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Comparison of different metrics, using three large samples of haplotypes from different populations, demonstrates that rho is the most efficient measure of association between pairs of single nucleotide polymorphisms (SNPs). Pairwise data can be modeled, using composite likelihood, to describe the decline in linkage disequilibrium with distance (th...
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... We understand that inaccuracies in genetic maps can result from genotyping errors, but the limited number of informative meiosis needed to generate maps is the major limiting factor, which have been also reported previously 26 , which could be the reason of missing intervals on different linkage groups in our case. Errors in the order of markers on physical maps might arise due to problems with assembly or incorrect identification of marker positions 27,28 , but even if the order of markers is known to be without error, accurate estimates of recombination fractions will play an important role in linkage, which in turn depends on the number of cross over events 29 , further limited by number of progenies considered. The SSR makers present across all chromosomes can be utilized further to develop high density linkage map in order to curtail this discrepancy in advanced mapping population like RILs. ...
Cluster bean (Cyamopsis tetragonoloba (L.) Taub 2n = 14, is commonly known as Guar. Apart from being a vegetable crop, it is an abundant source of a natural hetero-polysaccharide called guar gum or galactomannan. Here, we are reporting a chromosome-scale reference genome assembly of a popular cluster bean cultivar RGC-936, by combining sequencing data from Illumina, 10X Genomics, Oxford Nanopore technologies. An initial assembly of 1580 scaffolds with an N50 value of 7.12 Mb was generated and these scaffolds were anchored to a high density SNP linkage map. Finally, a genome assembly of 550.31 Mb (94% of the estimated genome size of ~ 580 Mb (through flow cytometry) with 58 scaffolds was obtained, including 7 super scaffolds with a very high N50 value of 78.27 Mb. Phylogenetic analysis using single copy orthologs among 12 angiosperms showed that cluster bean shared a common ancestor with other legumes 80.6 MYA. No evidence of recent whole genome duplication event in cluster bean was found in our analysis. Further comparative transcriptomics analyses revealed pod-specific up-regulation of genes encoding enzymes involved in galactomannan biosynthesis. The high-quality chromosome-scale cluster bean genome assembly will facilitate understanding of the molecular basis of galactomannan biosynthesis and aid in genomics-assisted improvement of cluster bean.
... Even when the order of markers is known to be without error, accurate estimates of recombination fractions will play an important role in linkage studies [54]. ...
... A disadvantage of these approaches is that they have limitations in resolution and high-throughput capability. Recently, single nucleotide polymorphism (SNP) microarrays have been introduced and vastly improve detection limits of DNA copy number variants (CNV) for more than 100,000 loci in all human chromosomes in the genome [8]- [10]. SNP array technology also allows for DNA allelotyping and identification of LOH to identify chromosomal regions containing novel tumor suppressor genes [11]- [13]. ...
We identified 90 germline single nucleotide polymorphisms (SNPs) that were informative for discriminative analysis of 9 major cancers among genotyped Framingham Heart Study participants. Support vector machines resulted in the greatest classification performance, which was in the range of 70-100%. The germline SNPs identified are based on DNA from peripheral blood lymphocytes obtained during non-invasive blood draws, and unlike SNPs in tumor DNA, may not be functionally related to tumor characteristics. Further validation studies are required in order to understand the role of the seeding, genetic selection, and lifetime cumulative effects of these germline SNPs in cancer development.
... No further backcross levels were checked because of the very low percentage of A. chukar present (3% in a B4 backcrossing, for example). Evidence from isolated populations suggested that linkage disequilibrium extends to a few hundred kilobases (Collins et al. 2001 ). In our study, the shortest distance in G. gallus between two multiplexed SNPs(GMCSF vs. PCBD2) was 1.1 Mb, while the rest of the pair-wise distances among SNPs were >8 Mb (seeTable 2). ...
Using the chicken genome, 114 polymorphisms (109 SNPs and 5 INDELs) were identified in the Alectoris genus by polymerase chain reaction-single strand conformation polymorphism. Using these, a panel of SNPs is described, which allows easy detection of introgression of Alectoris chukar in wild Alectoris rufa populations, when used with a primer extension protocol. The selected polymorphisms were genotyped and their allelic frequencies estimated on 98 A. rufa partridges sampled from nonrestocking Spanish areas, and 63 A. chukar partridges from Greek and Spanish farms. Power calculations to determine an optimum subset of markers for a given significance level were performed.
