Dissertations / Theses on the topic 'Genetics and genomics/genetics of disease'
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1
Carr, E. J. "Genetics and genomics in autoimmune disease and healthy individuals." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597304.
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To look for common genetic variants associated with systemic lupus erythematosus (SLE) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) we genotyped 11 loci previously associated with T1D and containing regulators of the immune response. CTLA4 and PTPN22 were found to be associated with AAV. IL2RA was a susceptibility locus for both AAV and SLE. The association of each disease with the IL2RA region is complex. T1D associated independently with 3 single nucleotide polymorphisms (SNPs), whereas AAV and SLE were each associated with a different one of the three T1D-associated SNPs. The IL2RA region is also a known susceptibility locus for multiple sclerosis (MS) and Graves’ disease. Transcriptional profiling of purified CD8 T cells has previously identified two distinct patient subgroups in both AAV and SLE. The patients from one subgroup (8.1) had significantly more frequency relapses and a significantly larger CD8 T cell memory compartment than the other subgroup (8.2). We looked for the presence of these subgroups in MS, along with their ability to predict conversion from clinically isolated syndrome to MS. We tested for an HLA association and for an association with cytomegalovirus and Epstein-Barr virus infection. Two analogous subgroups (c8.1 and c8.2) were identifiable in the healthy population. A study testing for association between c8.1 and c8.2 and vaccine response was conducted using both T-dependent and T-independent vaccines to S. pneumoniae. Antibody titres to some serotypes of S. pneumoniae were associated with CD8 T cell subgroup at a single time point. Intriguingly, this study demonstrated that healthy individuals were able to change from c8.1 to c8.2 and vice versa after vaccination with either vaccine.
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Hsu, Jeff. "It's Complicated: Analyzing the Role of Genetics and Genomics in Cardiovascular Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1373030141.
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Hershman, Steven Gregory. "Personal Genomics and Mitochondrial Disease." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10863.
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Mitochondrial diseases involving dysfunction of the respiratory chain are the most common inborn errors of metabolism. Mitochondria are found in all cell types besides red blood cells; consequently, patients can present with any symptom in any organ at any age. These diseases are genetically heterogeneous, and exhibit maternal, autosomal dominant, autosomal recessive and X-linked modes of inheritance. Historically, clinical genetic evaluation of mitochondrial disease has been limited to sequencing of the mitochondrial DNA (mtDNA) or several candidate genes. As human genome sequencing transformed from a research grade effort costing $250,000 to a clinical test orderable by doctors for under $10,000, it has become practical for researchers to sequence individual patients. This thesis describes our experiences in applying "MitoExome" sequencing of the mtDNA and exons of >1000 nuclear genes encoding mitochondrial proteins in ~200 patients with suspected mitochondrial disease. In 42 infants, we found that 55% harbored pathogenic mtDNA variants or compound heterozygous mutations in candidate genes. The pathogenicity of two nuclear genes not previously linked to disease, NDUFB3 and AGK, was supported by complementation studies and evidence from multiple patients, respectively. In an additional two unrelated children presenting with Leigh syndrome and combined OXPHOS deficiency, we identified compound heterozygous mutations in MTFMT. Patient fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of MTFMT. Furthermore, patient fibroblasts have dramatically reduced fMet-\(tRNA^{Met}\) levels and an abnormal formylation profile of mitochondrially translated \(COX_1\). These results demonstrate that MTFMT is critical for human mitochondrial translation. Lastly, to facilitate evaluation of copy number variants (CNVs), we developed a web-interface that integrates CNV calling with genetic and phenotypic information. Additional diagnoses are suggested and in a male with ataxia, neuropathy, azoospermia, and hearing loss we found a deletion compounded with a missense variant in D-bifunctional protein, \(HSD_{17}B_4\), a peroxisomal enzyme that catalyzes beta-oxidation of very long chain fatty acids. Retrospective review of metabolic testing from this patient revealed alterations of long- and very-long chain fatty acid metabolism consistent with a peroxisomal disorder. This work expands the molecular basis of mitochondrial disease and has implications for clinical genomics.
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Albers, Patrick K. "Rare and low-frequency variants and predisposition to complex disease." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:2d569297-5d2a-49c8-a1ca-32a978aec49d.
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Advances in high-throughput genomic technologies have facilitated the collection of DNA information for thousands of individuals, providing unprecedented opportunities to explore the genetic architecture of complex disease. One important finding has been that the majority of variants in the human genome are low in frequency or rare. It has been hypothesised that recent explosive growth of the human population afforded unexpectedly large amounts of rare variants with potentially deleterious effects, suggesting that rare variants may play a role in disease predisposition. But, importantly, rare variants embody a source of information through which we may learn more about our recent evolutionary history. In this thesis, I developed several statistical and computational methods to address problems associated with the analysis of rare variants and, foremost, to leverage the genealogical information they encode. First, one constraint in genome-wide association studies is that lower-frequency variants are not well captured by genotyping methods, but instead are predicted through imputation from a reference dataset. I developed the meta-imputation method to improve imputation accuracy by integrating genotype data from multiple, independent reference panels, which outperformed imputations from separate references in almost all comparisons (mean correlation with masked genotypes r2>0.9). I further demonstrated in simulated case-control studies that meta-imputation increased the statistical power to identify low-frequency variants of intermediate or high penetrance by 2.2-3.6%. Second, rare variants are likely to have originated recently through mutation and thereby sit on relatively long haplotype regions identical by descent (IBD). I developed a method that exploits rare variants as identifiers for shared haplotype segments around which the breakpoints of recombination are detected using non-probabilistic approaches. In coalescent simulations, I show that such breakpoints can be inferred with high accuracy (r2>0.99) around rare variants at frequencies <0.05%, using either haplotype or genotype data. Third, I show that technical error poses a major problem for the analysis of whole-genome sequencing or genotyping data, particularly for alleles below 0.05% frequency (false positive rate, FPR=0.1). I therefore propose a novel approach to infer IBD segments using a Hidden Markov Model (HMM) which operates on genotype data alone. I incorporated an empirical error model constructed from error rates I estimated in publicly available sequencing and genotyping datasets. The HMM was robust in presence of error in simulated data (r2>0.98) while nonprobabilistic methods failed (r2<0.02). Lastly, the age of an allele (the time since its creation through mutation) may provide clues about demographic processes that resulted in its observed frequency. I present a novel method to estimate (rare) allele age based on the inferred shared haplotype structure of the sample. The method operates in a Bayesian framework to infer pairwise coalescent times from which the age is estimated using a composite posterior approach. I show in simulated data that coalescent time can be inferred with high accuracy (rank correlation >0.91) which resulted in a likewise high accuracy for estimated age (>0.94). When applied to data from the 1000 Genomes Project, I show that estimated age distributions were overall conform with frequency-dependent expectations under neutrality, but where patterns of low frequency and old age may hint at signatures of selection at certain sites. Thus, this method may prove useful in the analysis of large cohorts when linked to biomedical phenotype data.
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Ahmed, Seemin Seher. "rAAV-Mediated Gene Transfer For Study of Pathological Mechanisms and Therapeutic Intervention in Canavan's Disease: A Dissertation." eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsbs_diss/749.
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Canavan’s Disease is a fatal Central Nervous System disorder caused by genetic defects in the enzyme – aspartoacylase and currently has no effective treatment options. We report additional phenotypes in a stringent preclinical aspartoacylase knockout mouse model. Using this model, we developed a gene therapy strategy with intravenous injections of the aspartoacylase gene packaged in recombinant adeno associated viruses (rAAVs). We first investigated the CNS gene transfer abilities of rAAV vectors that can cross the blood-brain-barrier in neonatal and adult mice and subsequently used different rAAV serotypes such as rAAV9, rAAVrh.8 and rAAVrh.10 for gene replacement therapy. A single intravenous injection rescued lethality, extended survival and corrected several disease phenotypes including motor dysfunctions. For the first time we demonstrated the existence of a therapeutic time window in the mouse model. In order to limit off-target effects of viral delivery we employed a synthetic strategy using microRNA mediated posttranscriptional detargeting to restrict rAAV expression in the CNS. We followed up with another approach to limit peripheral tissue distribution. Strikingly, we demonstrate that intracerebroventricular administration of a 50-fold lower vectors dose can rescue lethality and extend survival but not motor functions. We also study the contributions of several peripheral tissues in a primarily CNS disorder and examine several molecular attributes behind pathogenesis of Canavan’s disease using primary neural cell cultures. In summary, this thesis describes the potential of novel rAAV-mediated gene replacement therapy in Canavan’s disease and the use of rAAVs as a tool to tease out its pathological mechanism.
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Ahmed, Seemin Seher. "rAAV-Mediated Gene Transfer For Study of Pathological Mechanisms and Therapeutic Intervention in Canavan's Disease: A Dissertation." eScholarship@UMMS, 2012. http://escholarship.umassmed.edu/gsbs_diss/749.
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Canavan’s Disease is a fatal Central Nervous System disorder caused by genetic defects in the enzyme – aspartoacylase and currently has no effective treatment options. We report additional phenotypes in a stringent preclinical aspartoacylase knockout mouse model. Using this model, we developed a gene therapy strategy with intravenous injections of the aspartoacylase gene packaged in recombinant adeno associated viruses (rAAVs). We first investigated the CNS gene transfer abilities of rAAV vectors that can cross the blood-brain-barrier in neonatal and adult mice and subsequently used different rAAV serotypes such as rAAV9, rAAVrh.8 and rAAVrh.10 for gene replacement therapy. A single intravenous injection rescued lethality, extended survival and corrected several disease phenotypes including motor dysfunctions. For the first time we demonstrated the existence of a therapeutic time window in the mouse model. In order to limit off-target effects of viral delivery we employed a synthetic strategy using microRNA mediated posttranscriptional detargeting to restrict rAAV expression in the CNS. We followed up with another approach to limit peripheral tissue distribution. Strikingly, we demonstrate that intracerebroventricular administration of a 50-fold lower vectors dose can rescue lethality and extend survival but not motor functions. We also study the contributions of several peripheral tissues in a primarily CNS disorder and examine several molecular attributes behind pathogenesis of Canavan’s disease using primary neural cell cultures. In summary, this thesis describes the potential of novel rAAV-mediated gene replacement therapy in Canavan’s disease and the use of rAAVs as a tool to tease out its pathological mechanism.
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Shiyab, Amy S. "Knowledge and Perception of Nutritional Genomics Among Registered Dietitian Nutritionists." Kent State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=kent1563187321042113.
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McCann, Jennifer. "Variability of genomic imprinting in human disease." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84294.
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Genomic imprinting is the differential expression of genetic material depending on the parent from which it is transmitted. It is involved in the pathogenesis of many diseases, especially those involved in development, growth abnormalities and cancer. We examined the extent of and the variability of genomic imprinting amongst individuals in three human diseases, Wilms' tumour, Type 1 diabetes and Silver-Russell syndrome.Wilms' tumour (WT) is a renal embryonal cancer associated with overexpression of the insulin-like growth factor 2 (IGF2). IGF2 is directed to the lysosomes for degradation by the mannose-6-phosphate/insulin-like growth factor two receptor (M6P/IGF2R) encoded by the IGF2R gene, a known tumour suppressor gene on 6826. IGF2R is imprinted in the mouse, with exclusive maternal expression. In humans, however, IGF2R imprinting is a polymorphic phenomenon only being found in a small subset of people. We present results suggesting that IGF2R imprinting provides the first "hit" in IGF2R inactivation in WT, and show the presence of a second "hit" in the form of deletions detectable as loss of heterozygosity.
