No description available.

SNP (single nucleotide polymorphisms, pronounce as snip) is one nucleotide position difference within human population. These differences can be detected in human genome and the difference occurs once about every 1000 base pairs. There are only two possible nucleotides in each SNP position. As a genetic marker, SNP data can be used to capture human disease traits because of its abundance and low diversity. In recent research results, it has been shown that there is a block-like structure in human genome, and only limited haplotype diversity can be observed. Consequently, we can use only a small fraction of SNPs to capture haplotype diversity in each block, and these SNPs are called tagSNPs. We propose a fixed-diversity approach to capture the diversity of the entire data. After partitioning the haplotype blocks, we will provide an objective way for evaluating the result. We obtain that the diversity of chromosome 21 SNPs locates at 0.5 by using our algorithm. The partition result shows the concurrence property of the haplotype data downloaded from NCBI web site. Finally, we develop an algorithm for tagSNP selection within each block, and obtain the compression ratio 0.78.

Nous présentons un nouveau formalisme et des nouvelles méthodes pour modéliser le déséquilibre de liaison et tenir compte de la structure en haplotypes pour les données issues de la génomique des populations. La modélisation repose sur un problème d'optimisation avec contraintes qui est résolue avec un algorithme de programmation dynamique. Les méthodes établies ont toutes l'avantage d'avoir un coût algorithmique linéaire et donc de pouvoir traiter de grands jeux de données.Dans un premier temps, nous avons appliqué notre approche à l'étude des populations métisses et plus particulièrement au problème d'inférence des coefficients de métissage locaux.Notre méthode a été appliquée à des génotypes simulés de métissage humain ainsi qu'à des vrais génotypes obtenus dans des populations métisses de peupliers.Dans un second temps, nous avons développé notre formalisme d'optimisation pour traiter de l'inférence des haplotypes à partir des génotypes d'une population.L'ensemble de ces méthodes d'optimisation a été développé dans un module Python qui s'appelle Loter. / We present a new formalism and new methods to model linkage disequilibrium and to account for haplotype structure of population genomics data. Modeling relies on an optimization problem with constraints that is solved using dynamic programming. The algorithmic cost of proposed methods is linear, which is a desirable property to process large datasets.First, we applied our framework to study admixed populations and perform local ancestry inference. Our method is applied to simulated genotypes of admixed human populations and to real genotypes from admixed Populus species.Second, we developed our optimization framework to perform haploptype phasing and imputation based on a population of genotypes. All optimization methods have been developed in a Python package called Loter.

No description available.

No description available.

The purpose of this thesis is to explore methodology concerning Markov Chain Monte Carlo (MCMC), a powerful technique in the Bayesian framework, on binary variables. The primary application of interest in this thesis is applying this methodology to phase haplotypes, a type of categorical variable. Haplotypes are the combination of variants present in an individual’s genome. Phasing refers to estimating the true haplotype. By considering only biallelic and heterozygous variants, the haplotype can be expressed as a vector of binary variables. Accounting for differences in haplotypes is essential for the study of associations between genotype and disease. MCMC is an extremely popular class of statistical methods for simulating autocorrelated draws from target distributions, including posterior distributions in Bayesian analysis. Techniques for sampling categorical variables in MCMC have been developed in a variety of disparate settings. Samplers include Gibbs, Metropolis-Hastings, and exact Hamiltonian based samplers. A review of these techniques is presented and their relevance to the genetic model discussed. An important consideration in using simulated MCMC draws for inference is that they have converged to the distribution of interest. Since the distribution is typically of a non-standard form, convergence cannot generally be proven and, instead, is assessed with convergence diagnostics. The convergence diagnostics developed so far focus on continuous variables and may be inappropriate for binary variables or categorical variables in general. Two convergence diagnostics are proposed that are tailor-made for categorical variables by modeling the data using categorical time series models. Performance of the convergence diagnostics is evaluated under various simulations. The methodology developed in the thesis is applied to estimate haplotypes. There are two main challenges involved in accounting for haplotype differences. One is estimating the true combination of genetic variants on a single chromosome, known as haplotype phasing. The other is the phenomenon of allele-specific expression (ASE) in which haplotypes can be expressed non-equally. No existing method addresses these two intrinsically linked challenges together. Rather, current strategies rely on known haplotypes or family trio data, i.e. having data on subject of interest and their parents. A novel method is presented, named IDP-ASE, which is capable of phasing haplotypes and quantifying ASE using only RNA-seq data. This model leverages the strengths of both Second Generation Sequencing (SGS) data and Third Generation Sequencing (TGS) data. The long read length of TGS data facilitates phasing, while the accuracy and depth of SGS data facilitates estimation of ASE. Moreover, IDP-ASE is capable of estimating ASE at both the gene and isoform level.

