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Investigating Genetic Diversity of Phytophthora spp. and Related OomycetesHulvey, Jonathan Patrick 01 August 2010 (has links)
Oomycetes, like fungi, are filamentous heterotrophs, but unlike true fungi are diploid and share a photosynthetic ancestor. Many of these organisms are plant and animal pathogens, and members of the genus Phytophthora cause devastating disease on a diverse array of agricultural plant hosts. Several diverse topics in oomycete biology are investigated in this dissertation. Chapter 2 is a report on loss of heterozygosity in Phytophthora capsici in response to chemical mutagenesis.The research presented in Chapters 3 and 4 are centered on documenting biodiversity and genetic diversity of populations of Phytophthora species obtained from infected plant hosts. The final chapter (Chapter 5) involves determining genetic diversity, ecology, and enzymatic activities of Pythiaceous oomycetes from marsh wetlands of the southeastern US.
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Genetic association analysis incorporating intermediate phenotypes information for complex diseasesLi, Yafang 01 December 2011 (has links)
Genome-wide association (GWA) studies have been successfully applied in detection of susceptibility loci for complex diseases, but most of the identified variants have a large to moderate effect, and explain only a limited proportion of the heritability of the diseases. It is believed that the majority of the latent risk alleles have very small risk effects that are difficult to be identified and GWA study may have inadequate power in dealing with those small effect variants. Researchers will often collect other phenotypic information in addition to disease status to maximize the output from the study. Some of the phenotypes can be on the pathway to the disease, i.e., intermediate phenotype. Statistical methods based on both the disease status and intermediate phenotype should be more powerful than a case-control study as it incorporates more information. Meta-analysis has been used in genetic association analysis for many years to combine information from multiple populations, but never been used in a single population GWA study. In this study, simulations were conducted and the results show that when an intermediate phenotype is available, the meta-analysis incorporating the disease status and intermediate phenotype information from a single population has more power than a case-control study only in GWA study of complex diseases, especially for identification of those loci that have a very small effect. And compared with Fisher's method, the modified inverse variance weighted meta-analysis method is more robust as it is more powerful and has a lower type I error rate at the same time, which provides a potent approach in detecting the susceptibility loci associated with complex diseases, especially for those latent loci whose effect are very small.
In the meta-analysis of lung cancer with smoking data, the results replicate the signal in \emph{CHRNA3} and \emph{CHRNA5} genes on chromosome 15q25. Some new signals in \emph{CYP2F1} on chromosome 19, \emph{SUMF1} on chromosome 3, and \emph{ARHGAP10} on chromosome 4 are also detected. And the \emph{CYP2F1} gene, close to the already known cigarette-induced lung cancer gene \emph{CYP2A6}, is highly possible another cytochrome P450 (CYP) gene that is related to the smoking-involved lung cancer. The meta-analysis of rheumatoid arthritis with anti-cyclic citrullinated peptide (anti-CCP) data identified new signals on 9q24 and 16q12. There are evidences these two regions are involved in other autoimmune diseases and different autoimmune/inflammatory diseases may share same genetic susceptibility loci. Both the theoretical and empirical studies show that the modified variance weighted meta-analysis method is a robust method and is a potent approach in detecting the susceptibility loci associated with complex diseases when an intermediate phenotype is available.
