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At least 109 records · Page 6Linked to original sources
PubMed2005

Polymorphisms in cinnamoyl CoA reductase (CCR) are associated with variation in microfibril angle in Eucalyptus spp.

Linkage disequilibrium (LD) mapping using natural populations results in higher resolution of marker-trait associations compared to family-based quantitative trait locus (QTL) studies. Depending on the extent of LD, it is possible to identify alleles within candidate genes associated with a trait. Analysis of a natural mutant in Arabidopsis has shown that mutations in cinnamoyl CoA reductase (CCR), a key lignin gene, affect physical properties of the secondary cell wall such as stiffness and strength. Using this gene, we tested whether LD mapping could identify alleles associated with microfibril angle (MFA), a wood quality trait affecting stiffness and strength of wood. We identified 25 common single-nucleotide polymorphism (SNP) markers in the CCR gene in Eucalyptus nitens. Using single-marker and haplotype analyses in 290 trees from a E. nitens natural population, two haplotypes significantly associated with MFA were found. These results were confirmed in two full-sib families of E. nitens and Eucalyptus globulus. In an effort to understand the functional significance of the SNP markers, we sequenced the cDNA clones and identified an alternatively spliced variant from the significant haplotype region. This study demonstrates that LD mapping can be used to identify alleles associated with wood quality traits in natural populations of trees.

Aldehyde Oxidoreductases↗
PubMed2006

Investigation of genetic association between human Frizzled homolog 3 gene (FZD3) and schizophrenia: results in a Korean population and evidence from meta-analysis.

The neurodevelopmental hypothesis offers a promising approach through which to explore the pathogenesis of schizophrenia. Human Frizzled-3 protein is one of the major components of the Wnt signaling pathway and plays a crucial role in regulating early neurodevelopmental processes. Therefore, the human Frizzled homolog 3 (FZD3) gene, which encodes this protein, may be an excellent candidate gene for association studies of schizophrenia. To replicate the previously reported positive association between FZD3 and schizophrenia in Han Chinese and Japanese populations, we genotyped two single nucleotide polymorphism (SNP) markers of FZD3 in 241 unrelated schizophrenic patients and 192 control subjects. Fisher's exact test was used to compare the genotypic and allelic frequencies in the two groups. In addition, to integrate and evaluate the accumulated evidence published to date, we performed a meta-analysis on the published data, including our own. No evidence was found to support the association between either of the investigated SNP markers and schizophrenia in a Korean population. Moreover, the meta-analytic result did not support the association between several commonly investigated markers in FZD3 and schizophrenia. Failure to replicate previous positive association results could reflect various theoretical factors. Therefore, other sources of error have to be ruled out before coming to a conclusion. In the case of FZD3, it seems that repeated failures to replicate the original results by several independent research groups combine to provide evidence against an association between FZD3 and schizophrenia. Other candidate genes involved in early neurodevelopmental processes may deserve further investigation.

Alleles↗
PubMed1998

Overlapping genomic sequences: a treasure trove of single-nucleotide polymorphisms.

An efficient strategy to develop a dense set of single-nucleotide polymorphism (SNP) markers is to take advantage of the human genome sequencing effort currently under way. Our approach is based on the fact that bacterial artificial chromosomes (BACs) and P1-based artificial chromosomes (PACs) used in long-range sequencing projects come from diploid libraries. If the overlapping clones sequenced are from different lineages, one is comparing the sequences from 2 homologous chromosomes in the overlapping region. We have analyzed in detail every SNP identified while sequencing three sets of overlapping clones found on chromosome 5p15.2, 7q21-7q22, and 13q12-13q13. In the 200.6 kb of DNA sequence analyzed in these overlaps, 153 SNPs were identified. Computer analysis for repetitive elements and suitability for STS development yielded 44 STSs containing 68 SNPs for further study. All 68 SNPs were confirmed to be present in at least one of the three (Caucasian, African-American, Hispanic) populations studied. Furthermore, 42 of the SNPs tested (62%) were informative in at least one population, 32 (47%) were informative in two or more populations, and 23 (34%) were informative in all three populations. These results clearly indicate that developing SNP markers from overlapping genomic sequence is highly efficient and cost effective, requiring only the two simple steps of developing STSs around the known SNPs and characterizing them in the appropriate populations.

Bacteriophage P1↗
PubMed2005

Whole-genome amplification: relative efficiencies of the current methods.

