Genetics and Genomics Commons^™

An Investigation Of Gene Regulatory Network State Space Variability, Sara Faye Liesman

Theses and Dissertations

Genes are segments of DNA that provide a blueprint for cells and organisms to effectively control processes and regulations within individuals. There have been many attempts to quantify these processes, as a greater understanding of how genes operate could have large impacts on both personalized and precision medicine. Gene interactions are of particular interest, however, current biological methods can not easily reveal the details of these interactions. Therefore, we infer networks of interactions from gene expression data which we call a gene regulatory network, or GRN. Due to the robust behavior of genes and the inherent variability within interactions, models …

Elucidating The Role Of The High Aliphatic Glucosinolate ( Hag ) Genes In Pennycress ( Thlaspi Arvense L. ) Glucosinolate Production, Dalton Williams

Theses and Dissertations

Pennycress (Thlaspi arvense L.) is a Brassica species being developed into an oilseed-producing winter cash cover crop. Similar to its relatives, rapeseed (Brassica napus L.) and camelina (Camelina sativa L.), pennycress seeds produce high levels of oil and protein (~34% oil and ~19% protein dry weight). For pennycress to be economically viable and environmentally sustainable as a crop, both the oil and seed meal must be utilized. Pennycress like other Brassicaceae, produces high levels of glucosinolates in the seed coat. Glucosinolates taste bitter and can be metabolized by the enzyme, myrosinase, into toxic isothiocyanates, nitriles, and epithionitriles. Seed meal containing …

Checkmate: Exploring Father-Son Communication Regarding Reproduction And Sexual Health In Males With Cystic Fibrosis, Dianna C. Sanderson

Theses and Dissertations

Cystic fibrosis (CF) is a heritable monogenic condition with allelic heterogeneity. A variety of sequence alterations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene results clinically in multisystem disease including a reduced reproductive capacity in affected males. Knowledge of reproductive capacity is often disclosed to parents by medical providers and to affected male children by medical providers and their parents. Despite advanced technology and therapeutics yielding the benefits of increased life expectancy and quality of life, males affected with CF largely remain uninformed in broader areas of sexual health and particularly in how their concept of masculine …

Evaluating Pregnancy Outcomes Of Abnormal Non-Invasive Prenatal Screening Results In A High Risk Obstetrics Practice, Olivia Kesler

Theses and Dissertations

Non-invasive prenatal screening (NIPS) has rapidly grown in uptake since its introduction to clinical practice in 2011. In contrast to more traditional methods of screening, NIPS is the first to utilize cell-free fetal DNA for risk assessment of chromosomal aneuploidy and other conditions. Clinical validity has been established for the most common autosomal aneuploidies (Trisomy 21, Trisomy 18, and Trisomy 13) and sex chromosome aneuploidies, though some laboratories screen for conditions beyond these. A screen positive does not always indicate a true positive, therefore professional guidelines recommend diagnostic testing for confirmation and informed decision making on pregnancy management. Furthermore, the …

Experiences With And Knowledge Of Genetics In Families Affected By Congenital Adrenal Hyperplasia: The Parent Perspective, Christine Maccia

Theses and Dissertations

Purpose: This project was conducted in order to assess how parents of a child affected by CYP21A2-related classic CAH experienced receiving genetic information, The goal was to determine their knowledge of the genetics of the condition and how that knowledge has affected different aspects of their lives such as emotional well-being. Methods: Parents of a child with classic CAH diagnosed in the past 10 years were invited to participate in an online survey via an advertisement posted in the support group, Major Aspects of Growth in Children. Survey questions consisted of demographic information, experience with the diagnostic process, knowledge of …

Assessing Social Media For Themes Of Trisomy 18 And 13, Falecia Metcalf

Theses and Dissertations

Themes within virtual communities have been explored examining topics such as prenatal diagnosis and termination for fetal anomalies, and it is known that when receiving a diagnosis of trisomy 18 or 13 parents may turn to online resources for information and emotional support. Knowledge of what content patients may encounter on various social media platforms about prenatal testing for trisomy 18 and 13 at large has not yet been established. However, this information would aid healthcare professionals in providing anticipatory guidance for patients using social media.

