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1
Hernandez-Sanchez, Jules. "Gene mapping using linkage disequilibrium." Thesis, University of Edinburgh, 2002. http://hdl.handle.net/1842/14058.
Testo completoAbstract (sommario):
The power of QTL detection was studied both empirically and deterministically for several methods. TDT was more powerful than a linkage test, but less powerful than a pure association test. There were no great differences in power between TDTs. One of the TDTs was implemented in BLUP (Best Linear Unbiased Prediction) to study the effect of a candidate gene, the melanocortin 4- receptor (MC4R), on growth, appetite and fatness in pigs. We found significant effects on growth and fatness but not on appetite. TDT uses within families genetic variation. A novel parameter to estimate gene effects using between families genetic variation was also included. If there is no spurious disequilibrium both estimates should be identical, otherwise only the within-families estimator is unbiased. It was more powerful to simulate missing parental genotypes with Gibbs Sampling than analysing data with sib-ship TDTs disregarding parental information. TDT was also used in a genome-wide search for markers associated with bovine spongiform encaphalopathy (BSE). TDT was implemented using logistic regressions, more amenable to statistical modelling than the original form. Maker loci near the Prion Protein gene did not show any associations with BSE, however, markers located on chromosomes 5, 10 and 20, did. A second study that focused on these three chromosomal regions confirmed the association for the marker on chromosome 5. TDT has shown reasonable power and exceptional robustness when mapping QTL in structured populations. Therefore TDT should be part of the gene cartographers’ continuously evolving arsenal of tools for gene mapping. However, previously published TDTs were developed for analysing human populations, whereas domestic/wild populations have different structures and histories that may require alternative statistical analyses. Linked gene flow (LGF) theory can be used for predicting identity-by-descent (IBD) probabilities between individuals. IBD probabilities are at the core of mixed model equations for mapping QTL in outbred populations via variance components estimation. In this thesis, LGF theory was used for determining inbreeding within each individual and chromosomal location using multi-marker information, hence paving the way for further developments.
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Veroneze, Renata. "Linkage disequilibrium and genomic selection in pigs." Universidade Federal de Viçosa, 2015. http://www.locus.ufv.br/handle/123456789/7597.
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Previous issue date: 2015-09-25<br>Coordenação de Aperfeiçoamento de Pessoal de Nível Superior<br>A seleção genômica (SG) e associação genômica ampla (GWAS) são métodos que exploram o desequilíbrio de ligação (LD) entre marcadores e loci de características quantitativas (QTL). Um dos fatores limitantes para a implementação da SG é a necessidade de um grande número de animais genotipados e fenotipados para obtenção de valores genéticos com alta acurácia. Essa limitação pode ser superada combinando dados de múltiplas populações ou utilizando dados de animais cruzados. O objetivo geral desta tese foi caracterizar os padrões de LD de diferentes populações de suínos. Além disso, avaliar em que medida as diferenças de LD se refletem na acurácia da seleção genômica quando utilizadas diferentes metodologias e arranjos para população de referência e validação. Os arranjos testados foram: utilização de subconjuntos da mesma população como referência e validação (within), populações diferentes nos conjuntos de referência e validação (across) e combinação de duas populações na referência (multi). Nessa tese foram utilizados dados de suínos de linhas puras e de animais cruzados, genotipados com o PorcineSNP60 BeadChip. A regressão Loess proporcionou melhor ajuste aos dados de LD, bem como em predições mais acuradas em comparação a regressão não linear. Mostrou-se também, que a regressão Loess pode ser utilizada para realizar uma comparação estatística do LD decay de diferentes populações. A persistência de fase do LD entre animais cruzados e as linhas puras parentais foi alta, o que nos leva a hipotetizar que associações marcador-QTL similares poderiam ser encontradas em animais cruzados e as linhas parentais e, portanto, esperava-se encontrar altas acurácias de predição genômica entre essas populações. Entre as linhas puras a persistência de fase foi baixa, logo painéis de SNPs de maior densidade deveriam ser utilizados para manter a mesma associação marcador-QTL entre essas linhas. Acurácias obtidas na predição genômica utilizando animais cruzados assim como os arranjos across e multi, não seguiram as expectativas baseadas em LD. Portanto, a consistência de fase de ligação entre populações pode não ser tão importante para a acurácia da seleção genômica como se pensava, mas sim a ação combinada de LD, arquitetura genética e frequências alélicas. Portanto, foi desenvolvida uma metodologia que leva em consideração differenças nas frequências alélicas, bem como informações dos GWAS para comtemplar a arquitetura genética da característica. Esta estratégia trouxe alguns benefícios para a predição genônima para os arranjos within e multi. Ponderações obtidas por meio de GWAS em diferentes conjuntos de dados (uma única população e combinando múltiplas populações) nem sempre resultou em aumento da acurácia, sendo dependente da linha que estava sob seleção. O uso de pesos advindos do GWAS ao se utilizar uma população combinada resultou nas melhores acurácias tanto para os arranjos within quanto multi. A avaliação e o entendimento de como diferenças de LD, frequências alélicas e arquitetura genética afetam a acurácia da predição genômica é fundamental para otimizar a inserção da seleção genômica no melhoramento de suínos.<br>Genomic selection and genomic wide association studies (GWAS) are widely used methods that aim to exploit the linkage disequilibrium (LD) between markers and quantitative trait loci (QTL). Securing a sufficiently large set of genotypes and phenotypes can be a limiting factor when implementing genomic selection that may be overcome by combining data from multiple populations or using crossbred information. The overall objective of this thesis was to characterize LD patterns in different pig populations and to evaluate whether the differences in LD determine the accuracy of genomic predictions when using different reference sets (within-, across- and multi- population) and methodologies. In this thesis I used data from pure lines and crossbred pig populations genotyped with PorcineSNP60 BeadChip. Loess regression provided a better fit to the real LD data, and more accurate LD predictions could be made, compared to nonlinear regression. It was also shown that Loess regression can be used to statistically compare the LD decay of different populations. The persistence of LD phase between crosses and the parental pig lines was found to be high, from which it was hypothesized that similar marker-QTL associations would be found in a cross and in their purebred parent populations and therefore accuracies of genomic prediction across these populations should be high. Between the pure lines the persistence of phase was low, thus higher density panels should be used to have the same marker-QTL associations across these lines. Accuracies obtained from across- and multi-population genomic prediction and from using crossbred data did however not follow the expectations based on LD. Having the same LD phase may therefore not be as important for genomic prediction accuracy as previously thought but rather the interplay between LD, genetic architecture and allele frequencies also plays a major role. Differences in allele frequencies between lines and information from GWAS on the genetic architecture of traits for the different lines were taken into account in analyses developed in the later chapters. The use of weights, based on GWAS results, was expected to lead the GBLUP model towards the real genetic architecture of the traits. This strategy was shown to have some benefit for the genomic predictions with single- and multi-population data sets. Weights obtained from GWAS in different data sets (within and combining populations) did not always lead to increased accuracies of prediction, depending on which lines the weights are applied to. Using weights from GWAS in a combined population was the best approach, resulting in higher accuracy of GBLUP predictions within single- as well as in multi-population analysis. Understanding and evaluating how the accuracy of within-, across- and multi-population genomic prediction is affected by differences in LD, in genetic architecture and in allele frequencies is key to optimize the accuracy of genomic prediction in pig breeding.