Another disease investigated in this report is Type 1 diabetes (TID), an autoimmune, polygenic disease. Of the several T1D loci, IDDM8 on 6q, has been found to be subject to parent-of-origin effects and encompasses IGF2R. M6P/IGF2R is involved in immune system regulation. In this study we show an association between TID and IGF2R that is confined to maternally inherited alleles. Our results strongly suggest that IGF2R is a TID susceptibility gene and may be universally imprinted at some tissue or developmental stage not yet studied.
A third disease displaying both tissue-specific and isoform-specific imprinting is Silver-Russell syndrome (SRS), a growth disorder associated with double dose of a maternally expressed gene within 7p11.2--p13, a region in which the imprinted GRB10 gene was a prime candidate. We studied the complex tissue and isoform-dependence of GRB10 imprinting and demonstrated absence of imprinting in growth plate cartilage, the tissue most directly involved in linear growth thus eliminating GRB10 as the gene responsible for SRS.
It is evident that genomic imprinting plays a prominent role in various diseases. Imprinted genes can be expressed in a tissue-specific, isoform-specific or a temporally regulated manner. In addition, there is a wide variability of imprinting between individuals.
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Corradin, Olivia G. "Impact of DNA Variants in the Regulatory Circuitry of Gene Expression inHuman Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1427988486.
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Jostins, Luke. "Using next-generation genomic datasets in disease association." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608054.
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Ponte, Amy. "Paths to Tier 1 Genomics Implementation: A Survey of Chronic Disease Directors." ScholarWorks, 2017. https://scholarworks.waldenu.edu/dissertations/3822.
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Although evidence is currently available for population-based genetic screening and testing of individuals and their family members for certain hereditary chronic disease conditions (Tier 1), few states have integrated these genomic applications into chronic disease prevention programs. State and territorial chronic disease directors (CDDs) could provide the leadership needed to deliver these applications in more states. The purpose of this study was to determine whether an association exists between current chronic disease genomics funding or specific state genomic activities and the level of knowledge and interests in genomics by these directors. Rogers's diffusion of innovations (DIT) theory was used to explain the current climate of state chronic disease genomics and the need for an innovation champion to promote these evidence-based applications both in and out of the state health departments. A nonexperimental, cross-sectional, correlational survey of CDDs (N = 58) was performed using the Chronic Disease Director's Survey and results were analyzed using chi-square, independent t test, ANOVA, logistic regression, and Pearson's correlation coefficient. Results showed CDDs knowledge of genomics is unrelated to current state funding; however, CDD knowledge and interest in genomics was associated with inclusion of genetics in cancer control and cardiovascular health action plans, Tier 1 condition education, privacy and nondiscrimination laws, Behavioral Risk Factor Surveillance System (BRFSS) genomics questions, and frequent collaborations with outside entities. These results provide clear ideas to increase CDDs knowledge and interest in chronic disease genomics and potentially impact Tier 1 genomics implementation in more states.
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Noh, Hyun Ji. "Comparative approaches to the genetics of human neuropsychiatric disorders." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:8cb9ee02-1b12-4b78-bb62-3bbf4d5eba26.
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In this thesis, I investigate the genetics of neuropsychiatric disorders by analysing large data sets derived from high-throughput experiments, using novel comparative genomics approaches. In the first project, I explore characteristics of rare, de novo copy number variants identified among autism patients by employing various bioinformatics resources including Mouse Genome Informatics phenotypes, Gene Ontology terms, and protein-protein interactions. I describe how I objectively identified a number of mouse model phenotypes that are significantly associated with autism, and that provide insight into the aetiologies for both copy number deletions and duplications. In the second project, I investigate the genetics of obsessive-compulsive disorder by resequencing genomic regions of human case-control cohorts and the best spontaneous disease model organisms, namely dogs with canine compulsive disorder, and breed-matched controls. Targeted sequencing experiments yielded a large number of high-quality genetic variants in both humans and dogs. I prioritised variants and genes using case- control comparisons and functional annotations such as types of mutation, evolutionary conservation status and regulatory marks. In turn, I generated several hypotheses that are experimentally tractable. Replication of these findings in a larger cohort is necessary, although it lies beyond the scope of this thesis. Results from both projects indicate that the analytical frameworks employed in this thesis could be profitably applied to other neuropsychiatric disorders.
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Miller, Michael Ryan. "Functional Genomics of Nervous System Development and Disease." Thesis, University of Oregon, 2011. http://hdl.handle.net/1794/12102.
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xiii, 145 p. : ill. (some col.)The goal of functional genomics is to elucidate the relationship between an organism's genotype and phenotype. A key characteristic of functional genomics is the use of genome-wide approaches as opposed to more traditional single-gene approaches. Genome-wide expression profiling is used to investigate the dynamic properties of transcriptomes, provides insights into how biological functions are encoded in genomes, and is an important technique in functional genomics. This dissertation describes the use of genome-wide expression profiling and other functional genomics techniques to address a variety of biological questions related to development and disease of the nervous system. Our results reveal novel and important insights into nervous system development and disease and demonstrate the power of functional genomics approaches for the study of nervous system biology. This dissertation also describes a novel technique called TUtagging that facilitates cell type-specific RNA isolation from intact complex tissues. The isolation of RNA from specific cell types within a complex tissue is a major limiting factor in the application of genome-wide expression profiling, and TU-tagging can be used to address a wide array of interesting and important biological questions. This dissertation includes previously published and unpublished co-authored material.
Committee in charge: Dr. John Postlethwait， Chair； Dr. Chris Doe， Advisor； Dr. Bruce Bowerman， Member； Dr. Patrick Phillips， Member； Dr. Tom Stevens， Outside Member
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Ridge, Perry Gene. "Mitochondrial Genetics of Alzheimer's Disease and Aging." BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/3521.
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Mitochondria are essential cellular organelles and the location of the electron transport chain, the site of the majority of energy production in the cell. Mitochondria contain their own circular genome approximately 16,000 base pairs in length. The mitochondrial genome (mtDNA) encodes 11 protein-coding genes essential for the electron transport chain, 22 tRNA genes, and two rRNA genes. Mitochondrial malfunction occurs in many diseases, and changes in the mitochondrial genome lead to numerous disorders. Multiple mitochondrial haplotypes and sequence features are associated with Alzheimer's disease. In this dissertation we utilized TreeScanning, an evolutionary-based haplotype approach to identify haplotypes and sequence variation associated with specific phenotypes: Alzheimer's disease case-control status, mitochondrial copy number, and 16 neuroimaging phenotypes related to Alzheimer's disease neurodegeneration. In the first two studies we utilized 1007 complete mitochondrial genomes from participants in the Cache County Study on Memory Health and Aging. First, individuals with mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD. Our study is the largest to date and the only study with complete mtDNA genome sequence data. Next, each cell contains multiple mitochondria, and each mitochondrion contains multiple copies of its own circular genome. The ratio of mitochondrial genomes to nuclear genomes is referred to as mitochondrial copy number. Decreases in mitochondrial copy number are known to occur in many tissues as people age, and in certain diseases. Three variants belonging to mitochondrial haplogroups U5A1 and T2 were significantly associated with higher mitochondrial copy number in our dataset. Each of these three variants was associated with higher mitochondrial copy number and we suggest several hypotheses for how these variants influence mitochondrial copy number by interacting with known regulators of mitochondrial copy number. Our results are the first to report sequence variation in the mitochondrial genome that lead to changes in mitochondrial copy number. The identification of these variants that increase mtDNA copy number has important implications in understanding the pathological processes that underlie these phenotypes. Lastly, we used an endophenotype-based approach to further characterize mitochondrial genetic variation and its relationship to risk markers for Alzheimer's disease. We analyzed longitudinal data from non-demented, mild cognitive impairment, and late onset Alzheimer's disease participants in the Alzheimer's Disease Neuroimaging Initiative with genetic, brain imaging, and behavioral data. Four clades were associated with three different endophenotypes: whole brain volume, percent change in temporal pole thickness, and left hippocampal atrophy over two years. This was the first study of its kind to identify mitochondrial variation associated with brain imaging endophenotypes of Alzheimer's disease. Together, these projects provide evidence of mtDNA involvement in the risk and physiological changes of Alzheimer's disease.
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Chiang, Annie Pei-Fen. "Comparative and integrative genomic approach toward disease gene identification application to Bardet-Biedle Syndrome /." Diss., University of Iowa, 2006. http://ir.uiowa.edu/etd/47.
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Tsairidou, Smaragda. "Genetics of disease resistance : application to bovine tuberculosis." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25397.
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Bovine Tuberculosis (bTB) is a disease of significant economic importance, being one of the most persistent animal health problems in the UK and the Republic of Ireland and increasingly constituting a public health concern especially for the developing world. Limitations of the currently available diagnostic and control methods, along with our incomplete understanding of bTB transmission, prevent successful eradication. This Thesis addresses the development of a complementary control strategy which will be based on animal genetics and will allow us to identify animals genetically predisposed to be more resistant to disease. Specifically, the aim of my PhD project is to investigate the genetic architecture of resistance to bTB and demonstrate the feasibility of whole genome prediction for the control of bTB in cattle. Genomic selection for disease resistance in livestock populations will assist with the reduction of the in herd-level incidence and the severity of potential outbreaks. The first objective was to explore the estimation of breeding values for bTB resistance in UK dairy cattle, and test these genomic predictions for situations when disease phenotypes are not available on selection candidates. Through using dense SNP chip data the results of Chapter 2 demonstrate that genomic selection for bTB resistance is feasible (h2 = 0.23(SE = 0.06)) and bTB resistance can be predicted using genetic markers with an estimate of prediction accuracy of r(g, ĝ) = 0.33 in this data. It was shown that genotypes help to predict disease state (AUC ≈ 0.58) and animals lacking bTB phenotypes can be selected based on their genotypes. In Chapter 3, a novel approach is presented to identify loci displaying heterozygote (dis)advantage associated with resistance to M. bovis, hypothesising underlying non-additive genetic variation, and these results are compared with those obtained from standard genome scans. A marker was identified suggesting an association between locus heterozygosity and increased susceptibility to bTB i.e. a heterozygote disadvantage, with the heterozygotes being significantly more in the cases than in the controls (x2 = 11.50, p < 0.001). Secondly, this thesis focused on conducting a meta-analysis on two dairy cattle populations with bTB phenotypes and SNP chip genotypes, identifying genomic regions underlying bTB resistance and testing genomic predictions by means of cross-validation. In Chapter 4, exploration of the genetic architecture of the trait revealed that bTB resistance is a moderately polygenic, complex trait with clusters of causal variants spread across a few major chromosomes collectively controlling the trait. A region was identified on chromosome 6, putatively associated with bTB resistance and this chromosome as a whole was shown to contribute a major proportion (hc 2= 0.051) of the observed variation in this dataset. Genomic prediction for bTB was shown to be feasible even when only distantly related populations are combined (r(g,ĝ)=0.33 (SE = 0.05)), with the chromosomal heritability results suggesting that the accuracy arises from the SNPs capturing linkage disequilibrium between markers and QTL, as well as additive relationships between animals (~80% of estimated genomic h2 is due to relatedness). To extend the analysis, in Chapter 5, high density genotypes were inferred by means of genotype imputation, anticipating that these analyses will allow the identification of genomic regions associated with bTB resistance more closely, and that would increase the prediction accuracy. Genotype imputation was successful, however, using all imputed genotypes added little information. The limiting factor was found to be the number of animals and the trait definitions rather than the density of genotypes. Thirdly, a quantitative genetic analysis of actual Single Intradermal Comparative Cervical Test (SICCT) values collected during bTB herd testing was conducted aiming to investigate if selection for bTB resistance is likely to have an impact on the SICCT diagnostic test. This analysis demonstrated that the SICCT has a negligibly low heritability (h2=0.0104 (SE = 0.0032)) and any effect on the responsiveness to the test is likely to be small. In conclusion, breeding for disease resistance in livestock is feasible and we can predict the risk of bTB in cattle using genomic information. Further, putative QTLs associated with bTB resistance were identified, and exploration of the genetic architecture of bTB resistance revealed a moderately polygenic trait. These results suggest that given that larger datasets with more phenotyped and genotyped animals will be available, we can breed for bTB resistance and implement the genomic selection technology in breeding programmes aiming to improve the disease status and overall health of the livestock population. Using the genomics this can be continued as the epidemic declines.
