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The role of the NS segment of Influenza A virus in setting host range and pathogenicityTurnbull, Matthew Luke January 2017 (has links)
Influenza A virus (IAV) circulates in waterfowl, causing mostly asymptomatic infections. IAV can undergo host adaptation and evolve to cause significant disease and mortality in domestic poultry and mammals, applying an enormous socio-economic burden on society. Sporadically, IAV causes global pandemics in man due to its zoonotic nature, and this can result in millions of deaths worldwide during a single outbreak. Host adaptation of IAV is an incompletely understood phenomenon, but is known to involve both host and viral determinants. It is essential to improve the understanding of the factors governing host range and pathogenicity of avian IAV, especially given the absence of a universal influenza vaccine and a limited weaponry of effective antiviral compounds. This study set out to improve the understanding of host adaptation of avian IAV, focussing on segment 8 (NS segment) of the virus genome. The NS segment of non-chiropteran IAV circulates as two phylogenetically distinct clades – the ‘A-’ and ‘B-alleles’. The A-allele is found in avian and mammalian viruses, but the B-allele is considered to be almost exclusively avian. This might result from one or both of the major NS gene products (NS1 and NEP) being non-functional in mammalian host cells, or from an inability of segment 8 RNA to package into mammalian-adapted strains. To investigate this, the NS segments from a panel of avian A- and B-allele strains were introduced into human H1N1 and H3N2 viruses by reverse genetics. A- and B-allele reassortant viruses replicated equally well in a variety of mammalian cell types in vitro. Surprisingly, the consensus B-allele segment 8 out-competed an A-allele counterpart when reassortant H1N1 viruses were co-infected, with the parental WT segment 8 being most fit in this system. A- and B-allele NS1 proteins were equally efficient at blocking the mammalian IFN response both in the context of viral infection and in transfection-based reporter assays. Consensus A- and B-allele H1N1 viruses also caused disease in mice and replicated to high virus titre in the lung. Interestingly, the B-allele virus induced more weight-loss than the A-allele, although the parental WT virus was most pathogenic in vivo. To re-address the hypothesis that B-allele NS genes really are avian-restricted, the relative rates of independent Aves to Mammalia incursion events of A- and B-allele lineage IAV strains was estimated and compared using phylogenetic analyses of all publically available segment 8 sequences. 32 A-allele introduction events were estimated compared to 6 B-allele incursions, however the total number of avian Aallele sequences outnumbered B-allele sequences by over 3.5 to 1, and the relative rates of introduction were not significantly different across the two lineages suggesting no bias against avian B-allele NS segments entering mammalian hosts in nature. Therefore, this study provides evidence that avian B-allele NS genes are not attenuating in mammalian hosts and are able to cause severe disease. Thus, this lineage of IAV genes, previously assumed to be avian-restricted, should be considered when assessing zoonotic potential and pandemic risk of circulating avian IAVs.
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Allele sharing method for fine mapping linkage loci : application to bipolar affective disorderLee, Andrew J. January 2009 (has links)
Large family studies of complex disorders can be used to detect a genomic region linked with a particular illness. Where multiple families are found with common regions of linkage, this could be due to an ancestral mutation common to these families. In this thesis, I describe a method for studying allele sharing in families that share a linkage region, to identify a common founder mutation, thus maximising the results of replicated linkage studies. The method tests the hypothesis that the evidence for shared linkage is derived from the sharing of a common affected ancestor. By comparing the allelic similarity of haplotypes across common linkage regions, it is possible to identify any regions that are identical by descent between the families. A method of permutation analysis followed by a nested permutation technique have been developed to assess the statistical significance of allele sharing scores. Chapter 3 describes the proof of principle of the method through its application to known cystic fibrosis mutations and through simulated datasets. This provides both a real dataset and a much more diverse range of simulated conditions on which to test the method. The range of simulated data was also used to develop a set of criteria for the effective us of the method. In Chapter 4, the allele sharing method was applied to two replicated linkage regions on chromosome 4p15-16 that segregate with bipolar affective disorder. This was done over two phases, first taking in markers covering the genic regions of the shared linkage region and then followed up with a complete coverage of the region. This analysis identified a 200kb region with significant confidence within the 8Mb of the two linkage regions. The study of this region presents a clear example of how replicated linkage results that are caused by some founder effect, can be examined, and refined using this allele sharing method to vastly reduce the region under investigation.
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Haplotype evolution and human genetic diversityRogers, Emma Jayne January 2000 (has links)
No description available.
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Selective crossover as an adaptive strategy for genetic algorithmsVekaria, Kanta Premji January 2000 (has links)
No description available.
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MCMC sampling methods for binary variables with application to haplotype phasing and allele specific expressionDeonovic, Benjamin Enver 01 May 2017 (has links)
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.
