Genetics and Genomics Commons^™

Assessing Women's Attitudes Towards Genetic Testing For Hereditary Breast Cancer, Taylor Jane Apostolico

Theses and Dissertations

OBJECTIVES: Hereditary Breast and Ovarian Cancer (HBOC) is an autosomal dominant cancer predisposition syndrome with a 46-87% lifetime risk of breast cancer. Unaffected women who have HBOC are eligible for more screening procedures and prophylactic surgeries that may reduce the risk of developing cancer by up to 95%. The objectives of this study were to assess women’s awareness of and interest in breast cancer genetic testing services, as well as women’s attitudes and beliefs regarding the clinical utilization of HBOC genetic testing across demographic categories. METHODS: Two-hundred and sixty-eight women completed a 35-item survey designed to capture perceptions of HBOC …

The Role Of Klf1 In Regulating Γ-Globin Gene Repressors, Anna P. Kovilakath

Theses and Dissertations

Sickle cell disease and β-thalassemia affect millions of people worldwide. γ-globin is the fetal counterpart to the adult β-globin. Research has shown that affected patients with higher than normal γ-globin show less severe symptoms. Therefore, reversing or preventing the hemoglobin switch from γ- to β- globin is a promising avenue of research for treating these diseases. KLF1 is an erythroid transcription factor involved in hemoglobin switching. Herein, we show that KLF1 directly regulates the γ-globin repressor gene LRF in both the mouse and human systems. KLF1 may also directly activate γ-globin expression by binding the promoter. In human HUDEP-2 cells, …

Integrating Genetics And Neuroimaging To Study Subtypes Of Binge Drinkers, Megan E. Cooke

Theses and Dissertations

Risky alcohol use is a major health concern among college students, with 40.1% reporting binge drinking (5 or more drinks in one occasion) and 14.4% reporting heavy drinking (binge drinking on 5 or more occasions) in the past month. Risky alcohol use is thought to be the result of a complex interplay between genes, biological processes, and other phenotypic characteristics. Understanding this complex relationship is further complicated by known phenotypic heterogeneity in the development of alcohol use. Developmental studies have suggested two pathways to risky alcohol use, characterized by externalizing and internalizing characteristics, respectively. However, the underlying biological processes that …

Characterization Of Staphylococcal Nuclease And Tudor Domain Containing Protein 1 (Snd1) As A Molecular Target In Hepatocellular Carcinoma And Non-Alcoholic Steatohepatitis, Nidhi H. Jariwala

Theses and Dissertations

CHARACTERIZATION OF STAPHYLOCOCCAL NUCLEASE AND TUDOR DOMAIN CONTAINING PROTEIN 1 (SND1) AS A MOLECULAR TARGET IN HEPATOCELLULAR CARCINOMA AND NON-ALCOHOLIC STEATOHEPATITIS

Nidhi Jariwala, PhD

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Integrative Life Sciences

Virginia Commonwealth University, 2017

Devanand Sarkar, M.B.B.S., PhD.

Associate Professor, Department of Human and Molecular Genetics

Virginia Commonwealth University

Richmond, Virginia

SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). Oncoprotein SND1 regulates gene expression at a post-transcriptional level in multiple cancers including hepatocellular carcinoma (HCC). …

Sh3 And Multiple Ankyrin Repeat Domain 3 (Shank3) Affects The Expression Of Hyperpolarization-Activated Cyclic Nucleotide-Gated (Hcn) Channels In Mouse Models Of Autism, Nikhil N. Shah

Theses and Dissertations

SH3 and multiple ankyrin repeat domains 3 (SHANK3) is a multidomain scaffold protein that is highly augmented in the postsynaptic density (PSD) of excitatory glutamatergic synapses within the central and peripheral nervous systems. SHANK3 links neurotransmitter receptors, ion channels, and other critical membrane proteins to intracellular cytoskeleton and signal transduction pathways. Mutations in SHANK3 are linked with a number neuropsychiatric disorders including autism spectrum disorders (ASDs). Intellectual disability, impaired memory and learning, and epilepsy are some of the deficits commonly associated with ASDs that result from mutations in SHANK3. Interestingly, these symptoms show some clinical overlap with presentations of human …