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Causes and Consequences of Mitochondrial Variation in Caenorhabditid NematodesHicks, Kiley Ann 01 January 2012 (has links)
Mitochondria are dynamic organelles that harbor their own stream-lined genome and generate much of the ATP necessary to sustain eukaryotic life via an electron transport chain (ETC). Because of the central role for mitochondria in organismal physiology, mitochondrial genetic and phenotypic variation can alter organismal fitness and affect population genetic and evolutionary outcomes. Despite the far-reaching relevance of mitochondria to evolutionary processes and human health, we lack a basic understanding of the causes and consequences of mitochondrial genetic and phenotypic variation. In this thesis, I quantified mitochondrial reactive oxygen species (ROS), membrane potential (δΨM), and mitochondrial morphological traits within Caenorhabditis briggsae natural isolates and mutation-accumulation (MA) lines of both C. briggsae and Caenorhabditis elegans. Substantial natural variation was discovered for most mitochondrial form and function traits measured for a set of C. briggsae isolates known to harbor mitochondrial DNA structural variation in the form of a heteroplasmic nad5 gene deletion (nad5δ) that correlates negatively with organismal fitness. Most among-isolate phenotypic variation could be accounted for by phylogeographic clade membership rather than nad5δ level. Analysis of mitochondrial-nuclear hybrid strains provided support for both mtDNA and nuclear genetic variation as drivers of natural mitochondrial phenotype variation. An MA experimental approach revealed that average levels of both ROS and nad5δ heteroplasmy evolved in remarkably linear ways in C. briggsae maintained under extreme inbreeding. In particular, among C. briggsae isolates prone to acquiring the nad5δ deletion, nad5δ level increased to a plateau of ~50% during successive generations of MA treatment. Conversely, mitochondrial ROS level increased or declined in a strain-specific fashion, which also meant that the relationship between ROS and nad5δ was strain-specific. Further, all lines generated from the isolate with the highest starting level of nad5δ heteroplasmy went extinct prior to generation 20 of MA treatment. Patterns of among-line variance in ROS level were also strain-specific but generally did not conform to the canonical pattern of increasing among-line variance expected for MA experiments. MA lines of C. elegans that had previously been subjected to whole-genome sequencing were found to vary significantly in ROS levels but not in 8-oxo-dG content. Despite a significant positive correlation between 8-oxo-dG and ROS levels, no relationship between oxidative stress measures and base substitution rate or G-to-T transversion rate was revealed. Finally, analysis of patterns of phenotypic correlation for a suite of 24 mitochondrial traits measured in C. briggsae natural isolates support a role for ΔΨM in shaping mitochondrial dynamics, but no such role for mitochondrial ROS. Further, our study suggests a novel model of mitochondrial population dynamics dependent upon cellular environmental context and with implications for mitochondrial genome integrity. This work identifies extensive natural variation and capacity for evolution in organellar traits within multicellular eukaryotic species, with a central role for δΨM in mitochondrial dynamics that may have implications for evolutionary adaptation to thermal niches.
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Association statistics under the PPL frameworkHuang, Yungui 01 May 2011 (has links)
In this dissertation, the posterior probability of linkage (PPL) framework is extended to the analysis of case-control (CC) data and three new linkage disequilibrium (LD) statistics are introduced. These statistics measure the evidence for or against LD, rather than testing the null hypothesis of no LD, and they therefore avoid the need for multiple testing corrections. They are suitable not only for CC designs but also can be used in application to family data, ranging from trios to complex pedigrees, all under the same statistical framework, allowing for the unified analysis of these disparate data structures. They also provide the other core advantages of the PPL framework, including the use of sequential updating to accumulate LD evidence across potentially heterogeneous sets of subsets of data; parameterization in terms of a very general trait likelihood, which simultaneously considers dominant, recessive, and additive models; and a straightforward mechanism for modeling two-locus epistasis. Finally, being implemented within the PPL framework, the new statistics readily allow linkage information obtained from distinct data, to be incorporated into LD analyses in the form of a prior probability distribution. Performance of the proposed LD statistics is examined using simulated data. In addition, the effects of key modeling violations on performance are assessed. These statistics are also applied to a previously published type 1 diabetes (T1D) family dataset with a few candidate genes with previously reported weak associations, and another T1D CC dataset also previously published as a genome-wide association (GWA) study with some strong associations reported. The new LD statistics under the PPLD framework confirm most of the findings in the published work and also find some new SNPs suspected of being associated with T1D. Sequential updating between the family dataset and the CC dataset dramatically increased the association signal strength for a CTLA4 SNP genotyped in both studies. Linkage information gleaned from the family dataset is also combined into the LD analysis of the CC dataset to demonstrate the utility of this unique feature of the PPL framework, and specifically for the new LD statistics.