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McHenry, Michael Lyon. "Genomic and Co-Evolutionary Determinants of Clinical Severity in Active Tuberculosis Patients." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1623754259445275.
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LaHaye, Stephanie Donna. "Discovering and Modeling Genetic Causes of Congenital Heart Disease." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492610446228702.
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Cusanovich, Darren Anthony. "Integrative genomics approaches to understanding the role of gene regulation in human evolution, disease, and cellular networks| A triptych." Thesis, The University of Chicago, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3606309.
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Human development and health involves the complex and coordinated regulation of gene expression across diverse tissues. Gene regulation is therefore an essential process in human biology. In the field of human genetics, this has only become more apparent as genomic technologies have made genome-wide surveys of genetic variation underlying human traits possible. In my thesis work, I studied the impact of variation in gene regulation on human traits from three distinct perspectives of human genetics. I first examined the contribution of gene regulation to human disease susceptibility by combining gene expression data with a genome-wide association study to identify novel asthma susceptibility candidate genes. I then studied the effects of depleting specific transcription factors from the cell on downstream gene expression by incorporating gene expression data (following cellular depletion of those factors) with genomic transcription factor binding data. Finally, I considered the role of gene regulation in human evolution by integrating RNA-seq data collected in human, chimpanzee, and rhesus macaque lymphoblastoid cell lines with promoter reporter assays conducted in the same lines. Throughout this work, I have synthesized multiple genomic data sets and multiple distinct sub-disciplines of human genetics in order to arrive at a unified view of the role of gene regulation in determining human traits.
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Abbott, Diana Lee. "Conditional linkage methods--searching for modifier genes in a large Amish pedigree with known Von Willebrand disease major gene modification." Diss., University of Iowa, 2009. https://ir.uiowa.edu/etd/223.
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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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Fortune, Mary Doris. "Statistical techniques to fine map the related genetic aetiology of autoimmune diseases." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/264764.
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Genome Wide Association Studies (GWAS) have uncovered many genetic regions which are associated with autoimmune disease risk. In this thesis, I present methods which I have developed to build upon these studies and enable the analysis of the causal variants of these diseases. Colocalization methods disentangle whether potential causal variants are shared or distinct in related diseases, and enable the discovery of novel associations below the single-trait significance threshold. However, existing approaches require independent datasets to accomplish this. I extended two methods to allow for the shared-control design; one of these extensions also enables fine mapping in the case of shared variants. My analysis of four autoimmune diseases identified 90 regions associated with at least one disease, 33 of which were associated with 2 or more disorders; 14 of these had evidence of distinct causal variants. Once associated variants have been identified, we may wish to test some aggregate property, such as enrichment within an annotation of interest. However, the null distribution of GWAS signals showing association with a trait and preserving expected correlation due to linkage disequilibrium is complicated. I present an algorithm which computes the expected output of a GWAS, given any arbitrary definition of "null", and hence can be used to simulate the null distribution required for such a test. Commonly, GWAS report only summary data, and determining which genetic variants are causal is more difficult; the strongest signal may merely be correlated with the true causal variant. I have developed a statistical method for fine mapping a region, requiring only GWAS p-values and publicly available reference datasets. I sample from the space of potential causal models, rejecting those leading to expected summary data excessively different from that observed. This removes the need for the assumption of a single causal variant. In contrast to other summary statistic methods which allow for multiple causal variants, it does not depend upon availability of effect size estimates, or the allelic direction of effect and it can infer whether the pattern of association is likely caused by a non-genotyped SNP without requiring imputation. I discuss the effect of choice of reference dataset, and the implications for other summary statistics techniques.
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Durda, Jon Peter. "The Cardiovascular Epidemiology and Genome-Wide Associations of Biomarkers of Innate and Adaptive Immunity: sCD163 and sIL2RA." ScholarWorks @ UVM, 2017. http://scholarworks.uvm.edu/graddis/788.
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Cardiovascular disease (CVD) is a major cause of morbidity and mortality in the U.S. and worldwide. Atherosclerosis, the buildup of plaque in the arteries, is a common cause of CVD. For many years, research in atherosclerosis was focused on lipid metabolism and the accumulation of low-density lipoprotein in the arteries. While this research set public health guidelines for lipid management, lipid concentration was not the only factor influencing atherosclerosis and CVD events. Many scientists, as far back as the 1850’s recognized the role of inflammation in the progression of atherosclerotic disease. The continuous low levels of immune activation in the body contribute to atherosclerosis. Research in animal models and epidemiologic studies have shown the involvement of both the innate and the adaptive immune systems in plaque development and to elucidate the roles of monocytes and T cells. In addition to animal studies and epidemiologic research, CVD and atherosclerotic research has extended to genetic analysis in the search for associations with risk factors and outcomes.
The first chapter is a review of the literature studying the immune system’s involvement in atherosclerosis. Beginning with an examination of the impact of CVD and atherosclerosis, the basic pathophysiology, and the involvement of the innate and adaptive immune systems through animal models and epidemiology. Some of the significant cohort studies in CVD and genome wide association studies are also discussed.
Chapter 2 examines the associations of soluble interleukin 2 receptor alpha (sIL-2Rα) with clinical events in the Cardiovascular Health Study and genetic variants. Interleukin 2 (IL-2) and its receptor regulate both tolerance and immunity, IL-2 induces the proliferation and differentiation of T cells, part of the adaptive immune system. The results showed an association between sIL-2Rα and CVD events. The genome-wide association study found 52 variants to be significantly associated with sIL-2Rα in European Americans.
Chapter 3 assesses the involvement of the innate immune system in atherosclerosis through the associations of soluble CD163 (sCD163). CD163 is a marker of macrophage activation, specifically associated with M2 macrophages. In CHS, sCD163 levels were analyzed for associations with cardiovascular events and genetic variants. sCD163 was found to be associated with CVD risk factors and with cardiovascular events. In a genome-wide association study six variants in European Americans and three variants in African Americans were found to be significant.
Chapter 4 summarizes the results and discusses some bench to bedside translational science already seen in atherosclerosis treatment and prevention. Continued investigation of markers of T-cell and monocyte differentiation in animal models and cohort studies may lead to opportunities for the prevention of atherosclerosis and/or treatment through an increased understanding of the biology and genetics of the innate and adaptive immune.
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Orantes, Lucia Consuelo. "Assessing Community Dynamics and Colonization Patterns of Tritatoma dimidiata and Other Biotic Factors Associated with Chagas Disease Prevalence in Central America." ScholarWorks @ UVM, 2017. http://scholarworks.uvm.edu/graddis/769.
Full textAbstract:
Chagas disease is caused by the parasite Trypanosoma cruzi and transmitted by multiple triatomine vectors across the Americas. In Central America, the predominant vector is Triatoma dimidiata, a highly adaptable and genetically diverse Hemiptera. In this research, we used a novel reduced-representation DNA sequencing approach to discover community dynamics among multiple biotic factors associated with Chagas disease in Central America, and assess the infestation patterns of T. dimidiata after seasonal and chemical disturbances in Jutiapa, Guatemala. For our first study, we used a hierarchical sampling design to obtain multi-species DNA data found in the abdomens of 32 T. dimidiata specimens from Central America. We aimed to understand (1) the prevalence of T. cruzi infection, (2) the population genetics of the vector and parasite, (3) the blood meal history of the vector, and (4) gut microbial diversity. Our results indicated the presence of nine infected vectors harboring two distinct DTUs: TcI and possibly TcIV. We found significant clusters among T. dimidiata populations in countrywide and within-country levels associated with sylvatic ecotopes and diverse domestic genotypes. There was significantly higher bacteria species richness in infected T. dimidiata abdomens than those that were not infected, with further analysis suggesting that gut bacteria diversity relates to both T. cruzi infection and the local environment. We identified vertebrate blood meals from five T. dimidiata abdomens including chicken, dog, duck and human; however, additional detection methods are necessary to confidently identify blood meal sources. In our second study, we analyzed the GBS genotypes of 440 T. dimidiata specimens collected in two towns of Jutiapa, Guatemala. Our aim was to assess (1) the domestic population patterns that aid the recovery of T. dimidiata after an insecticide treatment in El Carrizal and (2) the seasonal changes that regulate the dispersal of the vector in the untreated communities of El Chaperno. Results showed that the insecticide application was effective at reducing the population abundance immediately after the application in El Carrizal; nevertheless, 18-month post-treatment the town-wide infestation and genetic diversity were recovering. Within-house relatedness among specimens recovered 18 months post-treatment, suggesting that the insecticide treatment failed to fully eliminate domiciliated colonies. In contrast, lack of change in abundance or genetic diversity in El Chaperno implied absence of dispersers from sources beyond the town periphery, while evidence of a decrease of relatedness among individuals implied dispersal among houses. After the insecticide treatment in El Carrizal, population reduction led to lack of genetic spatial autocorrelation; nevertheless, rapid dispersal into neighboring houses lead to autocorrelation 18 months after the insecticide treatment. This pattern was also observed in El Chaperno, where an increase in spatial autocorrelation during seasonal dispersal suggests spillover to close-by households. The creation of a novel genomics pipeline allowed us to understand community and dispersal patterns of T. dimidiata and other biotic factors important for the prevalence and transmission of Chagas disease at local and regional levels. Future studies should include complementary approaches for taxa verification (e.g. bacteria 16S barcoding, PCR-base detection), as well as expand the scope of local population analyses to peridomestic and sylvatic genotypes that could suggest a broader range of vector sources and region-wide patterns of temporal and spatial dispersion.
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Masekoameng, Tshepiso. "Sickle cell trait and targeted genomic variants in chronic kidney disease an African cohort." Master's thesis, Faculty of Health Sciences, 2019. http://hdl.handle.net/11427/31357.