Whole genome amplification (WGA) has emerged as a fundamental method for DNA analysis from limited quantities of genomic DNA in forensic analysis and disease gene discovery. Several strategies for WGA have been developed during the past decade, each with variable fidelity, yield and coverage of the amplified genome. In the search for a reliable and robust WGA method for genotyping short tandem repeat (STR) loci and single nucleotide polymorphic (SNP) markers, we initially tested four common methods, viz., degenerate oligonucleotide primed PCR (DOP), primer extension preamplification (PEP), improved-PEP (I-PEP) and multiple displacement amplification (MDA), typing the 13 CODIS tetranucleotide repeat loci. The results showed among all methods, I-PEP and MDA have higher genomic coverage. DOP and PEP produced locus and allelic dropouts. Therefore, we emphasized on the evaluation of I-PEP and MDA protocols, which shows that the two methods have their relative strengths and weaknesses. In general, the product yield of MDA is higher than that of I-PEP. However, the specificity of the I-PEP products appears to be higher, particularly in the analysis of STR loci. In the analysis of SNP markers, some loci amplify better using products obtained from I-PEP whereas some worked better with MDA. Our analyses also demonstrate that blood spots on FTA cards are a more efficient source of DNA for I-PEP as compared to MDA, especially for STR analysis.

Allelic Imbalance↗
PubMed2006

Measuring marker information content by the ambiguity of block boundaries observed in dense SNP data.

Recent studies have noted that the boundary of common haplotype blocks in hapmap constructions involve a certain degree of ambiguity, and so do the resulting "tagSNPs". Here, we report how to address this issue at the level of individual SNP markers. We introduce a measure called the marker ambiguity score (MAS), and evaluate its utility by simulation studies based on a real dataset of 2949 SNPs spanning a region of 56.1M bp. We show that the MAS method can be used to assess the level of boundary ambiguity caused by varying ethnic background, sample sizes for hapmap construction, and disease aggregation. We find a striking difference in overall patterns of block boundary distributions in two ethnic groups (blacks and whites), and subtle changes in block structures that agree with the evolutionary history of the two populations. Our analyses suggest that a sample size of 200 or more subjects is probably needed for "stable" hapmap constructions. In addition, we demonstrate that there are subtle changes in block boundaries in hapmaps constructed in disease populations versus normal controls. This approach can quantify the information content of individual markers in the context of highly dense SNP data, which may have important implications in designing efficient genome-wide association mapping projects.

Computer Simulation↗
PubMed2005

Genome-wide linkage analysis for alcohol dependence: a comparison between single-nucleotide polymorphism and microsatellite marker assays.

Both theoretical and applied studies have proven that the utility of single nucleotide polymorphism (SNP) markers in linkage analysis is more powerful and cost-effective than current microsatellite marker assays. Here we performed a whole-genome scan on 115 White, non-Hispanic families segregating for alcohol dependence, using one 10.3-cM microsatellite marker set and two SNP data sets (0.33-cM, 0.78-cM spacing). Two definitions of alcohol dependence (ALDX1 and ALDX2) were used. Our multipoint nonparametric linkage analysis found alcoholism was nominal linked to 12 genomic regions. The linkage peaks obtained by using the microsatellite marker set and the two SNP sets had a high degree of correspondence in general, but the microsatellite marker set was insufficient to detect some nominal linkage peaks. The presence of linkage disequilibrium between markers did not significantly affect the results. Across the entire genome, SNP datasets had a much higher average linkage information content (0.33 cM: 0.93, 0.78 cM: 0.91) than did microsatellite marker set (0.57). The linkage peaks obtained through two SNP datasets were very similar with some minor differences. We conclude that genome-wide linkage analysis by using approximately 5,000 SNP markers evenly distributed across the human genome is sufficient and might be more powerful than current 10-cM microsatellite marker assays.

Alcoholism↗
PubMed2026

Microsatellites Versus Genome-Wide SNPs Data for Pedigree Reconstruction in Twin Simmental Crossbred Cattle.

Accurate pedigree reconstruction is critical for genetic evaluation in admixed cattle populations, yet the relative performance of microsatellite and genome-wide SNP markers in twin-rich herds with incomplete pedigree records remains unclear. We compared 12 ISAG-recommended microsatellite markers with whole-genome SNP data for dam-calf assignment in a Simmental crossbred population (n = 43, 13 dam-calf groups) from southern China. Twin zygosity was determined from SNP identity-by-descent (PI_HAT) values: nine calf pairs were dizygotic, one pair was monozygotic (20A/21A), and one adult pair was composed of dizygotic twin sisters (31A/34A). Admixture analysis at K = 3 revealed ancestry proportions of 50.7% European taurine, 28.9% Chinese indicine and 20.4% East Asian taurine. The SNP-based neighbor-joining tree correctly recovered 12 of 13 groups (92.3%, 95% CI: 64.0-99.8%), whereas the microsatellite-based tree recovered 11 (84.6%, 95% CI: 54.6-98.1%); the difference was not statistically significant (exact McNemar test, p = 1.0). Locus INRA023 was monomorphic (PIC = 0), reducing the effective number of markers to 11. These results indicate that genome-wide SNPs show a favourable trend in accuracy and are less prone to false-positive clustering than a standard microsatellite panel in admixed, twin-rich cattle populations.