... Gene mapping research has illuminated the causes of rare monogenic conditions in humans [1] [2]. The challenge now is the search for prevalent chronic diseases such as cardiovascular diseases and obesity. ...
Identification of causative factors for common, chronic disorders is a major focus of current human health science research. These disorders are likely to be caused by multiple etiological agents. Available evidence also suggests that interactions between the risk factors may explain some of their pathogenic effects. While progress in genomics and allied biological research has brought forth powerful analytic techniques, the predicted complexity poses daunting analytic challenges. The search for pathogenesis of schizophrenia shares most of these challenges. We have reviewed the analytic and logistic problems associated with the search for pathogenesis. Evidence for pathogenic interactions is presented for selected diseases and for schizophrenia. We end by suggesting 'recursive analyses' as a potential design to address these challenges. This scheme involves initial focused searches for interactions motivated by available evidence, typically involving identified individual risk factors, such as candidate gene variants. Putative interactions are tested rigorously for replication and for biological plausibility. Support for the interactions from statistical and functional analyses motivates a progressively larger array of interactants that are evaluated recursively. The risk explained by the interactions is assessed concurrently and further elaborate searches may be guided by the results of such analyses. By way of example, we summarize our ongoing analyses of dopaminergic polymorphisms, as well as infectious etiological factors in schizophrenia genesis.
... Errors in the order of markers on physical maps can be due to problems with assembly or to incorrect identification of marker positions. Even when the order of markers is known to be without error, accurate estimates of recombination fractions will play an important role in linkage studies (Clerget-Darpoux et al., 1986;Risch and Giuffra, 1992;Goddard et al., 2000;Collins et al., 2001;Reich et al., 2001). ...
Genetic mapping (also known as linkage mapping or meiotic mapping) refers to the determination of the relative position and distances between markers along chromosomes. Genetic map distances between two markers are defined as the mean number of recombination events, involving a given chromatid, in that region per meiosis. Genetic map construction requires that the researcher develop appropriate mapping population, decide the sample size and type of molecular marker(s) for genotyping, genotype the mapping population with sufficient number of markers, and perform linkage analyses using statistical programs. The construction of detailed genetic maps with high levels of genome coverage is a first step for localizing genes or quantitative trait loci (QTL) that are associated with economically important traits, marker assisted selection, comparative mapping between different species, a framework for anchoring physical maps, and the basis for map-based cloning of genes. Highly reproducible, high throughput, codominant, and transferable molecular markers, especially developed from expressed regions, are sought to increase the utility of genetic maps. This article reviews the principles, requirements, and future prospects of genetic mapping in plants.
... The 'Fundamental Theorem of the HapMap' would have predicted that a sample size three times larger than needed to detect either functional variant would be sufficient to detect the association with the SNP C, but this is clearly untrue. This simple example is admittedly extreme, since both alleles are assumed to be very common, in accordance with the 'common disease/common variants' hypothesis, widely touted by the same scientists that are promoting HapMap 8,21,[56][57][58][59][60] Nonetheless, this example clearly shows that even with tight haplotype blocks, and common disease alleles, it is possible that functional variants can be detected if they are genotyped in a sample, and yet there might be absolutely no difference between cases and controls whatsoever for other common markers within the same haplotype block. ...
The International HapMap Project was proposed in order to quantify linkage disequilibrium (LD) relationships among human DNA polymorphisms in an assortment of populations, in order to facilitate the process of selecting a minimal set of markers that could capture most of the signal from the untyped markers in a genome-wide association study. The central dogma can be summarized by the argument that if a marker is in tight LD with a polymorphism that directly impacts disease risk, as measured by the metric r(2), then one would be able to detect an association between the marker and disease with sample size that was increased by a factor of 1/r(2) over that needed to detect the effect of the functional variant directly. This "fundamental theorem" holds, however, only if one assumes that the LD between loci and the etiological effect of the functional variant are independent of each other, that they are statistically independent of all other etiological factors (in exposure and action), that sampling is prospective, and that the estimates of r(2) are accurate. None of these are standard operating assumptions, however. We describe the ramifications of these implicit assumptions, and provide simple examples in which the effects of a functional variant could be unequivocally detected if it were directly genotyped, even as markers in high LD with the functional variant would never show association with disease, even in infinite sample sizes. Both theoretical and empirical refutation of the central dogma of genome-wide association studies is thus presented.