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Liu-Cordero, Shau Neen 1970. "Patterns of linkage disequilibrium in the human genome." Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/89344.
Testo completoAbstract (sommario):
Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Biology, 2002.<br>Includes bibliographical references.<br>Although enormous progress has occurred in the field of human genetics, the cloning of complex trait mutations remains a challenging and unresolved process. This continuing difficulty is responsible for an ever-increasing awareness of the phenomenon of linkage disequilibrium (LD). The principle behind LD is relatively simple. Over the lifetime of a population, the genetic markers that are adjacent to an ancestral mutation will recombine less often than more distant markers. Therefore, the ancestral alleles of the markers closest to the mutation should be most frequent in a collection of disease chromosomes. The allelic association should decrease as the distance from the ancestral disease mutation increases. This thesis is a collection of ideas and experiments aimed at dissecting the behavior of LD in the human genome. Specific studies examine LD in a variety of populations including isolated founder populations, as well as globally diverse population samples. A large number of regions throughout the genome are investigated using both pairwise comparisons of markers, as well as multimarker haplotypes. The X chromosome is more closely scrutinized because of its unique population history, as well as the advantages afforded to haplotyping due to hemizygosity of the X chromosome in males. Major conclusions include the observation that LD between pairs of markers is highly variable even at extremely close distances and multimarker haplotypes better serve to resolve the underlying haplotype structure of the genome.<br>(cont.) The genome appears to be structured as blocks of limited haplotype diversity that do not exhibit much internal recombination but which are separated by segments that show little or no LD. The lack of LD between haplotype blocks appears to be due to clustering of recombination events into specific hotspots. The size of the blocks and haplotype diversity varies slightly by population. In addition, the identity of the haplotypes varies between populations. The existence of 3-4 major haplotypes for specific regions in a diverse human population sample is a surprising finding that was originally believed to have only existed in very special isolated and young populations.<br>by Shau Neen Liu-Cordero.<br>Ph.D.
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Li, Na. "Modeling and inference for linkage disequilibrium and recombination /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/9532.
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Cummings, James Rowland Fraser. "Linkage Disequilibrium Mapping of Chromosome 19 on Crohn's Disease." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531666.
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Lawrence, Robert W. "Characterizing patterns of linkage disequilibrium in the human genome." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.496992.
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Holloway, J. Kim. "Linkage disequilibrium and meiotic recombination in the human genome." Thesis, University of Leicester, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426035.
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Dale, Kuys Ruth. "Linkage disequilibrium in the South African abalone, Haliotis midae." Thesis, Stellenbosch : Stellenbosch University, 2015. http://hdl.handle.net/10019.1/97991.
Testo completoAbstract (sommario):
Thesis (MSc)--Stellenbosch University, 2015.<br>ENGLISH ABSTRACT: Linkage disequilibrium (LD) is defined as the non-random association of alleles at two or more loci within a population. It is sensitive to a variety of locus-specific- and demographic factors, and can thus provide much insight into the micro-evolutionary factors that have shaped species of interest. It can also be exploited to identify the genomic regions determining complex traits of interest, which can then be applied as performance evaluation markers in marker-assisted selection (MAS). The South African abalone, Haliotis midae, supports a rapidly developing aquaculture production industry, in which genetic improvement potential is high. This species also represents an opportunistic model for studying the effects of early domestication in a shellfish species. The aim of this study was therefore to quantify and characterise levels of genome-wide LD within the South African abalone, and to demonstrate its utility within population genetic investigations and the characterisation of complex traits. Estimates of LD between 112 mapped microsatellite markers within wild and cultured H. midae revealed that levels of LD in abalone are high relative to other aquaculture species. This was attributed primarily to small effective population sizes produced by a combination of natural- and anthropogenic factors. The decay of LD with genetic distance was evident in both cultured cohorts, but almost absent in wild cohorts, likely reflecting the differences in size, age and sampling of wild populations relative to cultured. Putative evidence for the effects of recombination, selection, and epistasis were also evident in distinctive locus-specific patterns of LD on some of the linkage groups, many of which could represent the effects of domestication. The effects of selection associated with the domestication event were further investigated using a candidate locus LD mapping approach to determine the proportion of candidate loci under selection associated with artificial selection for faster growth rate in cultured abalone. Two loci (15%) were found to be significantly associated with differences in size of individual animals, both of which could be linked with genes potentially involved in growth and development. These markers could therefore find application in MAS programmes for abalone. Several promising candidates for natural selection were also identified based on similarity with known genes. As the latter represented the majority, natural selection, rather than artificial selection, appears to be predominant during the early stages of domestication in abalone. While some conclusions within the current study were speculative, both the direct and indirect applications of LD were clearly demonstrated. Linkage disequilibrium data can provide a unique perspective on many of the commonly used population genetic estimates, and is therefore of great value in population genetic investigations. Furthermore, these results also highlighted the effectiveness of the candidate locus approach in species with both limited molecular resources and extensive LD.<br>AFRIKAANSE OPSOMMING: Koppelingsonewewig (KO) word gedefinieer as die nie-lukrake assosiasie van allele by twee of meer lokusse binne 'n populasie. Koppelingsonewewig is sensitief vir 'n verskeidenheid van lokus-spesifieke- en demografiese faktore, en kan dus insiggewend wees m.b.t. mikro-evolusionêre faktore wat spesies van belang beïnvloed het. Dit kan ook benut word om die genoom-gebiede onderligend tot komplekse eienskappe te bespeur; wat dan aangewend kan word vir prestasie-evaluering m.b.v. merkerbemiddelde seleksie (MBS). Die Suid-Afrikaanse perlemoen, Haliotis midae, ondersteun 'n vinnig ontwikkelende akwakultuur produksie bedryf, waarin genetiese verbeteringspotensiaal hoog is. Hierdie spesie verteenwoordig ook 'n opportunistiese model vir die bestudering van die gevolge van vroeë domestiseering in 'n skulpvis spesie. Die doel van hierdie studie was dus om vlakke van genoom-wye KO binne die Suid-Afrikaanse perlemoen te kwantifiseer en te karakteriseer, en om die toepassing hiervan binne populasiegenetiese ondersoeke en die karakterisering van komplekse eienskappe te demonstreer. Ramings van KO tussen 112 gekarteerde mikrosatelliet-merkers binne wilde en gekultiveerde H. midae het aan die lig gebring dat die vlakke van KO in perlemoen hoog was, in vergelyking met ander akwakultuur spesies. Dit word hoofsaaklik toegeskryf aan klein effektiewe populasiegroottes wat deur 'n kombinasie van natuurlike- en antropogeniese faktore teweeg gebring word. Die verval van KO met genetiese afstand was duidelik waarneembaar in gekultiveerde kohorte, maar amper afwesig in die wilde kohorte, waarskynlik a.g.v. verskille in populasiegrootte, ouderdom, en streekproef-neemings metodieke van die verskeie populasies. Vermeende bewyse vir die gevolge van rekombinasie, seleksie en epistase kon ook gesien word a.g.v. lokus-spesifieke patrone van KO op sommige van die koppelingsgroepe, moontlik ‘n gevolg van domestisering. Die gevolge van seleksie wat verband hou met die domestiseringsgebeurtenis is verder ondersoek m.b.v 'n kandidaat-lokus KO karteringsbenadering om die verhouding van kandidaat lokusse wat geassosieer is met kunsmatige seleksie (vir vinniger groeikoers in perlemoen) te bepaal. Twee lokusse (15%) was beduidend geassosieer met verskille in grootte tussen individuele diere. Beide van die lokusse was gekoppel met gene wat potensieel betrokke is by groei en ontwikkeling. Hierdie merkers kan dus moontlik aangewend word in MBS programme vir perlemoen. Verskeie belowende kandidaat lokusse vir natuurlike seleksie is ook geïdentifiseer gebaseer op ooreenkoms met bekende gene. Gegewe dat die laasgenoemde die meerderheid van die merkers verteenwoordig, kan daar afgelei word dat natuurlike seleksie, eerder as kunsmatige seleksie, oorheersend is in die vroeë stadia van domestisering in perlemoen. Terwyl sommige gevolgtrekkings binne die huidige studie spekulatief was, is beide die direkte en indirekte toepassings van KO duidelik gedemonstreer. Koppelingsonewewig-data kan 'n unieke perspektief gee op baie van die algemeen gebruikte populasie genetiese skattings, en is dus van groot waarde in populasie genetiese ondersoeke. Verder demonstreer hierdie resultate ook die doeltreffendheid van die kandidaat lokus benadering in spesies met beide beperkte molekulêre hulpbronne en uitgebreide KO.