Otitis Media is one of the most common childhood diseases. Recurrent acute otitis media RAOM is characterized by repeated episodes of inflammation of the middle ear in conjunction with middle ear fluid, and often with an inflamed or bulging eardrum. Defective clearance by the Eustachian tube results in mucus build-up and is characteristic of otitis media with effusion (OME). Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, respiratory syncytial virus, and rhinovirus are the most common contributors to otitis media pathogenesis. In New Zealand, OME has been implicated with conductive hearing loss in childhood and has been shown to significantly impact on speech and language development. New Zealand Māori and Polynesian children have displayed significantly higher hearing test failure rates than European-Caucasian children. The collectins, Surfactant Protein (SP)-A and -D are encoded by three genes (SP-A1, SP-A2, and SP-D) and are host defense proteins present in the middle ear and Eustachian tube. Single nucleotide polymorphisms (SNPs) in SP-A1 and SP-A2 have been associated with increased or decreased susceptibility to otitis media, meningococcal disease, and range of respiratory diseases. Using allele-specific primers and real-time PCR with SYBR Green I melting curve analysis, four groups of individuals were genotyped for eleven SP-A1, SP-A2, and SP-D SNPs: European-Caucasian individuals with RAOM/OME; New Zealand Māori/Polynesian individuals with RAOM/OME; individuals with meningococcal disease; and a control group. The computer program, Haploview, was employed to perform χ2 analyses and identify statistically significant associations of alleles/haplotypes with RAOM/OME or meningococcal disease. In the European-Caucasian population, two SP-A1 alleles, one SP-A2 allele, and four haplotypes (CGAGC, 1A3, 1A9, and 1A10) were found to be associated with increased risk of RAOM/OME (P lt; 0.05). Conversely, haplotypes 6A2 and 1A2 were found to be protective against susceptibility to RAOM/OME (P lt; 0.05). In New Zealand Māori and Polynesian individuals, two SP-A1 alleles, three SP-A2 alleles, one SP-D allele, and four haplotypes (6A8, 6A10, 1A3, and 1A10) were found to be associated with increased risk of RAOM/OME (P lt; 0.05). An additional four haplotypes (6A2, 1A0, 1A2, and TA) were determined to be protective against susceptibility to RAOM/OME (P lt; 0.05). However, protective SPA1/SPA2/SPD haplotype 6A2-1A0-TA was significantly under-represented in the New Zealand Māori and Polynesian population (P lt; 0.05). A single allele and haplotype were associated with increased risk of meningococcal disease (P lt; 0.05). The findings of this study confirm that specific genetic variants of SP-A and SP-D are associated with either increased or decreased risk of developing RAOM and/or OME. Furthermore, it was demonstrated that New Zealand Māori and Polynesian individuals appear to exhibit more haplotypes susceptible to RAOM/OME. This may provide a partial explanation for the higher RAOM/OME-related failure rates of hearing tests in New Zealand Māori and Polynesian children. However, there are numerous socio-economic and environmental factors that also contribute to otitis media pathogenesis which were not considered in this study. The effects of the SP-A1, SP-A2, and SP-D alleles and haplotypes on the bacterial/viral binding efficiencies of SP-A and SP-D need to be investigated by further research, using a large population, to confirm the association with susceptibility or resistance with RAOM/OME.

The most intriguing problems in genetics epidemiology are to predict genetic disease susceptibility and to associate single nucleotide polymorphisms (SNPs) with diseases. In such these studies, it is necessary to resolve the ambiguities in genetic data. The primary obstacle for ambiguity resolution is that the physical methods for separating two haplotypes from an individual genotype (phasing) are too expensive. Although computational haplotype inference is a well-explored problem, high error rates continue to deteriorate association accuracy. Secondly, it is essential to use a small subset of informative SNPs (tag SNPs) accurately representing the rest of the SNPs (tagging). Tagging can achieve budget savings by genotyping only a limited number of SNPs and computationally inferring all other SNPs. Recent successes in high throughput genotyping technologies drastically increase the length of available SNP sequences. This elevates importance of informative SNP selection for compaction of huge genetic data in order to make feasible fine genotype analysis. Finally, even if complete and accurate data is available, it is unclear if common statistical methods can determine the susceptibility of complex diseases. The dissertation explores above computational problems with a variety of methods, including linear algebra, graph theory, linear programming, and greedy methods. The contributions include (1)significant speed-up of popular phasing tools without compromising their quality, (2)stat-of-the-art tagging tools applied to disease association, and (3)graph-based method for disease tagging and predicting disease susceptibility.

This study focuses how the MLR-tagging for statistical covering, i.e. either maximizing average R2 for certain number of requested tags or minimizing number of tags such that for any non-tag SNP there exists a highly correlated (squared correlation R2 > 0.8) tag SNP. We compare with tagger, a software for selecting tags in hapMap project. MLR-tagging needs less number of tags than tagger in all 6 cases of the given test sets except 2. Meanwhile, Biologists can detect or collect data only from a small set. So, this will bring a problem for scientists that the estimates accuracy of tag SNPs when constructing the complete human haplotype map. This study investigates how the MLR-tagging for statistically coverage performs under unbias study. The experiment results shows MLR-tagging still select small amount of SNPs very well even without observing the entire SNP in the sample.