SNP↗
PubMed2007

A functional SNP in ITIH3 is associated with susceptibility to myocardial infarction.

Myocardial infarction (MI) results from complex interactions of multiple genetic and environmental factors. To disclose genetic backgrounds of MI, we performed a large-scale, case-control association study using 52,608 gene-based single-nucleotide polymorphism (SNP) markers, and identified a candidate SNP located on chromosome 3p21.2-p21.1. Subsequent linkage-disequilibrium mapping indicated very significant association between MI and a SNP in exon 2 of the inter-alpha (globulin) inhibitor 3 gene (ITIH3; chi(2) = 24.88, P = 6.1 x 10(-7), 3,353 affected individuals versus 3,807 controls). In vitro functional analyses showed that this SNP enhanced the transcriptional level of the ITIH3 gene. Furthermore, we found expression of the ITIH3 protein in the vascular smooth muscle cells and macrophages in the human atherosclerotic lesions, suggesting ITIH3 SNP to be a novel genetic risk factor of MI.

Alpha-Globulins↗
PubMed2005

Comparison of marker types and map assumptions using Markov chain Monte Carlo-based linkage analysis of COGA data.

We performed multipoint linkage analysis of the electrophysiological trait ECB21 on chromosome 4 in the full pedigrees provided by the Collaborative Study on the Genetics of Alcoholism (COGA). Three Markov chain Monte Carlo (MCMC)-based approaches were applied to the provided and re-estimated genetic maps and to five different marker panels consisting of microsatellite (STRP) and/or SNP markers at various densities. We found evidence of linkage near the GABRB1 STRP using all methods, maps, and marker panels. Difficulties encountered with SNP panels included convergence problems and demanding computations.

Alcoholism↗
PubMed2003

Establishment of a high-efficiency SNP-based framework marker set for Arabidopsis.

The major goal of this project was the establishment of a tool for rapid mapping of new mutations and genotyping in Arabidopsis consisting of at least 100 evenly spaced framework markers. We assembled a single nucleotide polymorphism (SNP)-based marker set consisting of 112 polymorphic sites with average spacing of 1.15 Mbp derived from an SNP database that we recently developed. This information was used to set up efficient SNP detection reactions based on multiplexed primer extension assays. The 112 Columbia (Col-0)/C24 framework markers were used to assemble 18 multiplexed SNaPshot assays with which up to eight separate loci can be genotyped in a single-tube/single-capillary format. In addition, for 110 framework markers matrix-assisted laser desorption/ionization time of flight (MALDI-ToF) assays have been established for high throughput analyses. We demonstrated the usefulness and the robustness of both procedures of this tool by genotyping 48 BC3F1 individuals created between the accessions Col-0 and C24. Subsets of 10-62 of the established markers discriminate between various combinations of the accessions Col-0, C24, Landsberg erecta (Ler), Cape Verdi Islands (Cvi) and Niederzenz (Nd). Using a subset of 17 evenly distributed and established SNP markers that are also polymorphic between Ler and Col-0, we were able to rapidly map a mutant gene (tbr1) to an interval of 2.3 Mbp in an Ler (tbr1) x Col-0 cross.

Arabidopsis↗
PubMed2002

Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder.