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Sjölander, Anders. "Exploring linkage disequilibrium to date admixture using ancient DNA." Thesis, Uppsala universitet, Växtekologi och evolution, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-298198.
Testo completoAbstract (sommario):
Admixture studies based on contemporary DNA are well studied and results from these have shown to correlate well with other evidence. The study of using ancient DNA for determining admixture times is a less explored alternative for determining admixture. Admixture-induced Linkage Disequilibrium for Evolutionary Relationships (ALDER) is an established tool for determining admixture time from contemporary DNA. This project investigates the use of ALDER on simulated ancient DNA to determine if it can be used in actual ancient DNA studies. The results from this project suggest that ALDER can be used in actual studies, with good accuracy and reliability.
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Webb, Adam J. "Meiotic recombination and linkage disequilibrium in the human genome." Thesis, University of Leicester, 2006. http://hdl.handle.net/2381/30369.
Testo completoAbstract (sommario):
Evidence is accumulating that recombination events in humans are not randomly distributed, but clustered into hotspots 1-2 kb wide. The Xp/Yp pseudoautosomal region (PAR1) is a male-specific recombination hot domain. The PAR1 gene PPP2R3B shows unusually high levels of nucleotide diversity. I have used LD studies in this region to reveal a dearth of historical recombination, arguing against earlier speculation that high diversity is driven by mutagenic recombination. Chimp LD studies, the existence of recombination hotspots inside LD blocks, and the observation of meiotic drive within a hotspot favouring recombination suppressors all support the hypothesis that recombination hotspots turn over rapidly during evolution. To identify very recently arisen recombination hotspots, LD patterns between African-American and European-American populations were compared in 147 genes, revealing PON2 as the only gene with convincing evidence for a recently arisen recombination hotspot. A second approach, whereby contemporary linkage data is compared to historical LD data, was employed to identify putative young recombination hotspots. The 6 kb D6S383-D6S970 interval on chromosome 6 shows a recombination rate of 33 cM/Mb in pedigrees, yet lies within a block of strong LD. Sperm crossover analyses across this region in two men did not reveal a recombination hotspot, raising the possibility of a hotspot polymorphism at this locus. Finally, the release of data from phase II of the HapMap project allowed construction of genome-wide linkage disequilibrium unit (LDU) maps at high resolution. Sliding window analyses of these maps suggested putative recombination hotspots, directing future research into the characteristics and distribution of recombination hotspots in humans.
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Zaffaroni, Daniela. "Mapping of skin cancer susceptibility loci in mice." Thesis, Open University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270016.
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Kim, Yunjung. "Analysis of Multilocus Linkage Disequilibrium Structure in the Human Genome." NCSU, 2008. http://www.lib.ncsu.edu/theses/available/etd-03132008-075346/.
Testo completoAbstract (sommario):
The International HapMap Project and high- throughput genotyping technology have generated millions of genome-wide marker data that can be used in genetic studies. Each marker can be analyzed separately. But analyzing multiple markers simultaneously through haplotypes has generated great interest recently. Understanding the haplotype structure in the human genome may provide important information on human evolutionary history and identification of genetic variants responsible for human complex diseases. Since the alleles at closely linked markers on a single chromosome are often in statistical dependence (i.e. linkage disequilibrium (LD)), one crucial aspect of haplotype analysis is to characterize LD patterns in different regions and different populations. To assess the extent of correlation of genetic variation at multiple markers in a given region and a population, pairwise LD measures such as and have been commonly used. However, pairwise LD measures alone may be suboptimal to effectively capture the variability of background levels of disequilibrium since multilocus LD measures can provide information about simultaneous allele associations among multiple loci which pairwise LD measures miss. In addition, in order to fully characterize the haplotype structure and LD pattern at multiple markers, it is necessary to consider high order disequilibria and estimate their values.
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Johnson, Randall. "Modeling of linkage disequilibrium in whole genome genetic association studies." Thesis, Paris, CNAM, 2014. http://www.theses.fr/2015CNAM0963/document.
Testo completoAbstract (sommario):
L’approche GWAS est un outil essentiel pour la découverte de gènes associés aux maladies, mais elle pose des problèmes de puissance statistique quand il est impossible d’échantillonner génétiquement des dizaines de milliers de sujets. Les résultats présentés ici—ALDsuite, un programme en utilisant une correction nouvelle et efficace pour le déséquilibre de liaison (DL) ancestrale de la population locale, en permettant l'utilisation de marqueurs denses dans le MALD, et la démonstration que la méthode simpleM fournit une correction optimale pour les comparaisons multiples dans le GWAS—réaffirment la valeur de l'analyse en composantes principales (APC) pour capturer l’essence de la complexité des systèmes de grande dimension. L’APC est déjà la norme pour corriger la structure de la population dans le GWAS; mes résultats indiquent qu’elle est aussi une stratégie générale pour faire face à la forte dimensionnalité des données génomiques d'association<br>GWAS is an essential tool for disease gene discovery, but has severe problems of statistical power when it is impractical to genetically sample tens of thousands of subjects. The results presented here—a novel, effective correction for local ancestral population LD allowing use of dense markers in MALD using the ALDsuite and the demonstration that the simpleM method provides an optimum Bonferroni correction for multiple comparisons in GWAS, reiterate the value of PCA for capturing the essential part of the complexity of high- dimensional systems. PCA is already standard for correcting for population substructure in GWAS; my results point to it’s broader applicability as a general strategy for dealing with the high dimensionality of genomic association data
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Thunga, Venkata Raghava Pavankumar. "Nucleotide diversity and Linkage disequilibrium in Norway spruce (Picea abies)." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-221359.
