Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms.
Ontology highlight
ABSTRACT:
SUBMITTER: Niu T
PROVIDER: S-EPMC448439 | biostudies-other | 2002 Jan
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Many investigators are now using haplotype-tagging single-nucleotide polymorphism (htSNPs) as a way of screening regions of the genome for association with disease. A common approach is to genotype htSNPs in a study population and to use this information to draw inferences about each individual's haplotypic makeup, including SNPs that were not directly genotyped. To test the validity of this approach, we simulated the exercise of typing htSNPs in a large sample of individuals and compared the true and inferred haplotypes. The accuracy of haplotype inference varied, depending on the method of selecting htSNPs, the linkage-disequilibrium structure of the region, and the amount of missing data. At the stage of selection of htSNPs, haplotype-block-based methods required a larger number of htSNPs than did unstructured methods but gave lower levels of error in haplotype inference, particularly when there was a significant amount of missing data. We present a Web-based utility that allows investigators to compare the likely error rates of different sets of htSNPs and to arrive at an economical set of htSNPs that provides acceptable levels of accuracy in haplotype inference.
| S-EPMC1196396 | biostudies-literature
Project description:BACKGROUND: Single nucleotide polymorphisms (SNPs), the most abundant variations in a genome, have been widely used in various studies. Detection and characterization of citrus haplotype-based expressed sequence tag (EST) SNPs will greatly facilitate further utilization of these gene-based resources. RESULTS: In this paper, haplotype-based SNPs were mined out of publicly available citrus expressed sequence tags (ESTs) from different citrus cultivars (genotypes) individually and collectively for comparison. There were a total of 567,297 ESTs belonging to 27 cultivars in varying numbers and consequentially yielding different numbers of haplotype-based quality SNPs. Sweet orange (SO) had the most (213,830) ESTs, generating 11,182 quality SNPs in 3,327 out of 4,228 usable contigs. Summed from all the individually mining results, a total of 25,417 quality SNPs were discovered - 15,010 (59.1%) were transitions (AG and CT), 9,114 (35.9%) were transversions (AC, GT, CG, and AT), and 1,293 (5.0%) were insertion/deletions (indels). A vast majority of SNP-containing contigs consisted of only 2 haplotypes, as expected, but the percentages of 2 haplotype contigs varied widely in these citrus cultivars. BLAST of the 25,417 25-mer SNP oligos to the Clementine reference genome scaffolds revealed 2,947 SNPs had "no hits found", 19,943 had 1 unique hit / alignment, 1,571 had one hit and 2+ alignments per hit, and 956 had 2+ hits and 1+ alignment per hit. Of the total 24,293 scaffold hits, 23,955 (98.6%) were on the main scaffolds 1 to 9, and only 338 were on 87 minor scaffolds. Most alignments had 100% (25/25) or 96% (24/25) nucleotide identities, accounting for 93% of all the alignments. Considering almost all the nucleotide discrepancies in the 24/25 alignments were at the SNP sites, it served well as in silico validation of these SNPs, in addition to and consistent with the rate (81%) validated by sequencing and SNaPshot assay. CONCLUSIONS: High-quality EST-SNPs from different citrus genotypes were detected, and compared to estimate the heterozygosity of each genome. All the SNP oligo sequences were aligned with the Clementine citrus genome to determine their distribution and uniqueness and for in silico validation, in addition to SNaPshot and sequencing validation of selected SNPs.
| S-EPMC3827885 | biostudies-other
Project description:Although growing numbers of single nucleotide polymorphisms (SNPs) and microsatellites (short tandem repeat polymorphisms or STRPs) are used to infer population structure, their relative properties in this context remain poorly understood. SNPs and STRPs mutate differently, suggesting multi-locus genotypes at these loci might differ in ability to detect population structure. Here, we use coalescent simulations to measure the power of sets of SNPs and STRPs to identify population structure. To maximize the applicability of our results to empirical studies, we focus on the popular STRUCTURE analysis and evaluate the role of several biological and practical factors in the detection of population structure. We find that: (1) fewer unlinked STRPs than SNPs are needed to detect structure at recent divergence times <0.3 N(e) generations; (2) accurate estimation of the number of populations requires many fewer STRPs than SNPs; (3) for both marker types, declines in power due to modest gene flow (N(e)m=1.0) are largely negated by increasing marker number; (4) variation in the STRP mutational model affects power modestly; (5) SNP haplotypes (θ=1, no recombination) provide power comparable with STRP loci (θ=10); (6) ascertainment schemes that select highly variable STRP or SNP loci increase power to detect structure, though ascertained data may not be suitable to other inference; and (7) when samples are drawn from an admixed population and one of its parent populations, the reduction in power to detect two populations is greater for STRPs than SNPs. These results should assist the design of multi-locus studies to detect population structure in nature.