The serotonin transporter gene (SLC6A4, MIM 182138) is a candidate gene in autistic disorder based on neurochemical, neuroendocrine studies and the efficacy of potent serotonin transporter inhibitors in reducing ritualistic behaviors and related aggression. An insertion/deletion polymorphism (5-HTTLPR) in the promoter region and a variable number of tandem repeat polymorphism (VNTR) in the second intron, were previously identified and suggested to modulate transcription. Six previous family-based association studies of SLC6A4 in autistic disorder have been conducted, with four studies showing nominally significant transmission disequilibrium and two studies with no evidence of nominally significant transmission disequilibrium. In the present study, TDT was conducted in 81 new trios. A previous finding of transmission disequilibrium between a haplotype consisting of the 5-HTTLPR and intron 2 VNTR was replicated in this study, but not preferential transmission of 5-HTTLPR as an independent marker. Because of inconsistent transmission of 5-HTTLPR across studies, SLC6A4 and its flanking regions were sequenced in 10 probands, followed by typing of 20 single nucleotide polymorphisms (SNPs) and seven simple sequence repeat (SSR) polymorphisms in 115 autism trios. When individual markers were analyzed by TDT, seven SNP markers and four SSR markers (six SNPs, 5-HTTLPR and the second intron VNTR from promoter 1A through intron 2 of SLC6A4, one SSR from intron 7 of SLC6A4, one SNP from the bleomycin hydrolase gene (BLMH, MIM 602403) and one SSR telomeric to BLMH) showed nominally significant evidence of transmission disequilibrium. Four markers showed stronger evidence of transmission disequilibrium (TDT(max) P = 0.0005) than 5-HTTLPR.

Autistic Disorder↗
PubMed2003

Power of genome-wide linkage disequilibrium testing by using microsatellite markers.

Linkage disequilibrium (LD) testing is often used in the search for disease genes. In this study, we developed a method for calculating the expected power of genome-wide LD testing by using microsatellite markers under the following assumptions: (1) microsatellite markers have unequally frequent alleles, (2) markers are equally spaced through the human genome, (3) the degree of LD between the disease variant and the marker decays gradually because of recombination and mutation, (4) the population frequency of the disease variant is low (e.g., 0.05), (5) a single-marker test is performed in a case-control study, and (6) the significance level is adjusted by the number of tests to avoid inflation of the type I error. Our calculations revealed a markedly higher power for microsatellite markers than for single nucleotide polymorphism (SNP) markers, even if more SNPs are analyzed, suggesting that the use of microsatellite markers is preferable to the use of SNPs for genome-wide screening under the above assumptions. This method will be helpful to researchers who design genome-wide LD testing with microsatellite markers.

Alleles↗
PubMed2004

Complex haplotype structure of the human GNAS gene identifies a recombination hotspot centred on a single nucleotide polymorphism widely used in association studies.

The alpha subunit of the heterotrimeric G protein Gs (Gsalpha) is involved in numerous physiological processes and is a primary determinant of cellular responses to extracellular signals. Genetic variations in the Gsalpha gene may play an important role in complex diseases and drug responses. To characterize the genetic diversity in this locus, we resequenced exons and flanking introns of the gene in 44 genomic samples and analysed the haplotype structure of the gene in an additional 50 African-Americans and 50 Caucasians. Significant differences in allele frequency for nearly all the genotyped single nucleotide polymorphism (SNPs) were detected between the two ethnic groups. Linkage disequilibrium (LD) analysis of this locus revealed two haplotype blocks characterized by strong LD and reduced haplotype diversity, especially in Caucasians. Between the two blocks is a narrow (approximately 3 kb) recombination hotspot centred on exons 4 and 5, and a widely used genetic marker in association studies in this region (rs7121) was in linkage equilibrium with the rest of the gene. The haplotype structure of the GNAS locus warrants reevaluation of previous association studies that used marker rs7121 and affects choice of SNP markers to be used in future studies of this locus.

Black or African American↗
PubMed2005

[Progress in detection methods of single nucleotide polymorphisms].

Single nucleotide polymorphism (SNP) is the third generation genetic marker. SNP detection now is becoming increasingly important means in molecular diagnostics, clinical assay and novel drug development. It plays an essential role in drug resistance and anaphylactic reaction and has the importance in theoretical studies of gene location, hereditary diseases and human origin. With the accomplishment of human genome sequencing, the genotyping and discovering of SNP are becoming hot subjects in genetics and biomedicine researches. The methods for SNP detection were renewed rapidly and developed fast in past few years. In this review, several newly established detection methods including gene chip, molecular probe, fluorescence polarization and resonance, mass spectrometry, and bacterial magnetic particle are discussed. It could be expected that an accurate and sensitive, simple and easy-to-handle SNP technology with low cost and high throughput will be available on the basis of research breakthroughs of biochemistry, engineering and analytic software.

Fluorescence Polarization↗
PubMed2004

SNP haplotypes and allele frequencies show evidence for disruptive and balancing selection in the human leukocyte receptor complex.