Testo completoAbstract (sommario):
Pattern of Linkage Disequilibrium (LD) is a major factor largely determining the power of association mapping studies. Along with nucleotide diversities and DNA polymorphism, knowledge of patterns of LD along the genome needs to be to known to effectively design association mapping studies. In this study, patterns of nucleotide diversity, population structure, LD was estimated in Norway spruce (Picea abies). The data used for this were 23 nuclear loci sequenced in around 90 individuals originating from natural populations of Norway spruce throughout the current distribution range in Sweden and Finland. The observed levels of nucleotide diversity are variable among loci varying between 0.002 and 0.008 if measured by average pairwise nucleotide diversity. Despite the samples stretching large part of Finland and Sweden there were no evidence for strong population structure. As in earlier studies LD decays fast with distance and the average pattern of the squared correlation of allele frequencies drops to less than 0.2 within 100bp. In order to put the data in perspective previously generated data sets were re-analyzed and compared to the inferred results.
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Petryshen, Tracey Lynn. "Localization of susceptibility genes involved in phonological coding dyslexia by family linkage and linkage disequilibrium studies." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ64882.pdf.
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Zhao, Honghua. "Use of linkage disequilibrium for quantitative trait loci mapping in livestock." [Ames, Iowa : Iowa State University], 2006.
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Lau, Winston Wai Shing. "Exploiting large scale computing for the analysis of genetic linkage disequilibrium." Thesis, University of Southampton, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.443042.
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Younkin, Samuel G. "The Linkage Disequilibrium LASSO for SNP Selection in Genetic Association Studies." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1291219489.
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Dehman, Alia. "Spatial clustering of linkage disequilibrium blocks for genome-wide association studies." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLE013/document.
Testo completoAbstract (sommario):
Avec le développement récent des technologies de génotypage à haut débit, l'utilisation des études d'association pangénomiques (GWAS) est devenue très répandue dans la recherche génétique. Au moyen de criblage de grandes parties du génome, ces études visent à caractériser les facteurs génétiques impliqués dans le développement de maladies génétiques complexes. Les GWAS sont également basées sur l'existence de dépendances statistiques, appelées déséquilibre de liaison (DL), habituellement observées entre des loci qui sont proches dans l'ADN. Le DL est défini comme l'association non aléatoire d'allèles à des loci différents sur le même chromosome ou sur des chromosomes différents dans une population. Cette caractéristique biologique est d'une importance fondamentale dans les études d'association car elle permet la localisation précise des mutations causales en utilisant les marqueurs génétiques adjacents. Néanmoins, la structure de blocs complexe induite par le DL ainsi que le grand volume de données génétiques constituent les principaux enjeux soulevés par les études GWAS. Les contributions présentées dans ce manuscrit comportent un double aspect, à la fois méthodologique et algorithmique. Sur le plan méthodologie, nous proposons une approche en trois étapes qui tire profit de la structure de groupes induite par le DL afin d'identifier des variants communs qui pourraient avoir été manquées par l'analyse simple marqueur. Dans une première étape, nous effectuons une classification hiérarchique des SNPs avec une contrainte d'adjacence et en utilisant le DL comme mesure de similarité. Dans une seconde étape, nous appliquons une approche de sélection de modèle à la hiérarchie obtenue afin de définir des blocs de DL. Enfin, nous appliquons le modèle de régression Group Lasso sur les blocs de DL inférés. L'efficacité de l'approche proposée est comparée à celle des approches de régression standards sur des données simulées, semi-simulées et réelles de GWAS. Sur le plan algorithmique, nous nous concentrons sur l'algorithme de classification hiérarchique avec contrainte spatiale dont la complexité quadratique en temps n'est pas adaptée à la grande dimension des données GWAS. Ainsi, nous présentons, dans ce manuscrit, une mise en œuvre efficace d'un tel algorithme dans le contexte général de n'importe quelle mesure de similarité. En introduisant un paramètre $h$ défini par l'utilisateur et en utilisant la structure de tas-min, nous obtenons une complexité sous-quadratique en temps de l'algorithme de classification hiérarchie avec contrainte d'adjacence, ainsi qu'une complexité linéaire en mémoire en le nombre d'éléments à classer. L'intérêt de ce nouvel algorithme est illustré dans des applications GWAS<br>With recent development of high-throughput genotyping technologies, the usage of Genome-Wide Association Studies (GWAS) has become widespread in genetic research. By screening large portions of the genome, these studies aim to characterize genetic factors involved in the development of complex genetic diseases. GWAS are also based on the existence of statistical dependencies, called Linkage Disequilibrium (LD) usually observed between nearby loci on DNA. LD is defined as the non-random association of alleles at different loci on the same chromosome or on different chromosomes in a population. This biological feature is of fundamental importance in association studies as it provides a fine location of unobserved causal mutations using adjacent genetic markers. Nevertheless, the complex block structure induced by LD as well as the large volume of genetic data arekey issues that have arisen with GWA studies. The contributions presented in this manuscript are in twofold, both methodological and algorithmic. On the methodological part, we propose a three-step approach that explicitly takes advantage of the grouping structure induced by LD in order to identify common variants which may have been missed by single marker analyses. In thefirst step, we perform a hierarchical clustering of SNPs with anadjacency constraint using LD as a similarity measure. In the second step, we apply a model selection approach to the obtained hierarchy in order to define LD blocks. Finally, we perform Group Lasso regression on the inferred LD blocks. The efficiency of the proposed approach is investigated compared to state-of-the art regression methods on simulated, semi-simulated and real GWAS data. On the algorithmic part, we focus on the spatially-constrained hierarchical clustering algorithm whose quadratic time complexity is not adapted to the high-dimensionality of GWAS data. We then present, in this manuscript, an efficient implementation of such an algorithm in the general context of anysimilarity measure. By introducing a user-parameter $h$ and using the min-heap structure, we obtain a sub-quadratic time complexity of the adjacency-constrained hierarchical clustering algorithm, as well as a linear space complexity in thenumber of items to be clustered. The interest of this novel algorithm is illustrated in GWAS applications
20
WANG, TAO. "MODELING AND INFERRING QUANTITATIVE TRAIT LOCI USING LINKAGE DISEQUILIBRIUM IN NATURAL POPULATIONS." NCSU, 2001. http://www.lib.ncsu.edu/theses/available/etd-20011012-133341.