Full textAbstract:
Background Chronic Kidney Disease (CKD), has a high and increasing burden in sub-Saharan Africa. Environmental factors that have been associated to CKD are associated with multiple co-morbidities such as hypertension, diabetes, and HIV. Some genetics factors such APOL1 have been associated with the highest burden of CKD among population of African ancestries. Other emerging genetic factors such as Sickle Cell trait (SCT) have been investigated mostly among African Americans. Sickle Cell trait (SCT) has the highest burden in sub-Saharan Africans, because of a natural selection, attributed to its protective advantages against the severest form of Malaria, caused by Plasmodium falciparum. Many studies showed that SCT has an impact on the normal functioning of the kidneys among African Americans with some studies indicating significant association between SCT and CKD. However, no study has been reported from Sub-Saharan Africa, where most SCT carrier reside. Moreover, there are multiple other loci and variants in the genome that have been associated with CKD in many populations, and that are used for Polygenic Risk Score (PRS) models but have not been explored in populations living in Africa. Aims This project aimed to study in a sub-Saharan African cohort, the association between 1) Sickle cell trait (SCT) with Chronic Kidney disease (CKD), and 2) the association of CKD with 29 targeted single nucleotide polymorphisms (SNPs) identified in multiple Genome-Wide Association studies (GWAS). Methods Patients and controls: 300 Cameroonian adult participants were included: 150 CKD cases and 150 non-CKD age, sex, and comorbidities matched controls. Molecular methods: SCT heterozygosity was determined by RFLP-PCR using the restriction enzyme DdeI. A total of 29 targeted SNPs was genotyped using MassArray and TaqMan techniques, followed by Sanger sequencing in a subset of samples. 11 Statistical Analysis: Descriptive statistics and logistic regression, and Fisher exact test were used. Functional pathway analysis: following the identification SNPs with significant association with CKD, we performed functional pathway test using the Linux programme Cytoscape. Results The mean age of cases was 53 years (range 46-55 years), with 43% that were female; there were no age and sex significant differences with controls. We identified, an expected, association between CKD and various co-morbidities, demographic and anthropometric variables: hypertension (p value = 5.16X10-9 ), HIV (p value = 2.68x10- 9 ), diabetes (p value = 7.12X10-7 ), BMI (p value = 4.58X10-8 ) and age (p value = 4.5X10-8 ). HbAS carrier status was significantly associated CKD (p value= 4.3X10-9 ; Odds Ratio:7.05). Only three targeted SNPs (3/29) previously associated with CKD in GWAS among African Americans, European and Asian population, were significantly associated with CKD among this group of Cameroonians (KBTBD2 rs3750082, PTPRO rs7956634 and LPR2 rs4667594 with p values of 0.02335, 0.0408 and 0.0398). Genes protein-protein interactions analysis identified the two key functional pathways and one network cluster that could play a crucial role in kidney dysfunctions. Lastly, we distinguished that HbS carrier state doesn’t influence the relationship between APOL1 G1/G2 risk alleles and CKD (p value = 0.5725) in this group from subSaharan Africans. Conclusion and perspectives Our study illustrates a strong association between SCT and CKD, an important discovery that will have a major implication in preventative medicine policies and practices in both sub-Saharan African where there is a very high prevalence of SCT. The data also has global resonance, with the projected increase in the prevalence of 12 individual with SCT, due to migration and the improve life expectancy and genetic fitness of people living with both SCT and SCD. We identified a relatively low proportion of (3/29) of target SNPs positively associated with CKD among this group of Cameroonians. The study illustrates that the vast majority of targeted SNPs associated with CKD in GWAS studies in multiple populations including African American, Europeans, and Asians, are not relevant for sub-Saharan Africans, indicating the urgent need to include diverse populations, specifically those living in Africa. Therefore, the data support the possible bias in currently available Polygenic Risk Score generated from GWAS data, where population from sub-Saharan Africa are largely underrepresented. The data further indicate that there is potential to discover new loci associated with CKD when investigating populations of African ancestry living in Africa.
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Kitami, Toshimori. "GENETIC, EVOLUTIONARY, AND GENOMIC ANALYSIS OF HOMOCYSTEINE AND FOLATE PATHWAY REGULATION." Connect to text online, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1127865525.
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Hastings, Rob. "Using 'next-generation' sequencing in the identification of novel causes of inherited heart diseases." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:6555e02b-e0e9-4632-9f75-f403dfcc35a3.
Full textAbstract:
Next-generation sequencing methods now allow rapid and cost-effective sequencing of DNA on a scale not previously possible. This offers great opportunities for the research of Mendelian disorders, but also significant challenges. The sequencing of exomes, or whole genomes, has emerged as a powerful clinical research tool, with targeted gene analyses generally being preferred in the clinical diagnostic setting. These methods have been employed here with the aim of identifying novel genetic causes of inherited heart disorders and to gain insights into the utility and limitations of these techniques for clinical diagnosis in these disorders. Data produced from the introduction of a targeted multi-gene next-generation sequencing test into clinical practice has been studied. Variation within the mitochondrial genome has been analysed to assess the importance of mitochondrial DNA variants in patients with hypertrophic cardiomyopathy. The m.4300A>G mutation is identified as an important cause of this disorder, with other previously cardiomyopathy-associated and novel variants also identified. Such multi-gene tests can facilitate interpretable and phenotype-relevant results, but at the expense of limiting more extensive data acquisition. Whole-genome sequencing has been performed in five families with different autosomal dominant inherited heart disease phenotypes of unknown genetic aetiology. In two of these likely pathogenic variants were identified, one in the gene encoding titin (TTN) and the other in the calcium channel subunit gene CACNA1C. In vitro studies were undertaken to support the pathogenicity of the TTN variant and understand the functional effects of this. In the other three families either multiple candidate gene variants were identified or no clear candidate variant was identified. This highlights the difficulties in interpreting these results, even in carefully selected families. Overall, although the research benefits of exome or genome studies are evident, the interpretation and validation of genetic variant data produced remains highly challenging for clinical diagnosis.
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Wilder, Steven P. "Computational analysis of susceptibility genes for diabetes and cardiovascular diseases in animal models." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670109.
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Raza, Abbas. "Genetic And Functional Approaches To Understanding Autoimmune And Inflammatory Pathologies." ScholarWorks @ UVM, 2020. https://scholarworks.uvm.edu/graddis/1175.
Full textAbstract:
Our understanding of genetic predisposition to inflammatory and autoimmune diseases has been enhanced by large scale quantitative trait loci (QTL) linkage mapping and genome-wide association studies (GWAS). However, the resolution and interpretation of QTL linkage mapping or GWAS findings are limited. In this work, we complement genetic predictions for several human diseases including multiple sclerosis (MS) and systemic capillary leakage syndrome (SCLS) with genetic and functional data in model organisms to associate genes with phenotypes and diseases.
Focusing on MS, an autoimmune inflammatory disease of the central nervous system (CNS), we experimentally tested the effect of three of the GWAS candidate genes (SLAMF1, SLAMF2 and SLAMF7) in the experimental autoimmune encephalomyelitis (EAE) mouse model and found a male-specific locus distal to these loci regulating CNS autoimmune disease. Functional data in mouse suggests this male-specific locus modulates the frequency of immune cells including CD11b+, TCRαβ+CD4+Foxp3+, and TCRαβ+CD8+IL-17+ cells during EAE disease. Orchiectomy experiments demonstrate that this male specific phenotype is dependent on testis but not testosterone (T) or 5α-dihydrotestosterone (DHT). Using a bioinformatic approach, we identified SLAMF8 and SLAMF9 along with other differentially expressed genes in linkage with MS-GWAS predictions whose expression is testis-dependent, but not directly regulated by T or DHT, as potential positional candidates regulating CNS autoimmune disease. Further refinement of this locus is required to identify the causal gene(s) that may be targeted for prevention and/or treatment of MS in men.
Using SCLS, an extremely rare disorder of unknown etiology characterized by recurrent episodes of vascular leakage, we identified and modeled this disease in an inbred mouse strain, SJL, using susceptibility to histamine- and infection-triggered vascular leak as the major phenotypic readout. This trait “Histamine hypersensitivity” (Histh/Histh) was mapped to a region on Chr 6. Remarkably, Histh is syntenic to the genomic locus most strongly associated with SCLS in humans (3p25.3). Subsequent studies found that the Histh locus is not unique to SJL but additional mouse strains also exhibit Histh phenotype. Considering GWAS studies in SCLS are limited by the small number of patients, we utilized interval-specific SNP-based association testing among Histh phenotyped mouse strains to predict Histh candidates. Furthermore, to dissect the complexity of Histh QTL, we developed network-based functional prediction methods to rank genes in this locus by predicting functional association with multiple Histh-related processes. The top-ranked genes include Cxcl12, Ret, Cacna1c, and Cntn3, all of which have strong functional associations and are proximal to SNPs segregating with Histh.
Lastly, we utilized the power of integrating genetic and functional approaches to understand susceptibility to Bordetella pertussis and pertussis toxin (PTX) induced histamine sensitization (Bphs/Bphs), a sub-phenotype with an established role in autoimmunity. Congenic mapping in mice had earlier linked Bphs to histamine H1 receptor gene (Hrh1/H1R) and demonstrated that H1R differs at three amino acid residues in Bphs-susceptible and -resistant mice. Our subsequent studies identified eight inbred mouse strains that were susceptible to Bphs despite carrying a resistant H1R allele. Genetic analyses mapped the locus complementing Bphs to mouse Chr 6, in linkage disequilibrium with Hrh1; we have designated this Bphs-enhancer (Bphse). Similar to the approaches used for Histh, we utilized interval-specific SNP based association testing and network-based functional enrichment to predict nine candidate loci for Bphse including Atp2b2, Atg7, Pparg, Syn2, Ift122, Raf1, Mkrn2, Timp4 and Gt(ROSA)26Sor. Overall, these studies demonstrate the power of integrating genetic and functional methods in humans and animal models to predict highly plausible loci underlying QTL/GWAS data.
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Lees, John Andrew. "Host and pathogen genetics associated with pneumococcal meningitis." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/269395.
Full textAbstract:
Meningitis is an infection of the meninges, a layer of tissue surrounding the brain. In cases of pneumococcal meningitis (where the bacterium Streptococcus pneumoniae is the causat- ive agent) this causes severe inflammation, requiring intensive care and rapid antibiotic treatment. The contribution of variation in host and pathogen genetics to pneumococcal meningitis is unknown. In this thesis I develop and apply statistical genetics techniques to identify genomic variation associated with the various stages of pneumococcal meningitis, including colonisation, invasion and severity. I start by describing the development of a method to perform genome-wide association studies (GWAS) in bacteria, which can find variation in bacterial genomes associated with bacterial traits such as antibiotic resistance and virulence. I then applied this method to longitudinal samples from asymptomatic carriage, and found lineages and specific variants associated with altered duration of carriage. To assess meningitis versus carriage samples I applied similar analysis techniques, and found that the bacterial genome is crucial in determining invasive potential. As well as bacterial serotype, which I found to be the main effect, I discovered many independent sequence variants associated with disease. Separately, I analysed within host-diversity during the invasive phase of disease and found it to be of less relevance to disease progression. Finally, I analysed host genotype data from four independent studies using GWAS and heritability estimates to determine the contribution of human sequence variation to pneumococcal meningitis. Host sequence accounted for some variation in susceptibility to and severity of meningitis. The work concludes with a combined analysis of pairs of bacterial and human sequences from meningitis cases, and finds variation correlated between the two.
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Logue, Kyle J. "Genomic Analyses of the Anopheles punctulatus Group: Insights into Mosquito Biology and Implications for Vector Control and Disease Transmission." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1455900373.
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Wu, Congqing. "THE ROLE OF ANGIOTENSINOGEN IN ATHEROSCLEROSIS AND OBESITY." UKnowledge, 2014. http://uknowledge.uky.edu/nutrisci_etds/16.
Full textAbstract:
Angiotensinogen is the only known precursor in the renin-angiotensin system, a hormonal system best known as an essential regulator of blood pressure and fluid homeostasis. Angiotensinogen is sequentially cleaved by renin and angiotensin- converting enzyme to generate angiotensin II. As the major effector peptide, angiotensin II mainly function through angiotensin type 1 receptor.
Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and more recently renin inhibitors are widely known as the 3 classic renin-angiotensin system inhibitory drugs against hypertension and atherosclerosis. Here, we developed an array of regents to explore the effects of angiotensinogen inhibition. First, we demonstrated that genetic deficiency of angiotensinogen not only protected against hypercholesterolemia- induced atherosclerosis but also prevented diet-induced obesity. Then we found weekly intraperitoneal injection of antisense oligonucleotides against angiotensinogen remarkably surpressed body weight gain in mice fed a western diet, which was absent from classic renin-angiotensin system inhibition. The suppressed body weight gain was attributable to diminished body fat mass gain and enhanced energy expenditure. More excitingly, angiotensinogen antisense oligonucleotides regressed body weight gain on obese mice. Together, our findings revealed a unique feature of angiotensinogen inhibition beyond classic renin angiotensin inhibition and demonstrated therapeutic potentials of angiotensinogen antisense oligonucleotides against hypertension, atherosclerosis, and obesity.
We also developed an in vivo system to explore the functional consequences of disrupting a conserved Cys18-Cys137 disulfide bridge in angiotensinogen. The formation of this disulfide bridge could trigger conformational changes in angiotensinogen, thereby facilitating renin cleavage of angiotensinogen. It was predicted that the redox-sensitive disulfide bridge might change the efficiency of angiotensinogen/renin reaction to release angiotensin II, thus modulate angiotensin II-dependent functions. We determined effects of the presence and absence of the disulfide bridge on angiotensin II concentrations and responses in mice expressing either native angiotensinogen or Cys18Ser, Cys137Ser mutated angiotensinogen in liver via adeno-associated viral vectors. Contrary to the prediction, disruption of Cys18-Cys137 disulfide bridge in angiotensinogen had no discernible effects on angiotensin II production and angiotensin II-dependent functions in mice.
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Kaymaz, Yasin. "Genomic and Transcriptomic Investigation of Endemic Burkitt Lymphoma and Epstein Barr Virus." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/914.
Full textAbstract:
Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein-Barr virus (EBV), unlike sporadic Burkitt Lymphoma (sBL) that occurs with a lower incidence in developed countries. Despite this increased burden the study of eBL has lagged. Additionally, while EBV was isolated from an African Burkitt lymphoma tumor 50 years ago, however, the impact of viral variation in oncogenesis is just beginning to be fully explored. In my thesis research, I focused on investigating molecular genetics of the endemic form of this lymphoma with a particular emphasis on the role of the virus and its variation in pathogenesis using novel sequencing and bioinformatic strategies.
First, we sought to understand pathogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from 30 primary eBL tumors and compared to sBL tumors. BL tumor samples were prospectively obtained from 2009 until 2012 in Kenya. Within eBL tumors, minimal expression differences were found based on anatomical presentation site, in-hospital survival rates, and EBV genome type; suggesting that eBL tumors are homogeneous without marked subtypes. The outstanding difference detected using surrogate variable analysis was the significantly decreased expression of key genes in the immunoproteasome complex in eBL tumors carrying type 2 EBV compared to type 1 EBV. Secondly, in comparison to previously published pediatric sBL specimens, the majority of the expression and pathway differences were related to the PTEN/PI3K/mTOR signaling pathway and was correlated most strongly with EBV status rather than the geographic designation. Moreover, the common mutations were observed significantly less frequently in eBL tumors harboring EBV type 1, with mutation frequencies similar between tumors with EBV type 2 and without EBV. In addition to the previously reported genes, we identified a set of new genes mutated in BL. Overall, these suggested that EBV, particularly EBV type 1, supports BL oncogenesis alleviating the need for particular driver mutations in the human genome.
Second, we sought to comprehensively define sequence variations of EBV across the viral genome in eBL tumor cells and normal infections, and correlate variations with clinical phenotypes and disease risk. We investigated the whole genome sequence of EBV from primary tumors (N=41) and plasma from eBL patients (N=21) as well as EBV in the blood of healthy children (N=29) within the same malaria endemic region. We conducted a genome wide association analysis study with viral genomes of healthy kids and BL kids. Furthermore, we found that the frequencies of EBV types among healthy kids were at equal levels while they were skewed in favor of type 1 (70%) among eBL kids. To pinpoint the fundamental divergence between viral genome subtypes, type 1 and type 2, we constructed phylogenetic trees comparing to all public EBV genomes. The pattern of variation defined the substructures correlated with the subtypes. This investigation not only deciphers the puzzling pathogenic differences between subtypes but also helps to understand how these two EBV types persist in the population at the same time.
Overall, this research provides insight into the molecular underpinning of eBL and the role of EBV. It further provides the groundwork and means to unravel the complexity of EBV population structure and provide insight into the viral variation that may influence oncogenesis and outcomes in eBL and other EBV-associated diseases. In addition, genomic and mutational analyses of Burkitt lymphoma tumors identify key differences based on viral content and clinical outcomes suggesting new avenues for the development of prognostic molecular biomarkers and therapeutic interventions.
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Kaymaz, Yasin. "Genomic and Transcriptomic Investigation of Endemic Burkitt Lymphoma and Epstein Barr Virus." eScholarship@UMMS, 2007. http://escholarship.umassmed.edu/gsbs_diss/914.
Full textAbstract:
Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein-Barr virus (EBV), unlike sporadic Burkitt Lymphoma (sBL) that occurs with a lower incidence in developed countries. Despite this increased burden the study of eBL has lagged. Additionally, while EBV was isolated from an African Burkitt lymphoma tumor 50 years ago, however, the impact of viral variation in oncogenesis is just beginning to be fully explored. In my thesis research, I focused on investigating molecular genetics of the endemic form of this lymphoma with a particular emphasis on the role of the virus and its variation in pathogenesis using novel sequencing and bioinformatic strategies.
First, we sought to understand pathogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from 30 primary eBL tumors and compared to sBL tumors. BL tumor samples were prospectively obtained from 2009 until 2012 in Kenya. Within eBL tumors, minimal expression differences were found based on anatomical presentation site, in-hospital survival rates, and EBV genome type; suggesting that eBL tumors are homogeneous without marked subtypes. The outstanding difference detected using surrogate variable analysis was the significantly decreased expression of key genes in the immunoproteasome complex in eBL tumors carrying type 2 EBV compared to type 1 EBV. Secondly, in comparison to previously published pediatric sBL specimens, the majority of the expression and pathway differences were related to the PTEN/PI3K/mTOR signaling pathway and was correlated most strongly with EBV status rather than the geographic designation. Moreover, the common mutations were observed significantly less frequently in eBL tumors harboring EBV type 1, with mutation frequencies similar between tumors with EBV type 2 and without EBV. In addition to the previously reported genes, we identified a set of new genes mutated in BL. Overall, these suggested that EBV, particularly EBV type 1, supports BL oncogenesis alleviating the need for particular driver mutations in the human genome.
Second, we sought to comprehensively define sequence variations of EBV across the viral genome in eBL tumor cells and normal infections, and correlate variations with clinical phenotypes and disease risk. We investigated the whole genome sequence of EBV from primary tumors (N=41) and plasma from eBL patients (N=21) as well as EBV in the blood of healthy children (N=29) within the same malaria endemic region. We conducted a genome wide association analysis study with viral genomes of healthy kids and BL kids. Furthermore, we found that the frequencies of EBV types among healthy kids were at equal levels while they were skewed in favor of type 1 (70%) among eBL kids. To pinpoint the fundamental divergence between viral genome subtypes, type 1 and type 2, we constructed phylogenetic trees comparing to all public EBV genomes. The pattern of variation defined the substructures correlated with the subtypes. This investigation not only deciphers the puzzling pathogenic differences between subtypes but also helps to understand how these two EBV types persist in the population at the same time.
Overall, this research provides insight into the molecular underpinning of eBL and the role of EBV. It further provides the groundwork and means to unravel the complexity of EBV population structure and provide insight into the viral variation that may influence oncogenesis and outcomes in eBL and other EBV-associated diseases. In addition, genomic and mutational analyses of Burkitt lymphoma tumors identify key differences based on viral content and clinical outcomes suggesting new avenues for the development of prognostic molecular biomarkers and therapeutic interventions.
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Li, Yafang. "Genetic association analysis incorporating intermediate phenotypes information for complex diseases." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/2739.
Full textAbstract:
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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Fetter, Karl Christian. "Natural Selection For Disease Resistance In Hybrid Poplars Targets Stomatal Patterning Traits And Regulatory Genes." ScholarWorks @ UVM, 2019. https://scholarworks.uvm.edu/graddis/1162.
Full textAbstract:
The evolution of disease resistance in plants occurs within a framework of interacting
phenotypes, balancing natural selection for life-history traits along a continuum of
fast-growing and poorly defended, or slow-growing and well-defended lifestyles. Plant
populations connected by gene flow are physiologically limited to evolving along a
single axis of the spectrum of the growth-defense trade-off, and strong local selection
can purge phenotypic variance from a population or species, making it difficult to
detect variation linked to the trade-off. Hybridization between two species that have
evolved different growth-defense trade-off optima can reveal trade-offs hidden in either
species by introducing phenotypic and genetic variance. Here, I investigated the
phenotypic and genetic basis for variation of disease resistance in a set of naturally
formed hybrid poplars.
The focal species of this dissertation were the balsam poplar (Populus balsamifera),
black balsam poplar (P. trichocarpa), narrowleaf cottonwood (P. angustifolia), and
eastern cottonwood (P. deltoides). Vegetative cuttings of samples were collected from
natural populations and clonally replicated in a common garden. Ecophysiology and
stomata traits, and the severity of poplar leaf rust disease (Melampsora medusae)
were collected. To overcome the methodological bottleneck of manually phenotyping
stomata density for thousands of cuticle micrographs, I developed a publicly available
tool to automatically identify and count stomata. To identify stomata, a deep con-
volutional neural network was trained on over 4,000 cuticle images of over 700 plant
species. The neural network had an accuracy of 94.2% when applied to new cuticle
images and phenotyped hundreds of micrographs in a matter of minutes.
To understand how disease severity, stomata, and ecophysiology traits changed
as a result of hybridization, statistical models were fit that included the expected
proportion of the genome from either parental species in a hybrid. These models in-
dicated that the ratio of stomata on the upper surface of the leaf to the total number
of stomata was strongly linked to disease, was highly heritable, and wass sensitive
to hybridization. I further investigated the genomic basis of stomata-linked disease
variation by performing an association genetic analysis that explicitly incorporated
admixture. Positive selection in genes involved in guard cell regulation, immune sys-
tem negative regulation, detoxification, lipid biosynthesis, and cell wall homeostasis
were identified.
Together, my dissertation incorporated advances in image-based phenotyping with
evolutionary theory, directed at understanding how disease frequency changes when
hybridization alters the genomes of a population.
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Berisha, Stela Z. "Genetics and Genomics of Complex Diseases: Mouse Atherosclerosis Modifier Genes and Human Gene Expression after Bariatric Surgery." Cleveland State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=csu1285686720.
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Marian, Ali J., Rooij Eva van, and Robert Roberts. "Genetics and Genomics of Single-Gene Cardiovascular Diseases : Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders." ELSEVIER SCIENCE INC, 2016. http://hdl.handle.net/10150/623130.