This study is a preliminary scan of social media to identify content areas and …

The Utility Of Whole Exome Sequencing In Patients With Intellectual Disability And Developmental Delay As A First-Tier Diagnostic Testing Strategy, Ellen Richardson

Theses and Dissertations

The purpose of this study is to evaluate the diagnostic utility of whole exome sequencing (WES) in patients with intellectual disability (ID) or developmental delay (DD), and to determine which patients may be the best candidates for WES as a first-tier diagnostic test. The diagnostic and clinical utility of WES has emerged to be greater than that of karyotype and chromosomal microarray for patients with ID or DD of unknown etiology, which are currently recommended as first-tier diagnostic tests for these patients. The emergence of next generation sequencing has led to more rapid identification of rare and novel genetic disorders. …

Revisiting The Essential Informational Needs Of Parents Receiving A Diagnosis Of Down Syndrome, Margaret Jean Wilkes

Theses and Dissertations

Down syndrome is a condition characterized by varying degrees of intellectual disability (ID), distinctive facial appearance, and congenital anomalies that results from the presence of a third 21st chromosome. Down syndrome is the most common chromosomal condition, affecting approximately 12.6 per 10,000 live births in the United States, making it imperative that we determine which information is most essential to impart to parents when first presenting the diagnosis. The aim of the present study is to reassess the informational needs of parents during the presentation of a Down syndrome diagnosis. In 2009, data were collected to define the essential information …

Characterization Of The Dyrk1a Protein-Protein Interaction Network, Varsha Ananthapadmanabhan

Theses and Dissertations

Human Dual specificity tyrosine (Y)-Regulated Kinase 1A (DYRK1A) is a protein kinase encoded by a dosage-dependent gene. An extra copy of DYRK1A contributes to Down syndrome (DS) pathogenesis while loss of one allele causes severe mental retardation and autism. DYRK1A is involved in phosphorylation of several proteins that regulate cell cycle control and tumor suppression. However, the function and regulation of this kinase is not well understood and current knowledge does not fully explain dosage-dependent function of this important kinase. Our previous proteomic studies identified several novel DYRK1A interacting proteins including RNF169, FAM117B, TROAP, LZTS1, LZTS2 and DCAF7. In this …

The Role Of Manganese In Streptococcus Sanguinis, Tanya M. Puccio

Theses and Dissertations

Streptococcus sanguinis is primarily associated with oral health as a commensal bacterium. As an opportunistic pathogen, S. sanguinis is capable of colonizing heart valve vegetations, leading to the disease infective endocarditis. Previous studies from our lab have identified the high-affinity manganese transporter SsaACB as important for endocarditis virulence. The impact that manganese depletion has on S. sanguinis had never been evaluated and a secondary manganese transporter has not been identified. Thus, we employed the use of a fermentor to control large-scale growth over time and depleted manganese in an ΔssaACB mutant using a metal chelator, EDTA. The changes in …

Ndrg1 And Myelin-Related Disease: Alcoholism And Chemotherapy-Induced Neuropathy, Guy Harris

Theses and Dissertations

Alcohol use disorder (AUD) is a prevalent neuropsychiatric disease with profound health, social, and economic consequences. With an estimated 50% heritability, identifying genes that engender risk and contribute to the underlying neurobiological mechanisms represents an important first step in developing effective treatments. Gene expression studies are an important source of candidate genes for studying AUD, providing windows into the molecular machinery engaged by the brain in response to ethanol. Our laboratory has implicated N-myc down-regulated gene 1 (Ndrg1) as a potential candidate gene that modulates ethanol-induced changes in myelin-related gene expression and acute sensitivity to ethanol. Analysis of …

Transcriptomic Profiling Of Postmortem Prefrontal Cortex And Nucleus Accumbens From Chronic Alcohol Abusers., Eric S. Vornholt

Theses and Dissertations

Alcohol use disorder (AUD) is a debilitating psychiatric illness that develops from a combination of genetic and environmental factors. While it is well documented that AUD is heritable, the shift from recreational alcohol use to abuse/dependence is poorly understood. In this dissertation, using postmortem brain tissue from individuals with alcohol dependence (AD), we profiled the genome-wide expression of circular RNA (circRNA), microRNA (miRNA), and messenger RNA (mRNA) to better understand the impact of gene expression on the development of AUD. To achieve this, we performed two independent studies that explore transcriptome differences between AD cases and controls. The first of …

The Origin And Evolution Of Flower Characters In Angiosperms With A Case Study On The Genetic Basis Of Zygomorphic Corolla Development In Bee And Hummingbird Pollinated Species Of Schizanthus (Solanaceae), Ghadeer Bukhari

Theses and Dissertations

This Ph.D. dissertation investigates two main projects separated into two chapters, one for each. The first chapter explores the evolution of flowering plants (angiosperms), a macro-scale study. The second project is on a micro-scale that focus on exploring the genes that regulate the similarities and the differences of flower morphology reflecting their different pollination syndromes in two species of Schizanthus (Solanaceae), i.e., S. pinnatus, a bee-pollinated flower, and S. grahamii, a hummingbird- pollinated flower.