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The role of warfarin pharmacogenomics on the time it takes to reach stable therapeutic International Normalized Ratio (INR) and on warfarin dose required to maintain stable therapeutic INR in Black African and Mixed Ancestry South Africans: a focus on CYP2C9 and VKORC1Makambwa, Edson 20 February 2020 (has links)
Warfarin, the most commonly prescribed anticoagulant, is principally metabolized by cytochrome P450 2C9 which functions by inhibiting the Vitamin K epoxide reductase. Genes CYP2C9 and VKORC1 code for these two proteins, respectively. CYP2C9 and VKORC1 exhibit genetic polymorphisms that have been shown to affect warfarin response and favorably facilitate warfarin dosing and improve clinical outcomes. However, none of these studies have involved populations from sub-Saharan Africa where the potential benefit of optimal dosing and reduced complications is greatest. Therefore, the thesis describes a study designed to investigate the role of genetic variations in CYP2C9 and VKORC1 on the time taken to reach a stable therapeutic international normalized ratio (INR) and warfarin dose required to maintain a therapeutic INR. This was a cross-sectional study of patients on warfarin to determine the relationship between genetic polymorphism in CYP2C9 and VKORC1 amongst black and mixed ancestry South Africans and clinical surrogates of warfarin metabolism. Medical records were accessed to determine time to INR and warfarin doses. DNA was extracted from blood samples, and genotyping for polymorphism in CYP2C9 (*2,*3,*8,*11) and VKORC1 (1173C>T, 1639G>A, 3730G>A) was accomplished by PCR-RFLP, Sanger sequencing and iPlex Mass Sequencing. Our results show that the genetic profile of CYP2C9 and VKORC1 differs between Black Africans (BA) and their Mixed Ancestry (MA) counterparts. VKORC1-1639AA genotype was observed at frequencies of 0.11 and 0.01 in the MA and BA, respectively. Time to stable INR was not influenced by CYP2C9 and VKORC1. Furthermore, compared to known genetic polymorphisms in these genes from population out of Africa, both qualitative and quantitative differences were observed. Finally, we found that VKORC1 genetic variation significantly affected the doses of warfarin in MA but had no effect in BA. These results suggest that further research in this area is warranted, and that it will be important to include populations from sub-Saharan Africa in future if the potential to develop personalized algorithms which integrate pharmacogenomics to assist with effective warfarin dosing and prevention of warfarin related complications is to be realized.
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Genetic Susceptibility in Alzheimer’s Disease and the Role of Lipid MetabolismMiller, Katherine 17 January 2007 (has links)
No description available.
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Allele Fequency Distribution and Its Implication in Association StudiesXi, Huifeng January 2008 (has links)
No description available.
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Simulerad effektivisering av genotypdataanalys genom poolade data / Simulated optimization of genotype data analysis bypooling dataStrömstedt Hallberg, Simon, Giek, Jonas January 2016 (has links)
Målet med projektet är att undersöka om det går att effektivisera hur man undersöker människors gener. Detta görs genom att skapa ett program i Java. Resultatet är ett program som sorterar genotypdata från 1000 Genomes Project och utvärderar nyttan av att undersöka genotyper från flera individer samtidigt.
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Dna Profiling of Captive Roseate Spoonbill (Ajaia Ajaja) Populations As a Mechanism of Determining Lineage in Colonial Nesting Birds.Sawyer, Gregory M. 05 1900 (has links)
Roseate spoonbills are colonial nesting birds with breeding grounds extending from the United States Gulf coast to the pampas of Argentina. The U.S. population suffered a severe bottleneck from 1890 to 1920. The population's recovery was slow and partially credited to migrations from Mexican rookeries, but a gene pool reduction would be expected. Five polymorphic Spoonbill autosomal short tandem repeat (STR) loci [three (GAT)n, one (AAAG)n and one (GT)n] and one Z/W-linked microsatellite exhibiting sex-specific dimorphism were isolated and characterized. The Z/W-linked STR locus accurately confirmed the sex of each bird. Allelic profiles for 51 spoonbills obtained from Dallas (Texas), Fort Worth (Texas) and Sedgwick County (Kansas) zoos revealed a non-continuous distribution of allele frequencies, consistent with the effects of a population bottleneck. Allelic frequencies also differed significantly between the isolated zoo populations. Although extra-pair copulations were suspected and difficult to document, zoos commonly used observational studies of mating pairs to determine familial relationships among adults and offspring. STR parentage analysis of recorded family relationships excluded one or both parents in 10/25 cases studied and it was further possible to identify alternative likely parents in each case. Mistaken familial relationships quickly lead to the loss of genetic variability in captive populations. Here, a decreased heterozygosity (HO) in 2nd generation captive-bred birds was observed at 3 out of 4 loci evaluated. Although these results could not be statistically validated because of the small number of individuals available for study (15 wild birds with no offspring vs. eight 2nd generation captive birds), they are considered biologically important, as decreased HO is an indicator of inbreeding and this apparent decrease occurred within two generations of removal from the wild. Collectively, the evidence obtained from this study suggests that captive spoonbill populations are experiencing rapid loss of diversity from an already depleted wild gene pool.
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