Investigation On Genetic Modifiers Of Age At Onset Of Major Depressive Disorder, Huseyin Gedik

Theses and Dissertations

Major Depressive Disorder (MDD) is a complex multifactorial disorder, which would lead to disability. Environmental and genetic factors are involved in MDD etiology. The aim of this project was to identify loci modifying age at onset (AAO) of MDD using survival models after adjusting for Childhood Sexual Abuse (CSA). To achieve this aim, a dataset was made available by the China Oxford and VCU Experimental Research on Genetic Epidemiology (CONVERGE) consortium. The study population had 5,220 controls and 5,282 cases with MDD. We performed two univariate association analyses using Cox Proportional Hazard (Cox PH) models. These two are Full Sample …

Role Of Mitochondrial Beta-Oxidation In Ethanol Response: A Candidate Gene Study Using Caenorhabditis Elegans, Harini Pallikarana Tirumala

Theses and Dissertations

Alcohol use disorder (AUD) is the fourth leading cause of preventable death in the United States, and the fifth leading risk factor for premature death and disability, globally. There are currently very few treatment options for AUD and there is a need for effective preventive and treatment strategies for this condition. AUD risk has a significant hereditary component, with the contribution of genetic factors being estimated to be about 50%. The Davies-Bettinger laboratory uses C. elegans as a model organism to study the contribution of genetic factors in modulating neuronal responses to ethanol. In this project, we examined the role …

Epigenetic Editing To Validate Findings From Methylome-Wide Association Studies Of Neuropsychiatric Disorders, Robin F. Chan

Theses and Dissertations

DNA methylation is necessary for learning, memory consolidation and has been implicated in a number of neuropsychiatric disorders. Obtaining high quality and comprehensive data for the three common forms of methylation in brain is challenging for methylome-wide association studies (MWAS). To address this we optimized a panel of enrichment methods for screening the brain methylome. Results show that these enrichment techniques approach the coverage and fidelity of the current gold standard bisulfite based techniques. Our MBD-based method can also be used with low amounts of genomic material from limited human biomaterials. Psychiatric disorders have high prevalence and are often chronic …

Network Analytics For The Mirna Regulome And Mirna-Disease Interactions, Joseph Jayakar Nalluri

Theses and Dissertations

miRNAs are non-coding RNAs of approx. 22 nucleotides in length that inhibit gene expression at the post-transcriptional level. By virtue of this gene regulation mechanism, miRNAs play a critical role in several biological processes and patho-physiological conditions, including cancers. miRNA behavior is a result of a multi-level complex interaction network involving miRNA-mRNA, TF-miRNA-gene, and miRNA-chemical interactions; hence the precise patterns through which a miRNA regulates a certain disease(s) are still elusive. Herein, I have developed an integrative genomics methods/pipeline to (i) build a miRNA regulomics and data analytics repository, (ii) create/model these interactions into networks and use optimization techniques, motif …

Taf2: A Potential Oncogene For Hepatocellular Carcinoma, Saranya Chidambaranathan Reghupaty

Theses and Dissertations

Astrocyte Elevated Gene 1 (AEG1) is an oncogene for hepatocellular carcinoma (HCC). Its role in HCC pathogenesis has been well studied. A pan cancer analysis of gene expression in multiple databases identified TATA-box binding protein associated factor 2 (TAF2) as the gene that is most frequently co-expressed with AEG1. TAF2 is a protein that is involved in transcription of genes by RNA polymerase II. It is a factor that is dispensable for basal transcription but, required for activated transcription. It has also been shown to be involved in regulating cyclin levels and hence cell cycle progression. Bioinformatic analysis on data …

Pnpase In C. Elegans: Mutagenic Analysis To Complement Knockdown Studies, Danielle K. Seibert

Theses and Dissertations

PNPase is a gene implicated as a potential target for cancer therapy; human mutations also present with deafness, myopathies, and neuropathies. In this study, C. elegans was used to investigate the effect of knocking out PNPase in a whole animal. C. elegans knockdown studies have reported an extended lifespan via an increase in ROS production. Further noted are larger mitochondria and an increase in fzo-1 expression. Knockout animals previously constructed using CRISPR/Cas9 were used for this study. We aimed to confirm these findings validating previous studies. It was discovered that PNPase knockout animals demonstrated a similar lifespan extension that was …