Testo completoAbstract (sommario):
<p>Quantitative trait loci (QTL) are those chromosome regions that contribute to variation of quantitative traits. Analysis of QTL is helpful for further study of molecular basis of the quantitative genetic variation. The discovery of highly abundant and dense polymorphic markers (e.g., single nucleotide polynorphisms, or SNPs) covering a whole genome provides an opportunity to localize QTL in a variety of populations. While classical linkage studies have a relatively limited resolution in QTL localization, the association mapping or linkage disequilibrium (LD) mapping approach can offer an alternative way for fine mapping of genes. Currently there are few LD methods available for QTL mapping in natural populations. Development of more efficient methods is still a challenging problem. In this thesis, we first review the LD approach for fine mapping of QTL in Chapter 1. Some basic issues in LD analysis and recent developments in LD methodology are discussed. Particular attention is paid to limitations and potential problems of these methods. This provides the motivation for the research in this thesis.Next, we explore Cockerham's genetic model (Cockerham, 1954) for quantitative traits in Chapter 2. A revised form of the Cockerham model is presented using some coding variables. The relationship between Cockerham model and some specific genetic models for designed experimental populations, such as backcross or F2, is then established. We study extensively the properties of QTL effects and partitions of various genetic variance components for these reduced models under both linkage equilibrium and linkage disequilibrium situations. A general multi-locus-two-allele model is also proposed that may serve as a basis for mapping QTL in natural populations. The main research of the thesis is on development of an exact multipoint likelihood approach to infer QTL in natural populations. In Chapter 3, we first generalize the formulation of the likelihood analysis for a polymorphic marker locus and a trait locus in a general natural population. From this generalization, we derive a closed form solutionof an efficient EM algorithm for the likelihood analysis. This is a major achievement of the research. The importance of this generalization is that it can be readily and systematically extended to multiple markers and multiple QTL.Based on this formulation, a multipoint likelihood analysis with the EM algorithm is developed that can take into account higher-order linkage disequilibria between QTL and markers without making approximation to the likelihood function. This analysis can offer a simultaneous estimation of the linkage disequilibrium structure between a QTL and multiple markers. From this estimation, we find that the linkage disequilibrium between one or a subset of markers and a QTL conditional on other markers can offer as a more accurate measure for fine mapping of QTL. In Chapter 4, we further extend the analysis to multiple QTL and propose a general framework for likelihood analysis of multiple QTL and markers. With this approach, the joint gametic frequencies of QTL and markers (thus various measures of linkage disequilibria between QTL and markers) as well as various genetic effects of QTL (including epistasis) can be estimated simultaneously. This general approach has a lot of potential for a complete analysis of genetic architecture of quantitative traits in natural populations. Although the foundation of this general framework has been laid down, more studies are still needed on a number of issues, such as efficiency and reliability of the optimization algorithm, statistical tests for QTL identification, model selection of complex QTL, and more efficient approaches to analyze large data sets. In the last chapter (Chapter 5), we draw some general conclusions from the research. We discuss the advantages as well as limitations of the approach developed in this thesis and problems for further research.<P>
21
Li, Tao. "Linkage disequilibrium mapping of schizophrenia and related traits in a Chinese population." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416371.
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Jia, Tianye. "Strategies and statistical methods for linkage disequilibrium-based mapping of complex traits." Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3292/.
Testo completoAbstract (sommario):
Nowadays, there are many statistical methods available for genetic association analyses with data various designs. However, it is usually ignored in these analyses that an analytical method must be appropriate for an experimental design from which data is collected. In addition, association study is a population-based analysis and, thus its inference is highly vulnerable to many population-oriented confounding factors. This thesis starts with a comprehensive survey and comparison of those methods commonly used in the literature of genetic association study in order to obtain insights into the statistical aspects and problem of the methods. On the basis of these reviews, we managed to calculate the optimal trend set for the Armitage’s trend test for different penetrance models with a high level of genetic heterogeneity. We introduced two new strategies to adjust for the population stratification in association analyses. We proposed a maximum likelihood estimation method to adjust for biases in statistical inference of linkage disequilibrium (LD) between pairs of polymorphic loci by using non-random samples. In the process of the analysis, we derived a more sophisticated but robust likelihood-based statistical framework, accounting properly for the non-random nature of case and control samples. Finally, we developed a multi-point likelihood-based statistical approach for a genome-wide search for the genetic variants that contribute to phenotypic variation of complex quantitative traits. We tested these methods through intensive simulation studies and demonstrated their application in analyses with large case and control SNP datasets of the Parkinson’s disease. Despite that we have mainly focused on SNP data scored from microarray techniques, the theory and methodology presented here paved a useful stepping stone approach to the modeling and analysis of data depicting genome structure and function from the new generation sequencing techniques.
23
Oudot, Tiphaine. "Recherche de gènes de prédisposition à une maladie à hérédité complexe : le psoriasis." Thesis, Evry-Val d'Essonne, 2009. http://www.theses.fr/2008EVRY0034/document.
Testo completoAbstract (sommario):
Le psoriasis est une maladie complexe inflammatoire et chronique de la peau, due à une forte composante génétique et des facteurs environnementaux. Seule l'implication d'un locus majeur de prédisposition au psoriasis au niveau du chromosome 6p21, nommé PSORS1, a été démontrée dans diverses populations lors d'études de liaison et d'association. Ce locus ne serait responsable que de 30 à 50% de la part génétique. L'objectif de ma thèse était donc d'identifier les autres facteurs génétiques, en particulier dans un échantillon d'une population d'origine française. Pour identifier les loci, une étude de liaison a été réalisée, découvrant des régions potentielles en 12q, 14q, 16p, 20p, en plus de celle en 6p. Deux loci en 6p et 20p ont surtout été étudiés, amenant à la caractérisation de deux gènes, HLA-C et ADAM33. En parallèle, une stratégie de "gènes candidats" a été appliquée, conduisant à suspecter un rôle probable pour les gènes FLG, TGM5, CARD15 et CYLD et à confirmer celui de SLC12A8 dans l'étiologie du psoriasis<br>The psoriasis is a complex chronic inflammatory skin disease due to a strong genetic component as well as environmental factors. The only major locus for psoriasis susceptibility implicated to date, named PSORS1 on chromosome 6p21, has been demonstrated in various populations in linkage and association studies. It could nevertheless be responsible for up to 50% of the genetic contribution to the disease. The aim of my thesis was thus to identify the other genetic factors, in particular in the French population. To identify the loci, a linkage study was carried out, showing possible regions on 12q, 14q, 16p, 20p, in addition to that on 6p. Two loci on 6p and 20p were studied in more detail, revealing the contribution of the two genes, HLA-C and ADAM33. In parallel, a "candidate gene" strategy was undertaken, exposing a probable role of FLG, TGM5, CARD15 and CYLD genes and a confirmed role of SLC12A8 gene in the etiology of psoriasis
24
Lee, Yiu-fai. "Analysis for segmental sharing and linkage disequilibrium a genomewide association study on myopia /." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43912217.
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Adams, David R. "The low-density lipoprotein receptor as a model for studying candidate-locus linkage disequilibrium and allelic association /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/10852.
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Chapman, J. M. "Statistical methods for linkage disequilibrium mapping of disease susceptibility genes in candidate regions." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597484.