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Conditional linkage methods--searching for modifier genes in a large Amish pedigree with known Von Willebrand disease major gene modificationAbbott, Diana Lee 01 May 2009 (has links)
Von Willebrand Disease (VWD) is the most common bleeding disorder. In addition to known major genes, genetic modifiers, such as ABO blood group, affect quantitative outcome measures for VWD. The data consist of an 854-member Amish pedigree with established linkage of VWD to a locus within the Von Willebrand Factor (VWF) gene on chromosome 12. The DNA sequence of the causative mutation is known. Phenotypic information and genotypic data consisting of VWF mutation status and a genome screen of markers are available for 385 pedigree members. Genetic modifiers of the VWF mutation are investigated using known and new conditional linkage methods that search for modifier genes of a major gene with known mutation.
The MCMC-based program LOKI was used to conduct multipoint linkage analysis of VWD outcome measures while controlling for the VWF mutation. Adjustment for the mutation did not eliminate the linkage signal on chromosome 12 in the same location as the VWF mutation. Evidence for QTLs was also found on six other chromosomes.
Smod, a score statistic that detects evidence of a genetic modifier conditional on linkage to a major gene, was developed for sib pair data. To limit the modifier gene main effect, Smod was developed so that variance due to the modifier locus is bounded above by the variance of the interaction between major gene and modifier gene. The performance of Smod was compared to other published score statistics. Power to detect linkage to the modifier locus depended on major gene and modifier gene risk allele frequencies, relative contribution of the major gene main effect to the interaction effect, and the upper bound on the modifier gene main effect.
The Amish pedigree was broken up into sib pair data and analyzed using Smod and other score statistics. Using these statistics, the strongest evidence for QTLs for VWD was also found on chromosome 12 in the region of the VWF mutation. Combined with the LOKI results, further analysis will help determine if intragenic modification is occurring or if linkage disequilibrium between the mutation and analyzed markers is driving results.
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Automated Discovery of Pedigrees and Their Structures in Collections of STR DNA Specimens Using a Link Discovery ToolHaun, Alex Brian 01 May 2010 (has links)
In instances of mass fatality, such as plane crashes, natural disasters, or terrorist attacks, investigators may encounter hundreds or thousands of DNA specimens representing victims. For example, during the January 2010 Haiti earthquake, entire communities were destroyed, resulting in the loss of thousands of lives. With such a large number of victims the discovery of family pedigrees is possible, but often requires the manual application of analytical methods, which are tedious, time-consuming, and expensive. The method presented in this thesis allows for automated pedigree discovery by extending Link Discovery Tool (LDT), a graph visualization tool designed for discovering linkages in large criminal networks. The proposed algorithm takes advantage of spatial clustering of graphs of DNA specimens to discover pedigree structures in large collections of specimens, saving both time and money in the identification process.
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Automated Discovery of Pedigrees and Their Structures in Collections of STR DNA Specimens Using a Link Discovery ToolHaun, Alex Brian 01 May 2010 (has links)
In instances of mass fatality, such as plane crashes, natural disasters, or terrorist attacks, investigators may encounter hundreds or thousands of DNA specimens representing victims. For example, during the January 2010 Haiti earthquake, entire communities were destroyed, resulting in the loss of thousands of lives. With such a large number of victims the discovery of family pedigrees is possible, but often requires the manual application of analytical methods, which are tedious, time-consuming, and expensive. The method presented in this thesis allows for automated pedigree discovery by extending Link Discovery Tool (LDT), a graph visualization tool designed for discovering linkages in large criminal networks. The proposed algorithm takes advantage of spatial clustering of graphs of DNA specimens to discover pedigree structures in large collections of specimens, saving both time and money in the identification process.