The human leukocyte receptor complex (LRC) of Chromosome 19q13.4 encodes polymorphic and highly homologous genes that are expressed by cells of the immune system and regulate their function. There is an enormous diversity at the LRC, most particularly the variable number of killer cell immunoglobulin-like receptor (KIR) genes. KIR have been associated with several disease processes due to their interaction with polymorphic human leukocyte antigen class I molecules. We have assessed haplotype compositions, linkage disequilibrium patterns and allele frequencies in two Caucasoid population samples (n=54, n=100), using a composite of single-nucleotide polymorphism (SNP) markers and high-resolution, allele-specific molecular genotyping. Particular KIR loci segregated with SNP and other markers, forming two blocks that were separated by a region with a greater history of recombination. The KIR haplotype composition and allele frequency distributions were consistent with KIR having been subject to balancing selection (Watterson's F: P=0.001). In contrast, there was a high inter-population heterogeneity measure for the LRC-encoded leukocyte immunoglobulin-like receptor A3 (LILRA3), indicating pathogen-driven disruptive selection (Wright's FST=0.32). An assessment of seven populations representative of African, Asian and Caucasoid ethnic groups (total n=593) provided little evidence for long-range LRC haplotypes. The different natural selection pressures acting on each locus may have contributed to a lack of linkage disequilibrium between them.

Chromosomes, Human, Pair 19↗
PubMed2005

Standard linkage and association methods identify the mechanism of four susceptibility genes for a simulated complex disease.

The simulated dataset of the Genetic Analysis Workshop 14 provided affection status and the presence or absence of 12 traits. It was determined that all affected individuals must have traits E, F and H (EFH phenotype) and they must also have either trait B (B subtype) or traits C, D, and G (CDG subtype). A genome screen was performed, and linkage peaks were identified on chromosomes 1, 3, 5, and 9 using microsatellite markers. Dense panels of single-nucleotide polymorphism (SNP) markers were ordered for each of the four linkage peaks. In each case, association analyses identified a single SNP that accounted for the linkage evidence. The SNP on chromosome 1 appeared to primarily influence the B subtype, while the SNPs on chromosomes 5 and 9 primarily influenced the CDG subtype. The chromosome 3 SNP had the strongest effect and influenced both subtypes, as well as the requisite EFH phenotype. Recognizing the two subtypes prior to linkage analysis was key to identifying these loci using only a single replicate. This highlights the need in real life situations for careful examination of the phenotypic data prior to genetic analysis.

Chromosome Mapping↗
PubMed2003

SNP-based codominant markers for a recessive gene conferring resistance to corky root rot (Rhizomonas suberifaciens) in lettuce (Lactuca sativa).

The analysis of F2 progeny and derived F3 families of Lactuca sativa segregating for resistance to corky root rot caused by Rhizomonas suberifaciens permitted the identification of restriction fragment length polymorphism (RFLP) and single nucleotide polymorphism (SNP) markers linked to the recessive resistance gene cor. PCR-based markers were identified by bulked segregant analysis (BSA). Allele-specific primers were generally designed with the 3 terminal base coinciding with an SNP, matching one of the alleles and mismatching the other, and with an additional subterminal 3 base mismatching both alleles. Codominant, robust, and inexpensive molecular markers were obtained that used standardized PCR conditions. Some of the markers could be analyzed in multiple Lactuca mapping populations that did not segregate for disease resistance allowing the cor locus to be located on several maps. The consistent low density of markers around cor in these maps suggests that cor may be in an area with an elevated rate of recombination. Evaluation of these markers in a large sample of cultivars and landraces identified pairs of flanking polymorphic markers that can be used for marker-assisted selection of corky root resistance.

Chromosome Mapping↗
PubMed2003

Maximum-likelihood and markov chain monte carlo approaches to estimate inbreeding and effective size from allele frequency changes.

Maximum-likelihood and Bayesian (MCMC algorithm) estimates of the increase of the Wright-Malécot inbreeding coefficient, F(t), between two temporally spaced samples, were developed from the Dirichlet approximation of allelic frequency distribution (model MD) and from the admixture of the Dirichlet approximation and the probabilities of fixation and loss of alleles (model MDL). Their accuracy was tested using computer simulations in which F(t) = 10% or less. The maximum-likelihood method based on the model MDL was found to be the best estimate of F(t) provided that initial frequencies are known exactly. When founder frequencies are estimated from a limited set of founder animals, only the estimates based on the model MD can be used for the moment. In this case no method was found to be the best in all situations investigated. The likelihood and Bayesian approaches give better results than the classical F-statistics when markers exhibiting a low polymorphism (such as the SNP markers) are used. Concerning the estimations of the effective population size all the new estimates presented here were found to be better than the F-statistics classically used.

Gene Frequency↗