Testo completoAbstract (sommario):
Within tightly linked regions of the genome it is often inefficient to genotype and test all polymorphisms for an association with disease since the high degree of linkage disequilibrium causes high levels of redundancy. It has long been suggested that an informative subset of these polymorphisms should be selected as markers for analysis. Within the approach of this thesis, a causal polymorphism takes on the role of a latent variable, generating indirect association between phenotype and marker loci which are in linkage disequilibrium with the causal variant. Locally efficient test statistics are derived using arguments based upon incomplete data likelihood theory and their potential power is investigated. The central chapter sets up a formal mathematical framework on which all subsequent analysis is based, and focusing upon the simple multiplicative model, it investigates how the choice of markers and the degree of haplotype information included may affect the power of the proposed test statistic. The multiplicative disease model is then extended to the dominance model and a test statistic that allows for an indirect dominance effect is derived. The loss or gain in power that may occur in the absence or presence of an underlying dominance effect is examined. The thesis also considers the case of gene-gene interactions and addresses the question: when it is more powerful to test for numerous pairs of possibly interacting loci rather than testing their main effects singularly? This problem is considered in the case of known causal variants and then extended under the latent variable model, deriving a new test statistic in the process. The loss in power caused by allowing for unknown population structure is studied, as is the extent of power lost by analysing pooled genotype data.
27
Lee, Yiu-fai, and 李耀暉. "Analysis for segmental sharing and linkage disequilibrium: a genomewide association study on myopia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43912217.
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28
Jiang, Ning. "Linkage disequilibrium based eQTL analysis and comparative evolutionary epigenetic regulation of gene transcription." Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4031/.
Testo completoAbstract (sommario):
Genome-Wide Association Study (GWAS) has recently been proposed as a powerful strategy for detecting the many subtle genetic variants that underlie phenotypic variation of complex polygenic traits in population-based samples. One of the main obstacles to successfully using the linkage disequilibrium based methods is knowledge of any underlying population structure. The presence of subgroups within a population can result in spurious association. A robust statistical method is developed to remove the population structure interference in GWAS by incorporating single control marker into testing for significance of genetic association of a polymorphic marker (SNP) with phenotypic variance of a complex trait. The novel approach avoids the need of structure prediction which could be infeasible or inadequate in practice and accounts properly for a varying effect of population stratification on different regions of the genome under study. Both intensive computer simulation study and eQTL analysis in genetically divergent human populations show that the new method confers an improved statistical power for detecting genuine genetic association in subpopulations and an effective control of spurious associations stemmed from population structure.
29
Macpherson, James Neil. "Linkage disequilibrium between DNA polymorphisms in a natural population of Drosophila melanogaster Meigen." Thesis, University of Edinburgh, 1989. http://hdl.handle.net/1842/12530.
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30
Schramm, Heather Elizabeth. "Development of mapping by admixture linkage disequilibrium for understanding human complex genetic diseases /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2003. http://uclibs.org/PID/11984.
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Carvalho, Santos Pablo Sandro [Verfasser]. "Linkage disequilibrium and transmission distortion affecting human chromosome 6p / Pablo Sandro Carvalho Santos." Berlin : Freie Universität Berlin, 2010. http://d-nb.info/1025127048/34.
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Jung, Jeesun. "High resolution linkage and association study of quantitative trait loci." Texas A&M University, 2004. http://hdl.handle.net/1969.1/2681.
Testo completoAbstract (sommario):
As a large number of single nucleotide polymorphisms (SNPs) and microsatellite
markers are available, high resolution mapping employing multiple markers or
multiple allele markers is an important step to identify quantitative trait locus (QTL)
of complex human disease. For many complex diseases, quantitative phenotype values
contain more information than dichotomous traits do.
Much research has been done on conducting high resolution mapping using information
of linkage and linkage disequilibrium. The most commonly employed approaches
for mapping QTL are pedigree-based linkage analysis and population-based
association analysis. As one of the methods dealing with multiple alleles markers,
mixed models are developed to work out family-based association study with the information
of transmitted allele and nontransmitted allele from one parent to offspring.
For multiple markers, variance component models are proposed to perform association
study and linkage analysis simultaneously. Linkage analysis provides suggestive
linkage based on a broad chromosome region and is robust to population admixtures.
One the other hand, allelic association due to linkage disequilibrium (LD) usually
operates over very short genetic distance, but is affected by population stratification.
Combining both approaches plays a synergistic role in overcoming their limitations
and in increasing the efficiency and effectiveness of gene mapping.
33
Hyten, David Lee. "Genetic diversity and linkage disequilibrium in wild soybean, landraces, ancestral, and elite soybean populations." College Park, Md. : University of Maryland, 2005. http://hdl.handle.net/1903/2441.
Testo completoAbstract (sommario):
Thesis (Ph. D.) -- University of Maryland, College Park, 2005.<br>Thesis research directed by: Natural Resource Sciences. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
34
Zhu, Guohua. "Ascertainment in two-phase sampling designs for segregation and linkage analysis /." Connect to text online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1112844349.
Testo completoAbstract (sommario):
Thesis (Ph. D.)--Case Western Reserve University, 2005.<br>[School of Medicine] Department of Epidemiology and Biostatistics. Includes bibliographical references. Available online via OhioLINK's ETD Center.
35
Larsson, Hanna. "Population Genetics and Genome Organization of Norway Spruce." Doctoral thesis, Uppsala universitet, Växtekologi och evolution, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-180370.
Testo completoAbstract (sommario):
Understanding the underlying genetic causes of adaptation to local conditions is one of the main goals of population genetics. A strong latitudinal cline in the phenotypic trait of bud set is observed in present day populations of Norway spruce (Picea abies (L.) Karst). The first step towards determining how this strong selection on adaptive traits translates at the loci underlying the trait was to use multilocus sequence data to gain information on the fundamental population genetic properties of Norway spruce. We determined that the level of LD was low and genetic diversity was in the low range. Coalescent simulations revealed a demographic scenario of a fairly old and severe bottleneck as consistent with the observed data. To examine the role of selection at genes putatively involved in the control of bud set we, again, used a multilocus data set to test for deviations from neutrality and demographic scenarios inferred from background loci. Different candidate genes were identified by using different approaches, highlighting the difficulty in predicting how local adaptation will manifest itself on different time scales and in rangewide samples. When examining properties important in the design of association studies, the inevitable next step in identifying genes involved in local adaptation, we found that previous estimates of a low level of LD were highly influenced by the joint analysis of several loci over a large distribution range and that estimates of LD was in fact heterogeneous across loci and increased within populations. In addition, we found that within species tests for deviations from neutral expectations were highly sensitive to sample size. Additional genomic sequence characterization in Norway spruce is necessary to provide more comprehensive sets of markers for association studies, also including gene promoters and non-genic regions of the genome. In the final paper we show that the HMPR method is effective in constructing libraries enriched for the single copy fraction of the genome when applied to the large and dominantly repetitive genome of Norway spruce. In summary, the studies presented in this thesis together constitute a foundation for future studies on adaptive evolution in Norway spruce.