In the first chapter, I used floral diagrams to study the origin and the evolution of floral traits in angiosperms, a new set of morphological data …

Novel Strategies To Overcome Carboplatin Resistance In Triple Negative Breast Cancer Using Patient Derived Xenografts, Mohammad A. Al Zubi

Theses and Dissertations

Triple-negative breast cancer (TNBC) patients have a poor prognosis and rely on chemotherapeutic treatment as standard of care. Often, they develop chemotherapy resistance, which leaves them without more therapeutic options, like targeted therapy. New models have been developed to test targeted inhibitors in human tumors, and they are known as patient-derived xenografts (PDX). These tumors are obtained from patients, then established and maintained in mice where they areused for tumor studies. In this work, we characterized 14 PDXs for their primary tumor growth rate and investigated metastatic propensity using spontaneous and experiment metastasis models. We utilized RNA-sequencing to characterize contributions …

The Gamma-Globin Repressors Klf1, Bcl11a, And Mbd2: Knowledge Gaps In The Literature, Lauren Nufer

Theses and Dissertations

β-hemoglobinopathies affect millions of people around the world. Research into treatments for these conditions has focused on methods to increase γ-globin expression, because increased levels of γ-globin ameliorate or reduce the severity of symptoms. As more and more studies have been done, a few proteins have emerged as having crucial roles in γ-globin repression and have been established as key genes to study. These are Krüppel-like factor 1 (KLF1), B cell CLL/lymphoma 11A (BCL11A), and methyl binding domain 2 (MBD2). The roles of these proteins in the switch from fetal to adult hemoglobin and in repressing γ-globin expression have been …

Validation Of Ninein As An Ethanol-Related Quantitative Trait Gene: Reassessment, Design, And Functional Validation Of Reference Genes For Qpcr Analysis Of Brain Tissue In Mice, Jessica L. Jurmain

Theses and Dissertations

The increasing use of quantitative real-time polymerase chain reaction (qPCR) as a method for quantifying gene expression has led to an increased demand for standardization of data analysis methods to ensure accurate reporting and robust, reproducible results. The exponential nature of qPCR amplification results in the potential magnification of what are usually very small sources of error. Relative gene expression calculations circumvent this issue by normalizing target gene expression data to within-sample expression of a previously validated, stably expressed reference gene or genes. Multiple studies discussed herein have found that qPCR data are more reliable and reproducible when multiple reference …

The Functional Importance Of Methyl Cpg Binding Domain Proteins 2 And 3 In Regulating Fetal Hemoglobin Expression In Human Adult Erythroid Cells, Alexander Azzo

Theses and Dissertations

Humans undergo two developmental switches in the predominantly expressed β-like globin chain during embryogenesis and fetal development. The first switch from embryonic (ε) to fetal (γ) occurs around week 5 of embryonic development, while the second switch from fetal to adult (β) globin occurs shortly after birth. By adulthood, fetal hemoglobin represents only 1-2% of total hemoglobin in the blood. As sufficiently elevated levels of fetal hemoglobin are beneficial for improving clinical outcomes in sickle cell disease and β-thalassemia, the mechanisms that enforce silencing of fetal hemoglobin expression postnatally are of great clinical significance. The methyl-CpG binding domain protein MBD2 …

Role Of Nurd In Acute Leukemia Cell Survival, Javeria Aijaz

Theses and Dissertations

Depletion of the ATPase component of the Nucleosome Remodeling and Deacetylase (NuRD) complex, CHD4, reduces acute myeloid leukemia (AML) cell survival. This study identified other NuRD components, as potential therapeutic targets for disrupting protein-protein interactions within NuRD. In addition to AML, we established that T-cell Acute Lymphoblastic Leukemia (T-ALL) cell lines responded similarly to CHD4 depletion.