| S-EPMC2892635 | biostudies-other
Project description:BACKGROUND:Coronary artery disease (CAD) shares common risk factors with type 2 diabetes (T2DM). Variations in the transcription factor 7-like 2 (TCF7L2) gene, particularly rs7903146, increase T2DM risk. Potential links between genetic variants of the TCF7L2 locus and coronary atherosclerosis are uncertain. We therefore investigated the association between TCF7L2 polymorphisms and angiographically determined CAD in diabetic and non-diabetic patients. METHODOLOGY/PRINCIPAL FINDINGS:We genotyped TCF7L2 variants rs7903146, rs12255372, and rs11196205 in a cross-sectional study including 1,650 consecutive patients undergoing coronary angiography for the evaluation of established or suspected stable CAD. Significant CAD was diagnosed in the presence of coronary stenoses ?50%. Variant rs7903146 in the total study cohort was significantly associated with significant CAD (adjusted additive OR?=?1.29 [1.09-1.53]; p?=?0.003). This association was strong and significant in T2DM patients (n?=?393; OR?=?1.91 [1.32-2.75]; p?=?0.001) but not in non-diabetic subjects (OR?=?1.09 [0.90-1.33]; p?=?0.370). The interaction risk allele by T2DM was significant (p(interaction)?=?0.002), indicating a significantly stronger impact of the polymorphism on CAD in T2DM patients than in non-diabetic subjects. TCF7L2 polymorphisms rs12255372 and rs11196205 were also significantly associated with CAD in diabetic patients (adjusted additive OR?=?1.90 [1.31-2.74]; p?=?0.001 and OR?=?1.75 [1.22-2.50]; p?=?0.002, respectively). Further, haplotype analysis demonstrated that haplotypes including the rare alleles of all investigated variants were significantly associated with CAD in the whole cohort as well as in diabetic subjects (OR?=?1.22 [1.04-1.43]; p?=?0.013 and OR?=?1.67 [1.19-2.22]; p?=?0.003, respectively). CONCLUSIONS/SIGNIFICANCE:These results suggest that TCF7L2 variants rs7903146 rs12255372, and rs11196205 are significantly associated with angiographically diagnosed CAD, specifically in patients with T2DM. TCF7L2 therefore appears as a genetic link between diabetes and atherosclerosis.
| S-EPMC3058059 | biostudies-literature
Project description:UnlabelledDetailed analyses of the population-genetic nature of copy number variations (CNVs) and the linkage disequilibrium between CNV and single nucleotide polymorphism (SNP) loci from high-throughput experimental data require a computational tool to accurately infer alleles of CNVs and haplotypes composed of both CNV alleles and SNP alleles. Here we developed a new tool to infer population frequencies of such alleles and haplotypes from observed copy numbers and SNP genotypes, using the expectation-maximization algorithm. This tool can also handle copy numbers ambiguously determined, such as 2 or 3 copies, due to experimental noise.Availabilityhttp://emu.src.riken.jp/MOCSphaser/MOCSphaser.zip.
| S-EPMC2638261 | biostudies-literature
Project description:Glutathione S-transferase (GST) P1 is a major phase II xenobiotic-metabolizing enzyme in the human lung. Our laboratory had previously identified nine single nucleotide polymorphisms (SNPs) in the GSTP1 gene promoter, which were then grouped into three main haplotypes (Hap1, Hap2, and Hap3) based on statistical inference. Hap3 was found to display a high expression phenotype. The main objective of the current study was to test the association between GSTP1 promoter haplotypes with the risk of lung cancer after determining the promoter haplotypes experimentally through cloning and sequencing.We conducted a case-control analysis of 150 subjects with lung cancer and 329 controls with no personal history of the disease. The three statistically inferred GSTP1 promoter haplotypes were confirmed experimentally through cloning and sequencing. Haplotype-tagging SNPs were selected and GSTP1 haplotypes were tested for genetic association to lung cancer using unconditional logistic regression after adjusting for confounders. Statistical interaction between GSTP1 promoter haplotypes with either cigarette smoking or dietary fruit and vegetable intake were tested using the likelihood ratio test.We did not find protective effects of Hap3 against lung cancer, despite an adequately powered design for this main effect. Homozygous variants of tagSNPs -1738 T>A and -354 G>T, which tag Hap2, showed an increased (but statistically non-significant) risk of lung cancer among all subjects as well as among individuals with low fruit and vegetable intake, compared to homozygous wildtypes for these SNPs. We did not find significant interactions between Hap2 and dietary intake of fruits and vegetables.Our results do not support significant main and modifying effects for GSTP1 promoter haplotypes on susceptibility to lung cancer in this population, but reinforce the protective effects of dietary intake of fruits and vegetables.