36
Larsson, Hanna, Thomas Kallman, Niclas Gyllenstrand, and Martin Lascoux. "Distribution of Long-Range Linkage Disequilibrium and Tajima's D Values in Scandinavian Populations of Norway Spruce (Picea abies)." Uppsala universitet, Växtekologi och evolution, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-202930.
Testo completoAbstract (sommario):
The site frequency spectrum of mutations (SFS) and linkage disequilibrium (LD) are the two major sources of information in population genetics studies. In this study we focus on the levels of LD and the SFS and on the effect of sample size on summary statistics in 10 Scandinavian populations of Norway spruce. We found that previous estimates of a low level of LD were highly influenced by both sampling strategy and the fact that data from multiple loci were analyzed jointly. Estimates of LD were in fact heterogeneous across loci and increased within individual populations compared with the estimate from the total data. The variation in levels of LD among populations most likely reflects different demographic histories, although we were unable to detect population structure by using standard approaches. As in previous studies, we also found that the SFS-based test Tajima's D was highly sensitive to sample size, revealing that care should be taken to draw strong conclusions from this test when sample size is small. In conclusion, the results from this study are in line with recent studies in other conifers that have revealed a more complex and variable pattern of LD than earlier studies suggested and with studies in trees and humans that suggest that Tajima's D is sensitive to sample size. This has large consequences for the design of future association and population genetic studies in Norway spruce.
37
Kuo, Tai-Yue. "The construction of linkage disequilibrium maps and their application to association mapping of disease genes." Thesis, University of Southampton, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485527.
Testo completoAbstract (sommario):
Success in association mapping of disease genes depends on knowledge of Linkage Disequilibrium (LD) structure in candidate regions. An LD map characterising such structures is constructed by making use of the Malecot model which describes the decline of LD with physical distance based on pairwise measures of association between SNPs. The HapMap project provides a valuable resource that can be used to construct genome-wide LD maps. However, the millions of SNPs in the HapMap data pose a heavy computational challenge. This difficulty can be resolved by excluding the very dist'nt SNP pairs without losing map quality. Modern computational technology with parallel processing can be used to speed up the process of map construction. A composite likelihood approach employing LD maps for association mapping has successfully localised several causal variants. An application to Rheumatoid Arthritis (RA) is described here. This approach, utilising the genome-wide LD map, is very suitable for genome-wide association studies.
38
Backström, Niclas. "Gene Mapping in Ficedula Flycatchers." Doctoral thesis, Uppsala universitet, Institutionen för evolution, genomik och systematik, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9513.
Testo completoAbstract (sommario):
In order to get full understanding of how evolution proceeds in natural settings it is necessary to reveal the genetic basis of the phenotypic traits that play a role for individual fitness in different environments. There are a few possible approaches, most of which stem from traditional mapping efforts in domestic animals and other model species. Here we set the stage for gene mapping in natural populations of birds by producing a large number of anchor markers of broad utility for avian genetical research and use these markers to generate a genetic map of the collared flycatcher (Ficedula albicollis). The map reveals a very high degree of synteny and gene order conservation between bird species separated by as much as 100 million years. This is encouraging for later stages of mapping procedures in natural populations since this means that there is a possibility to use the information from already characterized avian genomes to track candidate genes for detailed analysis in non-model species. One interesting aspect of the low degree of rearrangements occurring in the avian genomes is that this could play a role in the low rate of hybridization barriers formed in birds compared to for instance mammals. An analysis of Z-linked gene markers reveals relatively long-range linkage disequilibrium (LD) in collared flycatchers compared to other outbred species but still, LD seems to decay within < 50 kb indicating that > 20.000 markers would be needed to cover the genome in an association scan. A detailed scan of 74 Z-linked genes evenly distributed along the chromosome in both the collared flycatcher and the pied flycatcher (Ficedula hypoleuca) indicates that there are regions that evolve under directional selection, regions that might harbor loci of importance for adaptive divergence and/or hybrid inviability.
39
Pungliya, Manish S. "Single nucleotide polymorphism analysis in application to fine gene mapping." Digital WPI, 2001. https://digitalcommons.wpi.edu/etd-theses/642.
Testo completoAbstract (sommario):
Single nucleotide polymorphisms (SNPs) are single base variations among groups of individuals. In order to study their properties in fine gene mapping, I considered their occurrence as transitions and transversions. The aim of the study was to classify each polymorphism depending upon whether it was a transition or transversion and to calculate the proportions of transitions and transversions in the SNP data from the public databases. This ratio was found to be 2.35 for data from the Whitehead Institute for Genome Research database, 2.003 from the Genome Database, and 2.086 from the SNP Consortium database. These results indicate that the ratio of the numbers of transitions to transversions was very different than the expected ratio of 0.5. To study the effect of different transition to transversion ratios in fine gene mapping, a simulation study was performed to generate nucleotide sequence data. The study investigated the effect of different transition to transversion ratios on linkage disequilibrium parameter (LD), which is frequently used in association analysis to identify functional mutations. My results showed no considerable effect of different transition to transversion ratios on LD. I also studied the distribution of allele frequencies of biallelic SNPs from the Genome Database. My results showed that the most common SNPs are normally distributed with mean allele frequency of 0.7520 and standard deviation of 0.1272. These results can be useful in future studies for simulating SNP behavior. I also studied the simulated data provided by the Genetic Analysis Workshop 12 to identify functional SNPs in candidate genes by using the genotype-specific linkage disequilibrium method.
40
Liu, Jin. "Penalized methods in genome-wide association studies." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/1242.
Testo completoAbstract (sommario):
Penalized regression methods are becoming increasingly popular in genome-wide association studies (GWAS) for identifying genetic markers associated with disease. However, standard penalized methods such as the LASSO do not take into account the possible linkage disequilibrium between adjacent markers. We propose a novel penalized approach for GWAS using a dense set of single nucleotide polymorphisms (SNPs). The proposed method uses the minimax concave penalty (MCP) for marker selection and incorporates linkage disequilibrium (LD) information by penalizing the difference of the genetic effects at adjacent SNPs with high correlation. A coordinate descent algorithm is derived to implement the proposed method. This algorithm is efficient and stable in dealing with a large number of SNPs. A multi-split method is used to calculate the p-values of the selected SNPs for assessing their significance. We refer to the proposed penalty function as the smoothed MCP (SMCP) and the proposed approach as the SMCP method. Performance of the proposed SMCP method and its comparison with a LASSO approach are evaluated through simulation studies, which demonstrate that the proposed method is more accurate in selecting associated SNPs. Its applicability to real data is illustrated using data from a GWAS on rheumatoid arthritis. Based on the idea of SMCP, we propose a new penalized method for group variable selection in GWAS with respect to the correlation between adjacent groups. The proposed method uses the group LASSO for encouraging group sparsity and a quadratic difference for adjacent group smoothing. We call it smoothed group LASSO, or SGL for short. Canonical correlations between two adjacent groups of SNPS are used as the weights in the quadratic difference penalty. Principal components are used to reduced dimensionality locally within groups. We derive a group coordinate descent algorithm for computing the solution path of the SGL. Simulation studies are used to evaluate the finite sample performance of the SGL and group LASSO. We also demonstrate its applicability on rheumatoid arthritis data.
