Genetics and Genomics Commons^™

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 …

Phylogenetic Inference Of Multiscale Selection Pressures Using A Continuous State Birth-Death Process, Marco Hamins-Puertolas, David Rasmussen

Biology and Medicine Through Mathematics Conference

No abstract provided.

Topology And Dynamics Of Gene Regulatory Networks: A Meta-Analysis, Claus Kadelka

Biology and Medicine Through Mathematics Conference

No abstract provided.

Dna Methylation Associated With Postpartum Depressive Symptoms Overlaps Findings From A Genome-Wide Association Meta-Analysis Of Depression, Dana M. Lapato, Roxann Roberson-Nay, Robert M. Kirkpatrick, Bradley T. Webb, Timothy P. York, Patricia A. Kinser

Human and Molecular Genetics Publications

Background Perinatal depressive symptoms have been linked to adverse maternal and infant health outcomes. The etiology associated with perinatal depressive psychopathology is poorly understood, but accumulating evidence suggests that understanding inter-individual differences in DNA methylation (DNAm) patterning may provide insight regarding the genomic regions salient to the risk liability of perinatal depressive psychopathology.

Results Genome-wide DNAm was measured in maternal peripheral blood using the Infinium MethylationEPIC microarray. Ninety-two participants (46% African-American) had DNAm samples that passed all quality control metrics, and all participants were within 7 months of delivery. Linear models were constructed to identify differentially methylated sites and regions, …

Glial Cell Mechanisms Regulate Alcohol Sedation In Drosophila Melanogaster, Kristen M. Lee

Theses and Dissertations

Approximately 16 million people in America are diagnosed with Alcohol Use Disorder (AUD) but no efficacious medical treatments exist. Alcohol-related behaviors can be studied in model organisms, and changes in these behaviors can be correlated with either (i) a risk for alcohol dependence or (ii) a symptom/feature of AUD itself. Although AUD is a disease of the central nervous system, a majority of research has focused on the neuronal underpinnings, leaving glial contributions largely undescribed. We used Drosophila melanogaster (fruit fly) to identify genes whose expression in glia regulates alcohol sedation. Mammals and Drosophila have conserved behavioral responses to alcohol …

Spatial Genetic Structure And Local Adaptation Within And Among Foxtail Pine (Pinus Balfouriana Subsp. Balfouriana) Populations Located In The Klamath Mountains, California, Rebecca D. Piri

Theses and Dissertations

Foxtail pine (Pinus balfouriana) is a subalpine conifer endemic to California, notably separated into two disjunct subspecies. Previous studies have described the northern subspecies,Pinus balfouriana subsp. balfouriana,as having an uncommonly high level of genetic differentiation and no discernible spatial patterns in phenotypic variation. This study seeks to characterize the spatial genetic structure and patterns of selection of the northern subspecies (Pinus balfouriana subsp. balfouriana) using genome-wide data and to identify the influence of ecology and environment on the unique genetic patterns. I show that genetic differentiation among populations is much less than previously estimated …

Genetic And Environmental Factors Influence Drosophila Ethanol Sedation, Rebecca E. Schmitt

Theses and Dissertations

Alcohol use disorder is a global health issue that affects a significant portion of the population, with affects including both negative mental and physical consequences. Currently, there are few treatment options available to those who suffer from alcohol use disorder, alcohol abuse, or alcohol dependence. Identifying candidate genes or environmental influences would therefore improve the means for possible treatments or identification of those people at risk for alcohol use disorder. Previous studies in humans have demonstrated an inverse association between initial sensitivity and risk for alcohol abuse. This connection allows investigators, and our laboratory, to investigate genetic and environmental factors …

Regulation Of Cancer-Specific Mirnas By Mda-7/Il-24, Danielle Scheunemann

Theses and Dissertations

Melanoma differentiation associated gene 7/Interleukin-24 (MDA-7/IL-24) is a secreted cytokine which acts as a tumor suppressor. It is capable of selectively killing cancer cells, regardless of anatomic origin, while sparing normal cells. miRNAs are master regulators of gene expression that can play two roles in cancer: tumor-suppression and oncogenesis. We identified a number of miRNAs that are regulated by MDA-7/IL-24 using a PCR plate array containing probes for miRNAs known to play a role in prostate cancer. We independently validated the array with qRT-PCR to identify three miRNAs which are downregulated by MDA-7/IL-24 treatment in DU145, PC3, and PC3ML prostate …

Translational Insights Into The Genetic Etiology Of Mental Health Disorders: Examining Risk Factor Models, Neuroimaging, And Current Dissemination Practices, Jessica L. Bourdon

Theses and Dissertations

Psychiatric genetics is a basic science field that has potential for practical application and effective translation. To date, translational frameworks utilized by this field have been linear (e.g., sequential) in nature, focusing on molecular genetic information. It is proposed that non-linear (e.g., socio-ecological) frameworks are a better way to immediately translate non-molecular genetic information. This dissertation explored the translation of psychiatric genetic information in two ways. First, a survey was sent to academic stakeholders to assess the state of the science regarding the translation of genetic information to the clinical care of mental health disorders. Findings from this indicate a …

Co-Localization Of Polycystic Ovary Syndrome Candidate Gene Products In Human Theca Cells Suggests Novel Signaling Pathways, Rewa M. Kulkarni

