence information emanating from the genome programs for various organisms, with the human genome playing the leading role. In fact there is a discernable trail stretching for more than a 100 years from the observations of Boveri on tissue instability involving polyploidy in sea urchin embryos and human tumours to the present day. This historical review follows that trail and shows that many theoretical and technical advantages taken for granted in today's genomics era rely heavily on earlier cytogenetic and gene mapping discoveries. Three specific examples of technical developmental paths involving in situ hybridisation, flow-sorting and DNA reassociation kinetics will be explored. In the mid-1980s the two former approaches merged to give rise to several applications of which chromosome painting and chromosome CGH are arguably the most important. The latter developed into array CGH which has now become the pre-eminent method for detecting micro-imbalances in a large number of targets. A competing emerging technology is that of genome-wide SNP typing, which itself is a product of the much earlier RFLP approach linked to DNA sequence information. Do such approaches spell the final demise of the microscope? Perhaps for narrowly defined activities this may occur, but for addressing general questions, microscopic examination will remain pre-eminent.

Genetic Techniques↗
PubMed2004

Genomics and microarray for detection and diagnostics.

Genomics provided biomedical scientists an inventory of all genes and sequences present in a living being. This provides an unique opportunity to the scientists to predict and study biological functions of these genes. The changes in the gene expression regulated by genomic sequences therefore reflect changes in the molecular processes working in a cell or tissue in response to external factors including exposure to toxic compounds and pathogens. Microarray offers a biotechnological revolution with the help of DNA chemistry, silicon chip technology and optics to be used to monitor gene expression for thousands of genes in one single experiment. Briefly, 20,000 to 100,000 unique DNA molecules get applied by a robot to the surface of silicon wafers (approximately the size of a microscope slide). Using a single microarray experiment, the expression level of 20,000 to 100,000 genes will be examined in one single experiment. Genomics and microarray have a significant role and impact on the design and development of modern detection and diagnostic tools in several different ways. Microarray tools are now used on regular basis for monitoring gene expression of large number of genes and also frequently applied to DNA sequence analysis, immunology, genotyping, and molecular diagnosing. For diagnostics, these tools can be used to distinguish and differentiate between different DNA fragments that differ by as little as a single nucleotide polymorphism (SNP). These microarrays can be divided based on the gene density spots that will be high density (>10,000 spots) per slide, medium (< 1000 > 100) and low density (< 100). High-density arrays have proven to be very useful in disease diagnosis especially in diagnosis and classification of different types of cancers. These microarray tools hold tremendous potential for pathogen detection, which will be comprised, of unique sets of genes (also referred to as "signatures") able to unambiguously identify the species and strain of pathogens of interest.

Drug Design↗
PubMed2000

Future molecular approaches to the diagnosis and treatment of glomerular disease.

Current diagnoses and treatment decisions for renal disease are made based upon a combination of clinical and pathological determinations. With the advances in both biochemical and molecular biological techniques, identifying the underlying biochemical and genetic changes that may have initiated and/or contributed to the disease is possible. We describe here technologies that may lead to significant changes in renal disease diagnosis, characterization, treatment, and potentially prevention. For example, differential display techniques and DNA gene chip arrays show the changes in mRNA expression patterns and can potentially identify previously unknown genes and reveal new roles for previously known genes in renal disease. The generation of the single nucleotide polymorphisms (SNP) genomic map will facilitate genetic screening that may identify a gene or combination of genes that produce enhanced disease susceptibility. Combining genomic analysis with epidemiological studies may identify environmental factors that contribute to renal disease onset in genetically susceptible individuals. A number of novel therapies are already on the horizon. These include reagents that abrogate the function of specific cytokines, chemokines, and effector cells. With the list of renal disease genes in hand, their role in renal physiology and pathophysiology can be determined, which should lead to the discovery of pharmacological intervention directed at those genes and their products that play a role in the pathogenesis of renal disease.

Biotechnology↗