Evolution Of Antagonistic Relationships In Proteins: A Case Study Of Radialis- And Diviricata-Like Genes, Ao Gao

Theses and Dissertations

The antagonistic relationship of proteins describes the opponent interactions that result in one protein suppressing the function of another. Developmental genetic studies of Antirrhinum majus demonstrated that two transcription factors from the MYB gene family, RAD and DIV, interact through antagonism to regulate floral dorsoventral asymmetry. Interestingly, similar antagonistic interactions were found among proteins of FSM1 (RAD-like), MYBI (DIV-like), and DRIF in Solanum lycopersicum, which is involved in fruit development. Here, we report on the homology of these antagonistic MYB proteins based on reconstruction of the phylogeny of I-box-like and R-R-type clades, where RAD- and DIV-like belong, …

Drinking Motives Underlying Internalizing And Externalizing Pathways To Alcohol Misuse In College Students, Jeanne Savage

Theses and Dissertations

Alcohol misuse, including heavy episodic use and negative consequences, is a major public health concern and a particular problem among college students. The etiology of alcohol misuse is not well resolved, with multiple and often contradictory factors implicated in its development. Genetic factors influence alcohol misuse but few specific genes have been identified. A potential reason for these challenges is that alcohol misuse is phenotypically and genetically heterogeneous; that is, there are multiple causal pathways underlying its development. Previous typologies have suggested that distinct internalizing and externalizing pathways are involved, with corresponding differences in profiles of personality, temperament, and comorbid …

The Influence Of Genetic And Environmental Factors On Quit Attempt In Adolescent And Young Adult Twins, Gladys Langi

Theses and Dissertations

The purpose of this study was to examine the genetic and environmental influences on lifetime quit attempt in three US adolescent and young adult twin samples (N total = 6,322). The study utilized a common-contingent-causal (CCC) model to estimate these factors for lifetime quit attempts, after accounting for the factors for lifetime cigarette use and cigarettes per day. The study also examined age and sex differences, as well as the degree of relationship between these smoking phenotypes. The results demonstrated significant genetic influences for lifetime quit attempts in adolescents and young adults. No sex differences were observed for the contributions …

Comparisons Of Isogenic Trisomic And Disomic Cells From People With Mosaicism For Down Syndrome Unmask Cellular Differences Related To Trisomy 21, Kelly A. Rafferty

Theses and Dissertations

It is known that age-related changes impacting multiple organ systems occur earlier in people with Down syndrome (Ds), but the biological basis underlying this trisomy 21-associated propensity for premature aging is poorly understood. Given that the trisomic/normal cells from people with mosaic Ds (mDs) are identical with regards to environmental exposures and genes (except for chromosome 21 copy number), comparisons of these isogenic trisomic/disomic cells allow one to “unmask” the cellular consequences of trisomy 21 by removing extraneous factors. The primary aim of this study was to determine if trisomy 21 results in an increase in the acquisition of age-related …

Unaffected Women’S Decisions To Have Prophylactic Risk-Reducing Mastectomies, Stephanie N. Galloway

Theses and Dissertations

When a woman is at an increased risk of developing breast cancer due to a pathogenic mutation or a significant family history of the disease, she will be faced with choosing from among multiple management options, including risk-reducing mastectomy (RRM). The relative rate of RRM for both diagnosed and unaffected high-risk women has increased in recent years. Previous research has investigated the factors that influence women diagnosed with the disease to undergo RRM, but has not fully addressed how unaffected women make their decisions to choose RRM as an option when they are still healthy. This study was designed to …

Reflections On The Current State Of Healthcare Transition For Young Adult Women With Turner Syndrome: Strategies For Facilitating Autonomy And Self-Management, Molly Elizabeth Snyder

Theses and Dissertations

The transition to adult-centered healthcare is a critical period for emerging adults, especially those with special healthcare needs (SHCNs). Considering the ongoing medical monitoring necessary for women with Turner syndrome (TS), it is essential that the transition process be comprehensive and well-coordinated. The aims of this study were to invite young women with TS to reflect on their healthcare transition experiences, to explore participants’ perceived control of their medical management, and to identify ways in which genetic counselors can be involved in multidisciplinary healthcare teams. The hypotheses were that young women with TS are motivated to learn more about their …