Theses and Dissertations

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility and the most common endocrinopathy of women of reproductive age. Genome-wide association studies (GWAS) identified a number of loci associated PCOS in different ethnic populations, including women with Asian and European ancestry. Replication studies have confirmed some of these associations. Among the loci identified are those located near the LH receptor gene (LHCGR), a clathrin-binding protein gene (DENND1A) that also functions as a guanine nucleotide exchange factor, and the gene encoding RAB5B, a GTPase and protein involved in vesicular trafficking. The functional significance of one …

Aeg-1 Knockout Sensitizes Hepatocellular Carcinoma (Hcc) Cells To Ionizing Radiation, Maheen Khan

Theses and Dissertations

Liver cancer is the fourth leading cause of cancer-associated deaths globally, and among primary liver cancers, hepatocellular carcinoma (HCC) encompasses 75-85% of all cases. HCC is a highly lethal disease due to limited treatment options – only a small subset of patients qualify for surgical resection or transplantation; the remaining patients often display resistance to radiation therapy or chemotherapy. Overexpression of the oncogene astrocyte elevated gene-1 (AEG-1) is associated with poorer survival and increased tumor recurrence in HCC, and numerous studies show its role in initiation of hepatocarcinogenesis. A prior study also demonstrated AEG-1 expression inhibits senescence by diminishing the …

Latent Growth Model Approach To Characterize Maternal Prenatal Dna Methylation Trajectories, Dana Lapato

Theses and Dissertations

Background. DNA methylation (DNAm) is a removable chemical modification to the DNA sequence intimately associated with genomic stability, cellular identity, and gene expression. DNAm patterning reflects joint contributions from genetic, environmental, and behavioral factors. As such, differences in DNAm patterns may explain interindividual variability in risk liability for complex traits like major depression (MD). Hundreds of significant DNAm loci have been identified using cross-sectional association studies. This dissertation builds on that foundational work to explore novel statistical approaches for longitudinal DNAm analyses. Methods. Repeated measures of genome-wide DNAm and social and environmental determinants of health were collected up to six …

Genome-Wide Systems Genetics Of Alcohol Consumption And Dependence, Kristin Mignogna

Theses and Dissertations

Widely effective treatment for alcohol use disorder is not yet available, because the exact biological mechanisms that underlie this disorder are not completely understood. One way to gain a better understanding of these mechanisms is to examine the genetic frameworks that contribute to the risk for developing this disorder. This dissertation examines genetic association data in combination with gene expression networks in the brain to identify functional groups of genes associated with alcohol consumption and dependence.

The first study took advantage of the behavioral complexity of human samples, and experimental capabilities provided by mouse models, by co-analyzing gene expression networks …

The Increased Frequency Of Micronuclei Seen In Women With A History Of Childhood Sexual Abuse Reflects More Numerical Than Structural Acquired Chromosomal Events: A Discordant Identical Co-Twin Study, Kaitlyn M. Dochelli

Theses and Dissertations

Childhood sexual abuse (CSA) is a stressful life experience with lasting/far-reaching health and psychopathological consequences. Our laboratory recently identified a significantly increased frequency of acquired chromosomal anomalies (assessed using the cytokinesis-blocked micronucleus assay) in adult female twins exposed to CSA when compared to their unexposed co-twin. The primary aim of this study was to evaluate potential mechanism(s) underlying the observed increases in levels of micronuclei in an expanded group of 90 female identical twins (61 CSA+ females and 29 CSA- females [including a total of 27 MZ co-twin pairs]) using fluorescence in situ hybridization (FISH) methodologies, with PNA probes specific …

Phenotypic Characterization Of Pnpase Mutation And Overexpression In C. Elegans, Brian J. Hur

Theses and Dissertations

PNPase, polynucleotide phosphorylase, is a multifunctional exoribonuclease protein with 3` terminal oligonucleotide polymerase activity. Coded by the PNPT1 gene, the protein is associated with mitochondrial homeostasis and functions as a possible target for cancer therapy. In this study, C. elegans was used to investigate the effect of mutation and overexpression of pnpt-1, the gene that encodes PNPase. It was determined that two specific mutations in pnpt-1 did not affect PNPase expression nor did they produce deleterious phenotypes that affected polycistronic transcript accumulation or ROS production. Creation of a stable overexpression model was achieved through Fusion PCR. However, different transgenic …

Testing For Cryptic Diversity And Inference Of Population Structure In The Cosmopolitan Hoplonemertean Emplectonema Gracile (Nemertea), Paul L. Delaney Iv

Theses and Dissertations

Emplectonema gracile (Johnston 1837) is a hoplonemertean of marine intertidal hard-bottom communities and is distributed throughout the Northern Hemisphere. Although possessing a planktonic larval stage in its life history, the range of such cosmopolitan marine invertebrate species is often explained by cryptic speciation and anthropogenic transport. The purpose of this study is to test for possible cryptic species using mtDNA markers (COI and 16S rDNA) and to investigate population structure in E. gracile over a portion of its geographic range using mtDNA markers and ddRADseq nuclear SNP data. The results of both phylogenetic- and tree-based species delimitation revealed that E. …

Polygenic Scores For Metabolic Traits And Related Drug Prescriptions In The Michigan Genomics Initiative, Samuel K. Handelman, Xiaomeng Du, Yanhua H. Chen, Elizabeth K. Speliotes

Biology and Medicine Through Mathematics Conference

No abstract provided.