... Compared with the frequently used LD measure D (Hedrick 1987), of which the distributional properties are unknown, we found, in independent data sets, that W was less sensitive to factors such as sample size and allele numbers and that it provided a better fit than did D to the decline of LD with interlocus distance (authors' unpublished data). We developed this measure rather than using the association metric that others introduced for a similar purpose (Collins et al. 2001), since this latter measure (swept radius) is better suited for diallelic markers and requires collapsing of nonassociated alleles to reduce the loci, in a biased way, to diallelic systems. All the genotypic data were used (i.e., haplotypes in males and diplotypes in females). ...
Few studies have investigated genetic differentiation within nonisolate European populations, despite the initiation of large national sample collections such as U.K. Biobank. Here, we used short tandem repeat markers to explore fine-scale genetic structure and to examine the extent of linkage disequilibrium (LD) within national subpopulations. We studied 955 unrelated individuals of local ancestry from nine Scottish rural regions and the urban center of Edinburgh, as well as 96 unrelated individuals from the general U.K. population. Despite little overall differentiation on the basis of allele frequencies, there were clear differences among subpopulations in the extent of pairwise LD, measured between a subset of X-linked markers, that reflected presumed differences in the depths of the underlying genealogies within these subpopulations. Therefore, there are strategic advantages in studying rural subpopulations, in terms of increased power and reduced cost, that are lost by sampling across regions or within urban populations. Similar rural-urban contrasts are likely to exist in many other populations with stable rural subpopulations, which could influence the design of genetic association studies and national biobank data collections.
... Recent findings indicate a structure with regions of high LD and with limited numbers of haplotypes, interspersed by regions of low LD [46,30,31,108,32,1,120,144,18]. The latter can be due to either high recombination rates ("hot spot") or high rates of gene conversion in that region [47,143,122,28,67,51,119]. This structure of cold and hot spots of recombination has already been confirmed by physical evidence in the MHC and SHOX genes [66,94]. ...
Bisherige Methoden der Haplotyp-Block-Definition zielen entweder auf abwesende Rekombinationsereignisse oder eine effiziente Beschreibung genomischer Variation. Die vorliegende Arbeit definiert Blöcke von Single Nucleotide Polymorphisms (SNP) als Gebiete erhöhten Kopplungsungleichgewichtes (LD). Für dieses Ziel wird ein neues, entropie-basiertes Maß für LD zwischen multiplen Markern/Loci (Normalized Entropy Difference) entwickelt und als eine Multilocus-Erweiterung des paarweisen Maßes r2 charakterisiert. Ein zugehöriger Algorithmus für die Block-Definition wird vorgeschlagen. Seine Evaluierung an einem Datensatz des menschlichen Chromosoms 12 vom Internationalen Haplotype Map Projekt zeigt die Nützlichkeit der abgeleiteten Blöcke in Hinblick auf verschiedene Eigenschaften, einschließlich ihrer chromosomalen Coverage und der Anzahl sowie des Anteils der häufigen Block-Haplotypen. Der wesentliche Einfluß der SNP-Dichte auf die zu entdeckenden LD- und Blockstrukturen wird demonstriert. Der Erfolg von Assoziationsstudien in komplexen Erkrankungen mit Block-Haplotypen als multiallelischen Markern wird davon abhängen, ob die Common Variants/Common Diseases (CV/CD) Hypothese für solche Erkrankungen erfüllt ist.
... Although there are many other measures of LD (Devlin and Risch 1995;Collins et al. 2001), we use the log of the odds ratio here because it provides a symmetric measure of LD between two loci and is invariant to changes in marginal frequencies due to oversampling of disease chromosomes (Edwards 1963). Moreover, logistic regression (1) allows one to include covariates in the model. ...
Linkage disequilibrium (LD) mapping offers much promise for the positional cloning of disease-causing genes. However, conventional estimates of LD may fluctuate substantially across contiguous genomic regions, because of population-specific phenomena such as mutation, genetic drift, population structure, and variations in allele frequencies. This fluctuation makes it difficult to interpret patterns of LD and distinguish where a causal gene is located. To address this issue, we propose hierarchical modeling of LD (HLD) for fine-scale mapping. This approach incorporates information on haplotype block structure and chromosomal spatial relations to refine the pattern of LD, increasing the ability to localize disease genes. Here, we present a framework for HLD, a simulation study assessing the performance of HLD under various scenarios, and an application of HLD to existing data. This work demonstrates that hierarchical modeling of linkage disequilibrium is a valuable and flexible approach for fine-scale mapping.