Greater than 90% depletion of either MBD2 or MBD3 (the mutually exclusive two DNA binding NuRD paralogues) – was unremarkable, but complete depletion of MBD3 increased apoptosis and genotoxic sensitivity. Combined depletion of MBD-NuRD proteins augmented apoptosis observed with complete MBD3 depletion - indicating …

Characterization Of The Tsc/Dyrk1a Interaction, Supriya Joshi

Theses and Dissertations

The Tuberous sclerosis complex (TSC) includes TSC1, TSC2 and the TBC1D7 subunits that together function as a principal inhibitor of the mTOR protein kinase complex 1 (mTORC1). mTORC1 is a master regulator of cell growth and proliferation that responds to signaling cues such as growth factors and nutrient availability. Proteomic studies in our lab revealed an interaction between the TSC subunits and DYRK1A, a ubiquitous protein kinase encoded by a gene located in the Down syndrome (DS) region on human chr21. In this study, we sought to validate the interaction of the TSC components with DYRK1A and to determine the …

Interspecific Gene Flow Potentiates Adaptive Evolution In A Hybrid Zone Formed Between Pinus Strobiformis And Pinus Flexilis, Mitra Menon

Theses and Dissertations

Species range margins are often characterised by high degrees of habitat fragmentation resulting in low genetic diversity and higher gene flow from populations at the core of the species range. Interspecific gene flow from a closely related species with abutting range margins can increase standing genetic diversity and generate novel allelic combinations thereby alleviating limits to adaptive evolution in range margin populations. Hybridization driven interspecific gene flow has played a key role in the demographic history of several conifer due to their life history characteristics such as weak crossability barriers and long generation times. Nevertheless, demonstrating whether introgression is adaptive …

Mathematical Models Of Cellular Signaling And Supramolecular Self-Assembly, Pratip Rana

Theses and Dissertations

Synthetic biologists endeavor to predict how the increasing complexity of multi-step signaling cascades impacts the fidelity of molecular signaling, whereby cellular state information is often transmitted with proteins diffusing by a pseudo-one-dimensional stochastic process. We address this problem by using a one-dimensional drift-diffusion model to derive an approximate lower bound on the degree of facilitation needed to achieve single-bit informational efficiency in signaling cascades as a function of their length. We find that a universal curve of the Shannon-Hartley form describes the information transmitted by a signaling chain of arbitrary length and depends upon only a small number of physically …

Epigenetic Regulation Of Drug Metabolizing Enzymes In Normal Aging, Mohamad M. Kronfol

Theses and Dissertations

Geriatric populations are at a higher risk for adverse drug reactions (ADRs). This may be partly due to changes in drug metabolism in old age, but the underlying mechanisms are poorly understood. Prior research in humans and mice has shown age-associated changes to the expression of several genes involved in drug metabolism. Furthermore, studies of human blood showed that epigenetic regulation of genes encoding drug metabolizing enzymes change with age. However, it is unknown if genes in the liver are similarly affected. Therefore, we hypothesize that genes encoding drug metabolizing enzymes may show differential epigenetic regulation in the liver with …

Role Of Clic4 And The Synaptic Transcriptome In The Behavioral And Molecular Neurobiology Of Ethanol, Rory M. Weston

Theses and Dissertations

Alcohol use disorder (AUD) is a prevalent neuropsychiatric disease with profound health, social, and economic consequences. With an estimated 50% heritability, identifying genes that engender risk and contribute to the underlying neurobiological mechanisms represents an important first step in developing effective treatments. Gene expression studies are an important source of candidate genes for studying AUD, providing windows into the molecular machinery engaged by the brain in response to ethanol. Published studies have identified chloride intracellular channel 4 (Clic4) as an ethanol-regulated gene in brain capable of modulating sensitivity to sedation in multiple species. The functions of Clic4 are …

Mef2-Bound Genes May Influence Ethanol Sedation In Drosophila Melanogaster, Katlyn M. Myers

Theses and Dissertations

Alcohol Use Disorder (AUD) is a global health issue that affects millions of people every year. This disorder has serious negative mental and physical consequences. Currently, treatment options for this disorder are largely limited to psychological therapy, with very few medications available to treat it. Being able to identify the environmental and genetic components that influence AUD can help improve diagnosis and treatment options. Previous studies in humans have shown a link between initial sensitivity and risk for alcohol abuse. Our laboratory uses Drosophila melanogaster as a model to study the genetic and environmental components of alcohol-related behaviors. Previous lab …