41
Graham, Jinko. "Disequilibrium fine-mapping of a rare allele via coalescent models of gene ancestry /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/9568.
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Lõhmussaar, Elin. "The comparative patterns of linkage disequilibrium in European populations and its implication for genetic association studies /." Tartu, Estonia, 2006. http://dspace.utlib.ee/dspace/bitstream/10062/978/5/lohmussaar.pdf.
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43
Tenesa-Prunyonosa, Albert. "Population-wide linkage disequilibrium and its uses in QTL mapping and estimation of ancestral population size." Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/11451.
Testo completoAbstract (sommario):
The extent of LD was studied in two population, a dairy cattle population from the United Kingdom (UK) and a human isolated Sardinian population. For the dairy cattle population, data from 50 young bulls were available. These bulls were typed at 6 markers on chromosome 2 and 7 markers on chromosome 6, spanning 38 and 20 cM, respectively. LD extended to about 10 cM between pairs of loci in syntenic groups. Given the observed level of LD, mapping methods based upon population-wide association might provide better resolution than linkage methods in the UK dairy cattle population, as well as reduce the required sample sizes of the experiments. For the human population, 381 individuals typed at 22 markers on chromosome 19 were studied. High levels of disequilibrium were found that extended to 8 cM, when based on the LD measure D’, and 11 cM when based on the significance level of the allelic association. It was also shown, using bootstrapping, that small sample sizes can overestimate both the mean value of D’ and its variance by up to factors of about 3 and 23, respectively, when the sample size decreases from 381 to 25 individuals. Due to the high sampling variance of LD measures, the use of at least 200 unrelated individuals when characterizing the extent of LD is recommended. Three different strategies and study designs to map quantitative trait loci (QTL) using LD were studied using analytical methods and computer simulation. Finally, published data from human chromosomes 22 and 19 was used to infer past effective population size in a population of European ancestry. To do so, the extent of LD was first estimated using a multilocus measure of LD, the chromosome segment homozygosity (CSH). Results suggest that this population has had an average effective population size of around 4500 breeding individuals for approximately the last 4500 generations. This population had a relatively constant size (of between 3000 and 5000 individuals) from about 130000 years ago to about 2000 years ago, when it expanded to more than 10000 individuals.
44
Varilo, Teppo. "[The]age of the mutations in the Finnish disease heritage : a genealogical and linkage disequilibrium study." Helsinki : University of Helsinki, 1999. http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/varilo/.
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Liu, Lian. "Topics in measurement error and missing data problems." Thesis, [College Station, Tex. : Texas A&M University, 2007. http://hdl.handle.net/1969.1/ETD-TAMU-1627.
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Söderholm, Simon. "The Complex Genetics of Multiple Sclerosis : A preliminary study of MS-associated SNPs prior to a larger genotyping project." Thesis, Linköpings universitet, Institutionen för fysik, kemi och biologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-129423.
Testo completoAbstract (sommario):
Biomedical research have been revolutionized by recent technological advances, both in the fields of molecular biology and computer science, turning the biomolecular and genetic research into “big data science”. One of the main objectives have been to improve our understanding of complex human diseases. Among those diseases, multiple sclerosis (MS) is considered as one of the most common. MS is a chronic autoimmune disease that cause inflammation and damage to the central nervous system. In this study, a set of bioinformatics analyses have been conducted on SNP data, as an initial step to gain more information prior to an upcoming genotyping project. The results showed extensive regulatory properties for the 761 selected SNPs, which is consistent with current scientific knowledge, and also identified another 332 SNPs in linkage to these. However, during the study some issues have also been identified, which need to be addressed going forward.
47
Doecke, James. "Genetic variation in Runx2 related to bone mineral density." Thesis, Griffith University, 2006. http://hdl.handle.net/10072/367841.
Testo completoAbstract (sommario):
The main hypotheses tested within this research focussed on the identification of polymorphisms within Runx2, and the classification of these with respect to bone mineral density (BMD). A separate set of hypotheses focussed upon the effects of calcium treatment in an elderly population, to identify any differences in BMD, bone mineral content (BMC) and bone area between the specific genotypes identified. The initial research strategy included taking subjects’ from the extremes of a population to identify alleles specifically related to the bone mineral density trait. The idea was tested using Runx2, the well known osteoblast transcription factor. From a population of 1300 subjects (from the Geelong Osteoporosis Study: the GOS) the age-weight adjusted femoral neck BMD was ranked and the upper and lower deciles taken to represent the adjusted extremes. After adjusting and ranking, the two groups (n=130 each) were not significantly different for age or weight. In these 260 subjects, we identified 16 allelic variations within the Runx2 gene and gene promoters (P1 and P2), and characterized these novel variations with respect to BMD strata by genotype using DHPLC.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Medical Science<br>Griffith Health<br>Full Text
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Soliai, Marcus Makina. "De novo Genome Assembly and SNP Marker Development of Pyrenophora semeniperda." BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/2960.
Testo completoAbstract (sommario):
Pyrenophora semeniperda (anamorph Drechslera campulata) is a necrotrophic fungal seed pathogen of a variety of grass genra and species, including Bromus tectorum, an exotic grass that has invaded many natural ecosystems of the U.S. Intermountain West. As a natural seed pathogen of B. tectorum, P. semeniperda has potential as a biocontrol agent due to its effectiveness at killing dormant B. tectorum seeds; however, few genetic resources exist for this fungus. Here, the genome assembly of a P. semeniperda isolate using 454 GS-FLX genomic and paired-end pyrosequencing techniques is presented. The total assembly is 32.5 Mb and contains 11,453 gene models greater than 24 amino acids. The assembly contains a variety of predicted genes that are involved in pathogenic pathways typically found in necrotrophic fungi. In addition, 454 sequence reads were used to identify single nucleotide polymorphisms between two isolates of P. semeniperda. In total, 20 SNP markers were developed for the purposes of recombination assesment of 600 individual P. semeniperda isolates representing 36 populations from throughout the U.S. Intermountain West. Although 17 of the fungal populations were fixed at all SNP loci, linkage disequilibrium was determined in the remaining 18 populations. This research demonstrates the effectiveness of the 454 GS-FLX sequencing technology, for de novo assembly and marker development of filamentous fungal genomes. Many features of the assembly match those of other Pyrenophora genomes including P. tritici-repentis and P. teres f. teres, which lend validity to our assembly. These findings present a significant resource for examining and furthering our understanding of P. semeniperda biology.
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Gibson, Jane. "Defining linkage disequilibrium patterns and tracts of extended homozygosity to compare populations and search for disease genes." Thesis, University of Southampton, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509463.
Testo completo
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Chretien, Jean-Paul. "Genetic mapping of between-population variation using mapping by admixture linkage disequilibrium methodology and application to lipoprotein(A) /." Available to US Hopkins community, 2003. http://wwwlib.umi.com/dissertations/dlnow/3080642.
Testo completo