Full textAbstract:
This is the first of 2 review papers on genetics and genomics appearing as part of the series on “omics.” Genomics pertains to all components of an organism’s genes, whereas genetics involves analysis of a specific gene(s) in the context of heredity. The paper provides introductory comments, describes the basis of human genetic diversity, and addresses the phenotypic consequences of genetic variants. Rare variants with large effect sizes are responsible for single gene disorders, whereas complex polygenic diseases are typically due to multiple genetic variants, each exerting a modest effect size. To illustrate the clinical implications of genetic variants with large effect sizes, 3 common forms of hereditary cardiomyopathies are discussed as prototypic examples of single-gene disorders, including their genetics, clinical manifestations,
pathogenesis, and treatment. The genetic basis of complex traits is discussed in a separate paper.
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Radhakrishnan, Jayachandran. "Functional genomics of severe sepsis and septic shock." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:2b2afd65-82e0-4847-b7ae-960635b7e884.
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Sepsis is the systemic inflammatory response to an infection. Severe sepsis with multi organ failure is one of the commonest causes of admission to intensive care units, and is associated with poor early and late outcomes. The pathophysiology of sepsis is complex, and poorly understood. This is reflected in the limited and contentious treatment options for sepsis. Genetic factors have been shown to be associated with the risk of and subsequent outcomes from infection. However, clear associations with bacterial sepsis are rare, and even when associations are present their functional effects are often unknown. Gene expression signatures in sepsis are investigated in this project using serial samples obtained from patients admitted to intensive care units with community-acquired pneumonia or faecal peritonitis. The evolving gene expression signatures that define the response to sepsis were identified with large changes seen in genes coding for ribosomal proteins RPS4Y1 and RPS26P54. The differences in the sepsis response between the two diagnostic classes were examined. The gene expression predictors of mortality in sepsis were determined and include genes from the class II MHC HLA-DRB4, HLA-DRB5 and the T cell differentiation protein MAL. The effects of important covariates on gene expression were investigated and their impact on survival related expression determined. The findings were confirmed in a validation cohort. A novel clustering of samples representing distinct inflammatory patterns in a clinically homogeneous population of sepsis patients was identified and related to differences in clinical behaviour. The biological relevance of the differentially expressed genes was ascertained by identifying enriched gene sets. The gene expression changes in sepsis were examined in the context of related clinically relevant immune phenomena: the sterile systemic inflammatory response in patients undergoing elective cardiac surgery and the phenomenon of endotoxin tolerance in PBMCs derived from healthy volunteers. The results highlight the complexities of clinical sepsis and identify hypotheses for future investigations.
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Heyns, I. C. "Mapping and restructuring of an Ae. kotschyi derived translocation segment in common wheat." Thesis, Stellenbosch : University of Stellenbosch, 2010. http://hdl.handle.net/10019.1/5172.
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Thesis (PhD (Genetics))--University of Stellenbosch, 2010.Includes bibliography.
ENGLISH ABSTRACT: The wild relatives are an important source of new genes for the genetic improvement of wheat. At Stellenbosch University the leaf and stripe rust resistance genes Lr54 and Yr37 were transferred from Aegilops kotschyi to chromosome 2DL of wheat. In an attempt to reduce the size of the whole-arm translocation on which the resistance genes occur, homoeologous pairing was induced between the wheat and corresponding Ae. kotschyi chromatin. The purpose of this study was to: (i) Evaluate the testcross progeny thus obtained; identify translocation recombinants that retained Lr54/Yr37 and to characterize these using molecular markers (ii) Test for the presence of genes for photoperiod insensitivity (Ppd) and reduced height (Rht) believed to be associated with the translocation (iii) Develop a SCAR marker for the most useful recombinant that could be recovered. Ten putative translocation recombinants were identified following the screening of 159 hemizygous testcross F1 plants with three microsatellite markers specific for chromosome arm 2DL. The recombinants were then characterized with another five microsatellite markers. Using the eight microsatellite markers the recombinants were ordered in two size categories with recombinant #74 being the shortest and having retained only proximal alien chromatin on 2DL. In addition to microsatellite markers, RAPDs, RGAs, AFLPs and SCAR markers were genetically mapped to the translocation and further resolved the recombinants into three size categories. In an attempt to find suitable markers linked to the shortest recombinant (#74) a polymorphic 410 bp AFLP fragment produced with the enzyme/selective nucleotide combination EcoRI – AAC/MseI – CAT, was converted into a dominant SCAR marker. In addition three microsatellite markers that mapped to recombinant #74 provided a useful recessive molecular marker system to detect Lr54/Yr37. Evaluation of the 10 recombinants with four 2DS-specific microsatellite markers revealed a large deletion of this chromosome arm in recombinant #74. This deletion may affect plant phenotypic characteristics and a strategy to replace the deleted region in recombinant #74 is proposed. To test for the presence of a gene for photoperiod insensitivity on the translocation, translocation-carriers plus controls were subjected to long and short day treatments, and the effect on time to flowering was studied. However, no evidence was found for the presence of such a gene. A height experiment to test for the presence of an Rht gene on the translocation confirmed its presence. This gene (designated H) appeared to be different from Rht8 on chromosome 2DS and was mapped on 2DL. While H does not occur in a chromosome region that corresponds with the location of Rht8, it does not rule out the possibility that they could be orthologous loci. Plant height data obtained for recombinant #74 suggested that H was lost through recombination in this particular recombinant. A greenhouse experiment suggested that the full-length translocation increased 100 kernel mass but had a detrimental effect on overall plant yield. Since a much shorter recombinant (#74) has been obtained, this will also have to be evaluated for associated effects. Such an evaluation needs to be done under commercial growing conditions and should involve the comparison of near-isogenic bulks with and without recombinant chromosome #74. The stripe rust resistance gene (Yr37) was mapped by screening hemizygous TF2 progeny of the 10 recombinants with Puccinia striiformis pathotype 6E22A+. Recombinant #74 retained both Lr54 and Yr37 and the two genes therefore occur towards the centromere.
AFRIKAANSE OPSOMMING: Wilde verwante spesies is ‘n belangrike bron van nuwe gene vir die genetiese verbetering van koring. By die Universiteit van Stellenbosch is die blaar-roes en streep-roes weerstandsgene Lr54 en Yr37 vanaf Aegilops kotschyi na chromosoom 2DL van koring oorgedra. ‘n Poging is vervolgens aangewend om die vol-armtranslokasie waarop die weerstandsgene voorkom te verklein deur homoeoloë paring tussen die koring en ooreenstemmende Ae. kotschyi chromatien te induseer. Die doelstelling van hierdie studie was daarom as volg: (a) Evaluering van die verkreë toetskruis-nageslag asook die identifisering en karakterisering van translokasie rekombinante wat Lr54/Yr37 behou het. (b) Toetsing vir fotoperiode onsensitiwiteits- (Ppd) en verkorte plant-hoogte (Rht) gene wat moontlik op die translokasie kon voorkom. (c) Die ontwikkeling van ‘n volgorde-spesifieke polimerase kettingreaksie (PKR) vir die mees bruikbare rekombinant. Tien translokasie rekombinante is geïdentifiseer nadat 159 hemisigotiese toetskruis F1-plante met drie mikrosatelliet-merkers, spesifiek vir chromosoom-arm 2DL, ge-evalueer is. Die rekombinante is hierna met vyf verdere mikrosatellietmerkers getoets. Die data van die agt mikrosatelliet-loci het die rekombinante in twee grootte-kategorieë geplaas waarvan rekombinant #74 die kortste was met slegs die proksimale gedeelte van 2DL wat uit vreemde chromatien bestaan. Behalwe mikrosatellite-merkers is toevallig-geamplifiseerde polimorfiese DNS (RAPD), weerstandsgeen-analoog (RGA), geamplifiseerde volgordelengte polimorfisme (AFLP) en volgorde-gekarakteriseerde geamplifiseerde-streke (SCAR) merkers ook geneties op die translokasie gekarteer. Data van die addisionele merkers het dit moontlik gemaak om die rekombinante in drie grootte-kategorieë te skei. Pogings om ‘n merker vir die kortse rekombinant (#74) te vind, het gelei tot die omskakeling van ‘n 410 bp polimorfiese AFLP-fragment (geproduseer met die ensiem/selektiewenukleotied kombinasie EcoRI - AAC/MseI - CAT), na ‘n dominante, volgordespesifieke PKR-merker. Hierbenewens kan drie mikrosatelliet-merkers wat op rekombinant #74 karteer as resessiewe merkers vir die identifisering van Lr54/Yr37 gebruik word. Die evaluering van die 10 rekombinante met vier chromosoom 2DSspesifieke mikrosatelliet-merkers het ‘n groot delesie van chromosoom-arm 2DS in rekombinant #74 uitgewys. Die delesie mag plant fenotipiese kenmerke beïnvloed en daarom is ‘n strategie vir die vervanging daarvan in rekombinant #74 voorgestel. Ten einde te toets of ‘n geen vir fotoperiode-onsensitiwiteit op die translokaie voorkom is translokasie-draers en kontroles aan lang- en kortdag-behandelings onderwerp en is die effek hiervan op dae-tot-blom gemeet. Geen bewyse vir so ‘n geen kon gevind word nie. ‘n Hoogte-eksperiment om te toets vir die teenwoordigheid van ‘n Rht-geen op die translokasie, het bevestig dat so ‘n geen wel voorkom. Die geen (voorgestelde simbool H) is gekarteer op 2DL en verskil oënskynlik van Rht8 op chromosoom 2DS. Die verskillende chromosoom-ligging van H en Rht8 skakel egter nie die moontlikheid dat hulle ortoloë loci mag wees uit nie. Plant-hoogte data vir rekombinant #74 het daarop gedui dat H nie meer in hierdie rekombinant voorkom nie. Data van ‘n glashuis-eksperiment het daarop gedui dat die vollengte-translokasie 100-korrel-massa verhoog maar dat dit plant-opbrengs verlaag. Aangesien ‘n aansienlike korter rekombinant (#74) verkry is, sal dit ook vir gekoppelde effekte getoets moet word. So ‘n evaluering moet egter onder kommersiële toestande gedoen word met gebruik van naby isogeniese-lyne met en sonder rekombinante chromosoom #74. Die streep-roes weerstandgeen (Yr37) is gekarteer deur hemisigotiese TF2- nageslag van die 10 rekombinante te toets vir weerstand teen Puccinia striiformis patotipe 6E22A+. Rekombinant #74 het beide Lr54 en Yr37 behou en die twee gene karteer dus naby die sentromeer.
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Beach, Joshua S. "Functional Characterization of rai1 in Zebrafish." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3826.