Orientador: Jose Eduardo Tanus dos Santos / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-14T19:43:36Z (GMT). No. of bitstreams: 1 Muniz_JaquelineJoice_M.pdf: 1631017 bytes, checksum: 07857094129c2a3044916bda7b45c0d5 (MD5) Previous issue date: 2009 / Resumo: O Fator de Crescimento Endotelial Vascular (VEGF, ou também conhecido como VEGF-A), é uma glicoproteína homodimérica de 45KDa que é produzida principalmente em células endoteliais em condições de hipóxia. VEGF leva a proliferação, migração e sobrevivência de células endoteliais; desenvolve um papel importante na regulação da permeabilidade vascular e angiogênese, tanto fisiológica como fisiopatológica, além de outras atividades biológicas, como vasodilatação, vasculogênese e homeostase vascular. Enquanto muitos SNPs (polimorfismos de base única) estão presentes no gene do VEGF, três SNPs clinicamente significantes localizados na região promotora do gene (C-2578A, G-1154A e G-634C) têm sido associados a várias doenças cardiovasculares. Porém associações inconsistentes entre esses polimorfismos e doenças cardiovasculares têm sido encontradas. Essas diferenças podem ser uma conseqüência da diversidade étnica, que leva a uma distribuição desproporcional dos variantes do gene do VEGF entre grupos étnicos. Embora alguns estudos sugiram que haja uma diferença na distribuição destes SNPs, nenhum estudo prévio analisou esta hipótese em populações miscigenadas. Nós analisamos a distribuição destes três SNPs em 175 brancos e 185 negros brasileiros, avaliamos também a distribuição haplotípica e a associação entre as variantes desses SNPs. O alelo C-2578 e o alelo G-1154 foram mais comuns em indivíduos negros do que brancos (71% e 61%, respectivamente), enquanto para o SNP G-634C não houve diferença quanto a frequência alélica e genotípica entre os dois grupos étnicos. O haplótipo contendo os alelos C-2578/G-1154/G-634 foi o mais comum em ambos grupos étnicos e também o mais freqüente em negros comparados a brancos. O haplótipo contendo os alelos C-2578/A-1154/C-634 e o haplótipo contendo os alelos C-2578/A-1154/G-634 foram mais frequentes em indivíduos brancos do que em negros. Estes resultados mostraram diferenças na distribuição de variantes genéticas e haplótipos do gene do VEGF relevantes clinicamente quando brancos e negros são comparados. Estas diferenças podem explicar, no mínimo em parte, os resultados inconsistentes em estudos de associação desses SNPs com doenças cardiovasculares e, as diferenças interétnicas na suscetibilidade a doenças cardiovasculares / Abstract: Vascular Endothelial Growth Factor (VEGF, or also known as VEGF-A) is a homodimeric glycoprotein of 45kDa produced mostly in endothelial cells in hypoxic conditions. VEGF leads to proliferation, migration and survival of endothelial cells, plays an important role in regulating vascular permeability and angiogenesis, both physiological and pathophysiological and other biological characteristics such as vasodilation, vasculogenesis and vascular homeostasis. While many Single Nucleotides Polimporphisms (SNPs) are present in the VEGF gene, three clinically significant SNPs in the promoter region of the gene (C-2578A, G-1154A and G-634C) have been associated with cardiovascular diseases, however inconsistent associations have been found between these polymorphisms and cardiovascular diseases. These differences may be a consequence of ethnic diversity, which leads to a distinct distribution of VEGF gene variants between ethnic groups. Although some studies suggest difference in the distribution of these SNPs, no previous study has examined this hypothesis in admixed populations. We examined the distribution of these three SNPs in 175 white and 185 black Brazilian subjects, we have also evaluated haplotype distribution and the association between variants of these SNPs. The C-2578 and G-1154 alleles were more frequent in black subjects than in white (71% and 61% respectively), while for the G-634C SNP no differences in allele and genotype frequencies were found between the two ethnic groups. The haplotype containing the alleles C-2578/G-1154/ G-634 was the most common in both ethnic groups and was more common in blacks compared to whites. The haplotype containing the alleles C-2578/A-1154/C-634 and the haplotype containing the alleles C-2578/A-1154/G-634 were more frequent in whites compared to blacks. These results showed differences in the distribution of clinically relevant genetic variants and haplotypes of VEGF gene when whites and blacks are compared. These differences may explain, at least in part, the inconsistent results in studies of association of these SNPs with cardiovascular disease, and ethnic disparities in susceptibility to cardiovascular disease / Mestrado / Mestre em Farmacologia