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Peroxisome Proliferator-Activated Receptor-γ Coactivator 1-α (PPARGC1A) Genetic Associations with Type 2 Diabetes in Three EthnicitiesCheema, Amanpreet K 28 October 2014 (has links)
Genetic heterogeneity, lifestyle factors, gene-gene or gene-environment interactions are the determinants of T2D which puts Hispanics and populations with African ancestry at higher risk of developing T2D. In this dissertation, the genetic associations of PPARGC1A polymorphisms with T2D and its related phenotypes (metabolic markers) in Haitian Americans (cases=110, controls=116), African Americans (cases=120, controls=124) and Cuban Americans (cases=160, controls=181) of South Florida were explored. Five single nucleotide polymorphisms of gene PPARGC1A were evaluated in each ethnicity for their disease association. In Haitian Americans, rs7656250 (OR= 0.22, pp=0.03) had significant protective association with T2D but had risk association in African Americans for rs7656250 (OR=1.02, p=0.96) and rs4235308 (OR=2.53, p=0.03). We found that in Haitian American females, both rs7656250 (OR=0.23, pp=0.03) had protective association with T2D. In African American females, rs7656250 (OR=1.14, p=0.78) had risk association whereas in males, it had significant protective effect (OR=0.37, p=0.04). However, the risk association exhibited by rs4235308 was stronger in African American females (OR=2.69, p=0.03) than males (OR=1.16, p=0.72). In Cuban Americans, only rs7656250 showed significant risk association with T2D (OR=6.87, p=0.02) which was stronger in females alone (OR=7.67, p=0.01). We also observed significant differences among correlations of PPARGC1A SNPs and T2D phenotypes. Positive correlation was observed for log Hs-CRP with rs3774907 (pp=0.03) in Cuban Americans respectively. Correlation of log A1C with rs7656250 (p=0.02) was positive in Cuban Americans while it was negative for rs3774907 in Haitian Americans (ppPPARGC1A correlations with T2D and its phenotypes among the three ethnicities studied (ii) the associations of PPARGC1A SNPs showed significant effect modification by sex. The findings suggest that variations in effects of PPARGC1A gene polymorphisms among three ethnicities and between sexes may have biomedical implications for the development of T2D as well as the phenotypes related to T2D.
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An Assessment of Environmental Dna as a Tool to Detect Fish Species in Headwater StreamsJane, Stephen F 01 January 2014 (has links) (PDF)
Recent years have seen an explosion of interest in the use of freely available DNA present in aquatic systems, otherwise known as environmental DNA (eDNA), as a tool for monitoring aquatic organisms. However, much remains unknown about the behavior of eDNA over a range of environmental conditions. This is particularly true in high gradient headwater streams, which have received less attention than other types of water bodies. In the summer of 2011, a headwater stream system with well established species distributions was sampled using eDNA techniques. Though species were detected where known to be present, detections also occurred where traditional techniques failed to detect species. This suggests that a cautious approach to positive eDNA detections is advisable. In 2012 a second study was conducted to better understand the dynamics of eDNA concentration in lotic systems. Caged brook trout (Salvelinus fontinalis) were introduced into two otherwise fishless headwater streams, and eDNA samples were collected at evenly spaced intervals downstream of the cage. This was repeated 19 times from mid-summer through autumn, over flows ranging from approximately 1 to 96 l/sec. Quantitative PCR was used to relate DNA copy number to distance from source for each of these 19 sampling events. In all cases, DNA was detectable at 239.5 m from the cage. Increasing flows generally decreased eDNA copy number near the cage but had relatively little effect at downstream sites. Additionally, the presence of leaf biomass during the fall period had the potential to completely erase otherwise high DNA levels.
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CPF1-BASED CRISPR GENOME EDITING IN THE CYANOBACTERIUM N. PUNCTIFORMEWoo, Soohan 01 January 2022 (has links)
CRISPR systems have been growing in their utility and their application throughout the biological field as researchers continue to grow in their understanding of the relatively novel genome editing technology. However, despite the potential of CRISPR as a genome editing tool, the complexity of applying this technology to a specific organism calls for custom modifications to the system to improve its success rate. In this project, a CRISPR-Cpf1 system that can be effectively employed in the cyanobacterium Nostoc punctiforme was designed, with a focus on the hormogonium development of this species. Multiple plasmids containing the CRISPR system and targeting different genes were constructed using a Gibson-based rapid assembly cloning method, and then were tested by introduction into Nostoc punctiforme via conjugation. Plasmids were constructed to mutate 7 different genes in N. punctiforme with 4 of the 7 successfully mutating their target genes. For one of the genes where the plasmid failed to produce mutants, the usage of a larger homology repair template (HRT) was found to enhance the efficiency of gene editing, allowing the gene to be knocked out. Thus, the length of the HRT appears to be a critical factor in designing successful constructs. The system developed in this project aims to make CRISPR a more viable tool in studying Nostoc cyanobacteria, and more specifically to aid in understanding the mechanisms behind hormogonium development in the studied species. This system may have a wider application for studying the Nostoc genus and related organisms, such as Anabaena.
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