The Pseudomonas Aeruginosa Interactome: Insights Into Srna-Mediated Regulatory Networks, Christine M. Van Duyn

Theses and Dissertations

Pseudomonas aeruginosa is a Gram-negative bacterium found in various environmental niches including soil, water, hospital environments, and within a broad range of hosts. It is well known for its metabolic versatility and intrinsic and acquired resistance to a variety of antimicrobial agents. Moreover, this bacterium has a remarkable ability to adapt and survive in suboptimal environments by altering its transcriptional profile in response to nutrient deprivation, changes in temperature and pH, osmotic stress, the presence of reactive oxygen species (ROS), and exposure to antibiotics and host defenses. P. aeruginosa colonizes individuals with compromised immune systems and severe burn injuries and …

Chromatin Digestion By The Chemotherapeutic Agent Bleomycin Produces Nucleosome And Transcription Factor Footprinting Patterns Similar To Micrococcal Nuclease, Joshua Michael Stolz

Theses and Dissertations

Bleomycin (BLM), a glycopeptide antibiotic commonly used in chemotherapeutic treatments, has been shown to produce single and double stranded DNA breaks. Subsequent analysis of DNA fragmentation patterns has demonstrated preferential digestion of chromatin in the TSS of active genes and the ability to produce nucleosome-sized fragments within intact chromatin. Nucleosome positioning plays a critical role in the regulation of gene activation. Currently, micrococcal nuclease (MNase) is used as the standard for mapping the position of nucleosomes in the genome. In order to identify whether BLM can be used as an effective nucleosome-mapping agent, BLM was used to digest chromatin in …

Receptor-Mediated Maturation Of Olfactory Sensory Neurons: A Time Course Evaluation Of Neuronal Maturation In Neomorphic Mutants, Elizabeth Miller

Theses and Dissertations

How expression of odorant receptors affects the maturation of olfactory sensory neurons (OSNs) is not known. In a time course experiment, we show that wild type OSNs mature significantly more than those expressing Neomorphic mutant receptors. We conclude that functional receptors are critical to the differentiation and survival of OSNs.

The Genome Of Cañahua: An Emerging Andean Super Grain, Hayley Jennifer Mangelson

Theses and Dissertations

Chenopodium pallidicaule, known commonly as cañahua, is a semi-domesticated crop grown in high-altitude regions of the Andes. It is an A-genome diploid (2n = 2x = 18) relative of the allotetraploid (AABB) Chenopodium quinoa and shares many of its nutritional benefits. Both species contain a complete protein, a low glycemic index, and offer a wide variety of nutritionally important vitamins and minerals. Due to its minor crop status, few genomic resources for its improvement have been developed. Here we present a fully annotated, reference-quality assembly of cañahua. The reference assembly was developed using a combination of established techniques, including multiple …

Evaluating The Social Informational Needs Of Emerging Adults With Genetic Conditions, Courtney Whitmore

Theses and Dissertations

Purpose: This study evaluated the healthcare provider’s role during the social development of emerging adults with a genetic condition. The study also identified the type of information and ways that these adolescents hope to receive information on the potential side effects or complications from engaging in risk taking behaviors and lifestyle choices.

Methods: Participants included both males and females aged 18-26 with achondroplasia, sickle cell disease, cystic fibrosis, or Marfan syndrome. Respondents were recruited to complete an anonymous online questionnaire via social media support groups or email notification.

Results: There were 103 total respondents that completed the questionnaire and met …

The Perspectives Of Emerging Adults With Hereditary Diffuse Gastric Cancer, Carrie Anderson

Theses and Dissertations

Individuals with hereditary diffuse gastric cancer (HDGC) caused by a CDH1 mutation have a high lifetime risk of developing gastric cancer. National guidelines recommend CDH1 carriers undergo a prophylactic total gastrectomy (PTG)— a surgery that greatly reduces the risk of developing gastric cancer but has significant comorbidities. This study explores the impact of a diagnosis of HDGC in the transitional life stage between the ages of 18-29 deemed “emerging adulthood.” We surveyed 21 CDH1 carriers and conducted semi-structured phone interviews with 6 CDH1 carriers between the ages of 18-29 to learn about their life experiences regarding education, career, relationships, and …