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Smith-Magenis Syndrome (SMS; OMIM #182290) is a multiple congenital abnormality and intellectual disability (ID) disorder caused by either an interstitial deletion of the 17p11.2 region containing the retinoic acid induced-1 (RAI1) gene or a mutation of the RAI1 gene. Individuals diagnosed with SMS typically present characteristics such as ID, self-injurious behavior, sleep disturbance, ocular and otolaryngological abnormalities, craniofacial and skeletal abnormalities, neurological and behavioral abnormalities, as well as other systemic defects and manifestations. Previous work by Vyas in 2009 showed temporal expression of rai1 in zebrafish embryos as early as 9 hpf. We hypothesize that there is maternal rai1 expression as early as zero hours post fertilization in wild type embryos. Using end-point PCR, we found that in fact there is maternal rai1 expression is detectable as early as 2 hours post fertilization (hpf) in wild type zebrafish embryos. Furthermore, we quantified rai1 expression using qPCR and found that rai1 expression declines significantly after 6 hpf. We hypothesize that a down regulation of rai1 or loss of rai1 will lead to morphological phenotypes, especially if that loss of rai1 function occurs during the earliest stages of zebrafish embryogenesis. Using a rai1morpholino oligonucleotide (MO), we found a loss of rai1 expression did not induce a morphological phenotype in in wild type embryos; furthermore, we also found that a loss of maternal rai1 expression did not induce a morphological phenotype as well. Utilizing a mutant rai1 zebrafish line, we found that both rai1 +/fh370 progeny nor rai1 fh370/fh370 progeny exhibited a morphological phenotype and that downstream targets such as bdnf were not affected by a reduction or complete loss of rai1. Prior research has shown that retinoic acid (RA) can induce rai1 expression. We hypothesize that RA can induce expression of rai1 during zebrafish embryogenesis. Using wild type fish and a rai1 in situ hybridization probe, we found that RA treatment at 25 hpf induced expression of rai1. The construction of a rai1 overexpression vector used for overexpression studies was started. Further development of GFP expression vector and zebrafish rai1 antibody are needed to determine if the morpholino is reducing rai1 protein expression.
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Radford, Elizabeth Jane. "Investigating the contribution of imprinting and epigenetic inheritance to the developmental origins of health and disease." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609907.
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Karaderi, Tugce. "Genetics of ankylosing spondylitis." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:8c0e848a-e712-4603-b923-a96a2f1644ac.
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Ankylosing spondylitis (AS) is a common inflammatory arthritis of the spine and other affected joints, which is highly heritable, being strongly influenced by the HLA-B27 status, as well as hundreds of mostly unknown genetic variants of smaller effect. The aim of my research was to confirm some of the previously observed genetic associations and to identify new associations, many of which are in biological pathways relevant to AS pathogenesis, most notably the IL-23/TH17 axis (IL23R) and antigen presentation (ERAP1 and ERAP2). Studies presented in this thesis include replication and refinement of several potential associations initially identified by earlier GWAS (WTCCC-TASC, 2007 and TASC, 2010). I conducted an extended study of IL23R association with AS and undertook a meta-analysis, confirming the association between AS and IL23R (non-synonymous SNP rs11209026, p=1.5 x 10-9, OR=0.61). An extensive re-sequencing and fine mapping project, including a meta-analysis, to replicate and refine the association of TNFRSF1A with AS was also undertaken; a novel variant in intron 6 was identified and a weak association with a low frequency variant, rs4149584 (p=0.01, OR=1.58), was detected. Somewhat stronger associations were seen with rs4149577 (p=0.002, OR=0.91) and rs4149578 (p=0.015, OR=1.14) in the meta-analysis. Associations at several additional loci had been identified by a more recent GWAS (WTCCC2-TASC, 2011). I used in silico techniques, including imputation using a denser panel of variants from the 1000 Genomes Project, conditional analysis and rare/low frequency variant analysis, to refine these associations. Imputation analysis (1782 cases/5167 controls) revealed novel associations with ERAP2 (rs4869313, p=7.3 x 10-8, OR=0.79) and several additional candidate loci including IL6R, UBE2L3 and 2p16.3. Ten SNPs were then directly typed in an independent sample (1804 cases/1848 controls) to replicate selected associations and to determine the imputation accuracy. I established that imputation using the 1000 Genomes Project pilot data was largely reliable, specifically for common variants (genotype concordence~97%). However, more accurate imputation of low frequency variants may require larger reference populations, like the most recent 1000 Genomes reference panels. The results of my research provide a better understanding of the complex genetics of AS, and help identify future targets for genetic and functional studies.
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Harshfield, Eric Leigh. "Genomics of lipid metabolism : identification of genetic determinants of lipid metabolites and the effect of perturbations of lipid levels on coronary heart disease risk factors." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/277818.
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Background: Coronary heart disease (CHD) is one of the leading causes of death worldwide, and global mortality rates are expected to continue to rise over the coming decades. In Pakistan in particular, chronic diseases are responsible for 50% of the total disease burden. Circulating lipids are strongly and linearly associated with risk of CHD; however, despite considerable efforts to demonstrate causality, available evidence is conflicting and insufficient. Study of the underlying metabolic pathways implicated in the association between lipids and CHD would help to disentangle and elucidate these complex relationships. Objectives: The primary objectives of this dissertation were to (1) identify the genetic determinants of lipid metabolites and (2) advance understanding of the effect of perturbations in lipid metabolite levels on CHD and its risk factors. Methods: Direct infusion high-resolution mass spectrometry was performed on 5662 participants from the Pakistan Risk of Myocardial Infarction Study to obtain signals for 444 known lipid metabolites. Correlations and associations of the lipids with smoking, physical activity, circulating biomarkers, and other CHD risk factors were assessed. Genome-wide analyses were conducted to analyse the association of each lipid with over 6.7 million imputed single nucleotide polymorphisms. Functional annotation and Gaussian Graphical Modelling were used to link the variants associated with each lipid to the most likely mediating gene, discern the underlying metabolic pathways, and provide a visual representation of the genetic determinants of human metabolism. Mendelian randomisation was also implemented to examine the causal effect of lipids on risk of CHD. Results: The lipids were highly correlated with each other and with levels of major circulating lipids, and they exhibited significant associations with several CHD risk factors. There were 254 lipids that had significant associations with one or more genetic variants and 355 associations between lipids and variants, with a total of 89 sentinel variants from 23 independent loci. The analyses described in this dissertation resulted in the discovery of four novel loci, identified novel relationships between genetic variants and lipids, and revealed new biological insights into lipid metabolism. Conclusion: Analyses of lipid metabolites in large epidemiological studies can contribute to enhanced understanding of mechanisms for CHD development and identification of novel causal pathways and new therapeutic targets.
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Yuan, Jiazheng. "MOLECULAR APPROACHES TO ANALYZE HORIZONTAL RESISTANCE AMONG PLANT SPECIES (MAIZE, SOYBEAN, AND ARABIDOPSIS) TO SYNTENIC FUSARIAL PATHOGENS (F. GRAMINEARUM AND F. VIRGULIFORME)." OpenSIUC, 2010. https://opensiuc.lib.siu.edu/dissertations/247.
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Numerous evidences showed that the resistance to syntenic fungal species Fusarium graminearum and Fusarium virguliforme infection in plants was partial, quantitative, and strongly influenced by environmental conditions. However, the molecular mechanisms underlying the resistance are still not fully understood. The objectives of this dissertation were to investigate the molecular mechanisms underlying the resistance in different plant species (mainly in maize, soybean, and Arabidopsis); identify and clone disease resistance genes; decipher their quantitative responses to Fusarial pathogens and mycotoxin deoxynivalenol (DON); identified genes that were transcriptionally regulated when the plants were treated with the pathogens and toxin. Methods were used to achieve these objectives including mapping, isolation, characterization, and functional analyses of genes implicated in disease resistance; analysis of microsynteny at their encoding loci; and identification of orthologs that might be associated with resistance to pathogen Fusaria across plant species etc. First, a maize gene that encoded a putative guanylyl cyclase-like protein (ZmGC1; EC 4.6.1.2) was characterized and shown to be associated with resistance to Gibberella ear rot caused by F. graminearum. The putative ZmGC1 amino acid sequence was 53% identical and 65% similar to AtGC1, one of the two Arabidopsis proteins known to possess an active and substrate specific guanylyl cyclase enzymatic function. Using a probe derived from the maize guanylyl cyclase-like gene (Zmgc1) to screen a recombinant inbred population developed from `CO387' (a partially resistant variety) X `CG62' (a partially susceptible variety), several polymorphic molecular markers were identified and four of them were significantly associated with Gibberella ear rot resistance in different environments. Polymorphisms were functional since the amount of Zmgc1 transcripts accumulating in ears increased more quickly and to a higher amount in the resistant genotype compared to the susceptible genotype after inoculation with F. graminearum. Furthermore, transcripts were responding to fungicidal activity when the maize seedlings (CO387) were treated with a fungicide, probenazole (3-allyloxy-1,2-benzothiazole-1,1-dioxide, PBZ). The transcript abundance (TA) of the maize Zmgc1 gene was increased more than 10 fold 8 hours after PBZ treatment. In contrast, the TA of Zmnbslrr1 (a NBS-LRR gene) transcript was significantly reduced in the Gibberella ear rot resistant genotype CO387 after the treatment with PBZ in the time-course study. Therefore, natural resistance and fungicide induced resistance may share common transcript abundance changes in maize plants. Second, to examine global effects of Fusarial pathogens on transcript abundance, cDNA microarrays from the model plant Arabidopsis thaliana were used. After Arabidopsis thaliana cv 'Columbia' was infested with Fusarium virguliforme, 168 transcripts were increased, nearly four times more than that of decreased. A. thaliana seedling growth was reduced by the pathogen in a proportional response to increasing spore concentrations. A set of putative resistance pathways involved in responding to the pathogen infection in A. thaliana was identified. Functional analyses of the orthologs of the responding genes between soybean and A. thaliana showed that the resistance responses had both common elements in some pathways (primary metabolism) and species specific differences in others (secondary metabolism). For example, the phenylpropanoid pathway response was different between the two species. In contrast to soybean, the phenylpropanoid pathway was not fully activated during the resistance response in Arabidopsis. Therefore, soybean and Arabidopsis did not share completely overlapping strategies in the specific pathways induced during resistance to F. virguliforme. Resistance to Fusarial toxins is a common mechanism for plant resistance. The mycotoxin deoxynivalenol (DON), produced by Gibberella zeae (the teleomorph of F. graminearum), was known to be both a virulence factor in the pathogenesis of wheat and an inhibitor of Arabidopsis seed germination. A. thaliana seedling growth was reduced by the toxin in a proportional response to increasing concentrations. A parallel comparison with a set of resistance pathways involved in response to the DON toxicity in A. thaliana was performed. The alterations of transcript abundances in the Arabidopsis plants treated with the toxin suggest that DON plays a significant role affecting the key primary metabolisms in Arabidopsis plants. The alterations ranged from the protein metabolism to redox production. New putative resistance pathways involved in responding to both pathogen and DON infestation in soybean and A. thaliana were described.
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Lemes, Da Silva Cristiano. "Genomic approaches for mapping and predicting disease resistance in wheat (Triticum aestivum L.)." Diss., Kansas State University, 2017. http://hdl.handle.net/2097/38555.
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Doctor of PhilosophyGenetics Interdepartmental Program
Allan K. Fritz
Wheat diseases cause significant economic losses every year. To ensure global food security, newly released cultivars must possess increased levels of broadly-effective resistance against wheat pathogens, acceptable end-use quality, and high yield potential. Genetic host resistance stands out from other management strategies as the most viable option for controlling diseases. New genotyping platforms allow whole genome marker discovery at a relatively low cost, favoring the identification of novel loci underlying traits of interest. The work presented here describes genomic approaches for mapping and predicting the resistance to Fusarium head blight (FHB) and wheat rusts. The first study used biparental mapping to identify quantitative trait loci (QTL) associated with Fusarium head blight (FHB) resistance. A doubled haploid population (DH) was originated from a cross of Everest and WB-Cedar, which are widely grown wheat cultivars in Kansas with moderately resistant and moderately susceptible reactions to FHB, respectively. We confirmed that neither of the parents carry known large-effect QTLs, suggesting that FHB resistance is native. Eight small-effect QTLs were identified as associated with multiple mechanisms of FHB resistance. All QTLs had additive effects, providing significant improvements in levels of resistance when they were found in combinations within DH lines. In the second study, a genome-wide association mapping (GWAS) and genomic selection (GS) models were applied for FHB resistance in a panel of 962 elite lines from the K-State Wheat Breeding Program. Significant single nucleotide polymorphisms (SNPs) associated with the percentage of symptomatic spikelets were identified but not reproducible across breeding panels tested in each year. Accuracy of predictions ranged from 0.25 to 0.51 depending on GS model, indicating that it can be a useful tool to increase levels of FHB resistance. GWAS and GS approaches were also applied to a historical dataset to identify loci underlying resistance to leaf and stem rust at seedling stage in a panel of elite winter wheat lines. Infection types of multiple races of wheat rusts from the last sixteen years of the Southern Regional Performance Nursery (SRPN) were used in this study. A total of 533 elite lines originating from several breeding programs were tested in the SRPN during this period of time. GWAS identified significant SNP-trait associations for wheat rusts, confirming the effectiveness of already known genes and revealing potentially novel loci associated with resistance.