| S-EPMC3730463 | biostudies-literature
Project description:This study, part of the Genetic Analysis Workshop 14 (GAW14), explored real Collaborative Study on the Genetics of Alcoholism data for linkage and association mapping between genetic polymorphisms (microsatellite and single-nucleotide polymorphisms (SNPs)) and beta (16.5-20 Hz) oscillations of the brain rhythms (ecb21). The ecb21 phenotype underwent the statistical adjustments for the age of participants, and for attaining a normal distribution. A total of 1,000 subjects' available phenotypes were included in linkage analysis with microsatellite markers. Linkage analysis was performed only for chromosome 4 where a quantitative trait locus with 5.01 LOD score had been previously reported. Previous findings related this location with the gamma-aminobutyric acid type A (GABAA) receptor. At the same location, our analysis showed a LOD score of 2.2. This decrease in the LOD score is the result of a drastic reduction (one-third) of the available GAW14 phenotypic data. We performed SNP and haplotype association analyses with the same phenotypic data under the linkage peak region on chromosome 4. Seven Affymetrix and two Illumina SNPs showed significant associations with ecb21 phenotype. A haplotype, a combination of SNPs TSC0044171 and TSC0551006 (the latter almost under the region of GABAA genes), showed a significant association with ecb21 (p = 0.015) and a relatively high frequency in the sample studied. Our results affirmed that the GABA region has potential of harboring genes that contribute quantitatively to the beta oscillation of the brain rhythms. The inclusion of the remaining 614 subjects, which in the GAW14 had missing data for the ecb21, can improve the strength of the associations as they have already shown that they contribute quite important information in the linkage analysis.
| S-EPMC1866685 | biostudies-literature
Project description:Statistical approaches for population structure estimation have been predominantly driven by a particular data type, single-nucleotide polymorphisms (SNPs). However, in the presence of weak identifiability in SNPs, population structure estimation can suffer from undesirable accuracy loss. Copy number variations (CNVs) are genomic structural variants with loci that are commonly shared within a specific population and thus provide valuable information for estimation of the ancestry of sampled populations. We develop a Bayesian joint modeling framework of SNPs and CNVs, called POPSTR, to better understand population structure than approaches that use SNPs solely. To deal with the increased data volume, we use the Metropolis Adjusted Langevin algorithm (MALA) that guides the target distribution in a computationally efficient way. We illustrate applications of our approach using the HapMap 2005 project data. We carry out simulation studies and show that the performance of our approach is comparable or better than that of popular benchmarks, STRUCTURE and ADMIXTURE. We also observe that using only CNVs can be remarkably efficient if SNP data are not available.
| S-EPMC5915226 | biostudies-literature
Project description:IntroductionCytochrome P-450 2E1 (CYP2E1) is an important member of the CYP superfamily, which is involved in the metabolism and activation of many low molecular weight toxic compounds. We tried to investigate the possible association of CYP2E1 tag single nucleotide polymorphisms (SNPs) with susceptibility to systemic lupus erythematosus (SLE) in a Chinese Han population.MethodsThe coding and flanking regions of the CYP2E1 gene were scanned for polymorphisms and tag SNPs were selected. A two-stage case-control study was performed to genotype a total of 876 SLE patients and 680 geographically matched healthy controls (265 cases and 288 controls in stage I and 611 cases and 392 controls in stage II). SLE associations of alleles, genotypes and haplotypes were tested by age and sex adjusted logistic regression. The gene transcription quantitation was carried out for peripheral blood mononuclear cell (PBMC) samples from 120 healthy controls.ResultsTag SNP rs2480256 was found significantly associated with SLE in both stages of the study. The "A" allele was associated with slightly higher risk (odds ratio (OR) = 1.165, 95% confidence interval (CI) 1.073 to 1.265, P = 2.75E-4) and "A/A" genotype carriers were with even higher SLE risk (OR = 1.464 95% CI 1.259 to 1.702, P = 7.48E-7). When combined with another tag SNP rs8192772, we identified haplotype "rs8192772-rs2480256/TA" over presented in SLE patients (OR 1.407, 95% CI 1.182 to 1.675, P = 0.0001) and haplotype "TG" over presented in the controls (OR 0.771, 95% CI 0.667 to 0.890, P = 0.0004). The gene transcription quantitation analysis further proved the dominant effect of rs2480256 as the "A/A" genotype showed highest transcription.ConclusionsOur results suggest the involvement of CYP2E1 as a susceptibility gene for SLE in the Chinese population.
| S-EPMC3241355 | biostudies-literature
Project description:Determination of haplotypes is important for modelling the phenotypic consequences of genetic variation in diploid organisms, including cis-regulatory control and compound heterozygosity. We realized that single-cell RNA-seq (scRNA-seq) data are well suited for phasing genetic variants, since both transcriptional bursts and technical bottlenecks cause pronounced allelic fluctuations in individual single cells. Here we present scphaser, an R package that phases alleles at heterozygous variants to reconstruct haplotypes within transcribed regions of the genome using scRNA-seq data. The devised method efficiently and accurately reconstructed the known haplotype for??93% of phasable genes in both human and mouse. It also enables phasing of rare and de novo variants and variants far apart within genes, which is hard to attain with population-based computational inference.scphaser is implemented as an R package. Tutorial and code are available at https://github.com/edsgard/scphaserrickard.sandberg@ki.seSupplementary data are available at Bioinformatics online.
| S-EPMC5039928 | biostudies-literature