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Voorhees, Grace Kathryn. "Understanding the Role of Androgen Receptor Signaling in Modulating p38-alpha Mitogen-Activated Protein Kinase in Experimental Autoimmune Encephalomyelitis." ScholarWorks @ UVM, 2019. https://scholarworks.uvm.edu/graddis/1144.
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Multiple Sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system, characterized by axonal demyelination and multifocal inflammation. Like many autoimmune diseases, it is a sexually dimorphic disease, being 3-4 times more common in females than in males. p38α MAP kinase (MAPK) has an integral role in modulating inflammatory processes in autoimmunity. Conditionally ablating p38α MAPK in myeloid cells in B6 mice shows a sex difference in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). In the absence of sex hormones, this sex difference was reversed, suggesting a role for sex hormones in modulating p38α MAPK signaling in EAE. Based on these findings, we hypothesized that pro-inflammatory functions in EAE is p38-indepdendent in the presence of androgens and p38-dependent in the presence of estrogens. For the purposes of this project, the role of androgens was evaluated. Both in vivo and in vitro techniques were used to assess how androgen receptor (AR) signaling: 1) impacts EAE pathogenesis, and 2) impacts the role of p38α in EAE pathogenesis and macrophage function. To this end, using Cre-Lox technology, we generated mice deficient in: 1) AR globally or conditionally in macrophages, as well as 2) mice doubly deficient in AR and p38α. In vivo results from p38α-sufficient global AR knockout mice show no effect of global AR deletion on EAE pathogenesis. Surprisingly, results from p38α-sufficient conditional AR knockout mice showed significant worsening in disease compared to WT counterparts, suggesting that AR signaling in myeloid cells has a protective role in EAE pathogenesis. These findings implicate a protective role for AR signaling in EAE. Studies with mice doubly deficient in p38α and AR to determine whether AR regulates the role of p38α in EAE are ongoing, but so far show no effect on AR deletion on the role of p38α MAPK. Further studies with larger cohorts of mice are needed elucidate the relationship between AR and p38α MAPK signaling in myeloid cells in EAE pathogenesis. In vitro studies using the immortalized macrophage cell line RAW 264.7 showed that pharmacologic inhibition of p38 MAPK after stimulation with LPS reduced the production of classic pro-inflammatory cytokines IL-6 and TNFα, and effect that was not affected by treatment with 5-dihydrotestosterone, suggesting that the AR does not modulate the role of p38α in cytokine production. These findings implicate no direct role of AR signaling on the functional role of p38α MAPK in the myeloid cell lineage in inflammatory and autoimmune responses.
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Reschen, Michael. "Epigenetic approaches to the study of macrophages in atherosclerosis." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:cb314b79-afc5-48a0-aa05-fe57843b8dcc.
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Coronary artery disease (CAD) is caused by atherosclerosis, a chronic inflammatory response to modified lipoproteins. A key pathophysiological event is the lipid-induced transformation of macrophages into lipid-laden foam cells and their accumulation in atherosclerotic plaques. Heritable CAD risk is associated with common genetic variants at over 40 genomic loci; the underlying causal mechanisms remain largely unknown and could affect transcriptional regulation in foam cells. Epigenetic and gene expression changes were measured in primary human macrophages before and after exposure to atherogenic, oxidized low-density lipoprotein—with resultant foam cell formation. This unbiased approach involved open chromatin mapping with formaldehyde-assisted isolation of regulatory elements with enhancer and transcription factor mapping using chromatin immuno-precipitation. Foam cell formation was associated with changes in a subset of open chromatin and enhancer sites that were strongly correlated with expression of nearby genes. OxLDL-regulated enhancers were enriched for several transcription factors—including C/EBP-beta— that have no previously documented role in foam cell formation. OxLDL exposure up-regulated C/EBP-beta expression and increased C/EBP-beta binding across the genome, most prominently around genes involved in inflammatory response pathways. Variants at CAD-associated loci were enriched in the subset of oxLDLregulated open chromatin sites. These included rs72664324 in an oxLDL-induced super-enhancer at the PPAP2B locus. OxLDL increased C/EBP-beta binding at rs72664324. C/EBP-beta binding, enhancer activity and oxLDL-induced upregulation of PPAP2B were stronger with the protective A allele of rs72664324. The PPAP2B protein product LPP3 was expressed in foam cells in human atherosclerotic plaques and was upregulated by oxLDL exposure in macrophages, so increasing the degradation of pro-inflammatory mediators. I also found several other CAD risk candidate genes were regulated by oxLDL: Phosphatase and actin regulator 1 (PHACTR1) and macrophage inducible Ca2+ dependent C-type lectin (Mincle). This led us to find a novel expression-quantitative-trait locus for PHACTR1 in macrophages and define new glycolipid ligands for Mincle. Our results demonstrate a genetic mechanism contributing to CAD risk at the PPAP2B locus and highlight the value of integrating gene expression and epigenetic changes to study disease processes involving pathogenic environmental stimuli.
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Meyer, Kacie Jo. "Detection, interpretation, and functional consequences of genomic copy number variation in human disease." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/1026.
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In recent years, microarray technology has revealed the widespread presence of submicroscopic deletions and duplications throughout the human genome termed copy number variants (CNVs). CNVs have a profound effect on gene expression and are an important source of normal genetic variation. In addition, a small proportion of CNVs contribute to genetically simple and complex disease. This thesis focuses on the identification of pathogenic CNVs contributing to the etiology of diseases with "missing heritability" using a well-planned study design individually tailored to each disease cohort to optimize CNV detection and interpretation.
We performed a genome-wide analysis for CNVs in five disease cohorts with genetic etiology: autism, age-related macular degeneration (AMD), glaucoma, clubfoot, and Bardet-Biedl syndrome (BBS). Our results indicate that CNVs likely account for a proportion of cases for each disease cohort reported in this thesis. Approximately 20% of our cohort of individuals with autism from trio pedigrees harbors a CNV known to confer risk to develop autism and we identified other novel and rare variants that may play a role in autism pathogenesis. We also characterized a duplication of 2p25.3 identified in two male half-siblings with autism and determined that their mother was somatic mosaic for the duplication. Our work provides evidence that this novel CNV disrupting the genes PXDN and MYT1L are the autism-causing mutation in this pedigree. A comparative cases experimental design was used in the study of AMD and glaucoma. While no common "risk CNVs" were identified for either eye disorder, we did identify several rare overlapping CNVs disrupting genes known to play a role in the eye that may confer risk to disease in a small proportion of individuals. In a fourth genetically complex disease, clubfoot, we identified a duplication of 17q23.2 disrupting the genes TBX4, NACA2, and BRIP1 that segregates with the autosomal dominant clubfoot phenotype in a large pedigree with 16 affected individuals. In addition, the duplication is within the linkage interval identified for this family. We also applied microarray technology to analyze the genomes of individuals with BBS, an autosomal recessive disorder, for the presence of CNVs in known BBS genes as well as CNVs that elucidate novel candidate genes for BBS. From 34 BBS patients with an unidentified mutation, we observed one CNV, a heterozygous deletion of BBS10, unmasking a BBS10 frameshift mutation. A promising BBS candidate gene also emerged from our studies, implicated by an intragenic deletion of the gene MARK3 predicted to result in a frameshift and premature truncation of the protein. Functional studies utilizing antisense morpholino gene knockdown in the zebrafish provide additional evidence that MARK3 is a BBS gene as knockdown of zebrafish mark3 results in a Kupffer's Vesicle defect and a melanosome transport delay, two cardinal BBS phenotypes in the zebrafish.
In addition to identifying CNVs involved in disease, the work outlined in this thesis provides valuable insight into the study design and interpretation of a genome-wide analysis of CNV. This includes the appropriate use of controls and publicly available control databases, methods for enriching for CNVs in a patient cohort to maximize efficiency and discovery, and the importance of analyzing all patient cohorts with heritable disease for the presence of CNVs disrupting known disease genes and CNVs that implicate novel genetic candidates. As the reliability and resolution of CNV detection continue to improve, allowing detection of > 1,000 CNVs in each individual genome, it becomes more important than ever to have a well-defined study design for both the detection and interpretation of CNVs.
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Lovmar, Lovisa. "Methods for Analysis of Disease Associated Genomic Sequence Variation." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4525.
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Wendler, Jason Patrick. "Accessing complex genomic variation in Plasmodium falciparum natural infections." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:c9f1ea37-7005-4757-a869-7eba82406a26.
Full textAbstract:
Genetic polymorphism in Plasmodium falciparum is a considerable obstacle to malaria intervention. Parasites have repeatedly evolved to overcome every front-line antimalarial deployed throughout history, and artemisinin resistant populations are expanding in Southeast Asia. Promising vaccine candidates routinely fail when challenged by the genetic diversity of natural parasite populations, and a recent trial using a blood-stage antigen showed immunity was allele specific. Modern sequencing technologies have revolutionized our understanding of parasite genomics and population genetics by providing access to single nucleotide variation, but characterizing more complex polymorphism remains a key challenge. Solving this problem is important because the selective pressures from drugs and host immunity often create complex polymorphism in the most clinically relevant genes that is missed using standard genotyping methods. In three sections, this thesis is a narrative about 1) encountering complex variation, 2) overcoming it with novel tools, and then 3) innovatively applying those tools to old and new questions. I first show examples of complex variation in a vaccine candidate (EBA-175) and a drug resistance gene (pfcrt) while reporting SNP based analyses of Kenyan and Tanzanian field isolates. While introducing this complex variation I also describe biological insights discovered in these populations. In Kenya I show evidence that chloroquine resistance selects for parasites that are primaquine sensitive, use a GWAS approach to discover new drug resistance loci, and catalogue variation in known resistance genes. In Tanzania I describe the population structure and allele frequencies of parasites from two geographic regions. In the second section of the thesis I develop methods for accessing complex variation and demonstrate their utility by producing de novo assemblies of eba-175, pfcrt, ama1, and msp3.4 from thousands of sequenced samples. Finally, in the third section I apply these tools in depth to eba-175. I comprehensively characterize the SNP and structural variation in eba-175 using an alignment of 1419 de novo assemblies. I use this resource to illustrate the profiles of positive selection across the gene, and corroborate these signals of balancing selection by showing the geographic distribution of the F/C indels and a lesser known 6bp indel positioned between the DBL domains. I then use the alignments to design Sequenom genotyping assays that facilitate a genome wide association study, testing for human associations with the eba-175 indels in the infecting parasite. I close by reporting a potential association on human chromosome 14 with the 6bp indel in eba-175.