Genetic Counseling For Alcohol Use Disorder: Assessment Of Need In Affected And At-Risk Populations, Fayth Michelle Kalb

Theses and Dissertations

Introduction: Alcohol use disorder (AUD) is highly heritable, yet there has been no investigation regarding the possible benefits of genetic counseling for AUD. This study assessed the beliefs individuals with and at risk for AUD have regarding recurrence risk and etiology of AUD, how the presence of the condition in themselves or their family history has affected their lifestyle decisions, and potential benefit from AUD genetic counseling. Methods: An online questionnaire was distributed through social media to support groups for AUD inviting adults 18 years and older with a personal or family history of AUD. Results: Of the 122 individuals …

Re-Contacting Cancer Genetic Counseling Patients: Expectations Of Patients And Physicians, Zoe Elizabeth Siegel

Theses and Dissertations

The landscape of cancer genetic counseling and testing is rapidly evolving. Genetic testing technology is improving, management guidelines are evolving, and genetic testing options are expanding. These frequent updates to the components of cancer genetics have increased the complexity of managing patient care over time. In particular, this raises questions on the duty to re-contact patients as new information becomes available. This study explored healthcare providers’ duty to re-contact through the interests and expectations of patients, including which circumstances warrant re-contacting, which healthcare provider is responsible for re-contacting the patient, and the preferred method of re-contacting. Physicians’ opinions on whether …

The Undiagnosed Patient And The Diagnostic Odyssey: Current Genetic Counseling Practices And Perspectives, Amelia Cordell Wardyn

Theses and Dissertations

Patients seen in genetics clinics often endure a diagnostic odyssey in their search for answers for their medical symptoms. This time is not only challenging for patients and their families, but also for the genetic counselors who are trying to help the patients. Previous research has shown that parents of children with undiagnosed medical disorders have specific goals and reasons for wanting to find a diagnosis, and there are many difficulties faced by these parents. Genetic counselors often serve as a prominent figure during the diagnostic odyssey, but little known research has assessed the current practices of and impact that …

Parents’ Understanding Of Sensory Processing In Their Child With Autism Spectrum Disorder, Katelynn M. Anderson

Theses and Dissertations

Purpose: The purpose of this study was to assess the need and desire of parents of children with Autism Spectrum Disorder (ASD) to receive sensory processing disorder (SPD) education. We hoped to identify misconceptions of parents about sensory processing and examined the utility of providing information on SPDs to these parents within the genetic counseling session. Methods: Invitations to participate were sent to support groups in the Southeast United States. A survey tool was used to obtain demographic information. A short presentation was given to clarify the definition of sensory processing, give examples of signs and symptoms of SPDs, and …

Identification Of Xpa And Xpc Gene Mutations In Patients With Xeroderma Pigmentosum, Eman Abdelalim Sidky Rabie

Theses and Dissertations

The human body employs different DNA repair pathways to protect itself against cancers induced by DNA damage. The nucleotide excision repair (NER) pathway comprises different synchronously working DNA repair proteins; two of which are XPA and XPC. Mutations of any of the genes encoding the NER proteins cause an autosomal recessive genetic disorder called Xeroderma Pigmentosum (XP). XP patients present with characteristic dry atrophic freckle-like pigmentation of the skin, photosensitivity and photophobia. Some patients develop neurodegenerative symptoms early in life, including mental retardation. Patients have a 10,000-fold increased risk for UV-induced skin cancers, moreover, a higher risk for ocular, oral …

Investigating The Roles And Interactions Of Sad-6 Within The Parameters Of Meiotic Silencing By Unpaired Dna ( Msud )., Zachary J. Smith

Theses and Dissertations

Meiotic silencing by unpaired DNA (MSUD) is a process observed in the model organism Neurospora crassa. During this process unpaired DNA between homologous chromosomes is detected and silenced, resulting in the suppression of unpaired genes. The effects of MSUD can be seen using phenotypic markers such as the Roundspore gene and evidence supports the existence of a physical search for unpaired DNA. However, the mechanism for detecting unpaired DNA remains uncertain. Previously, we have shown evidence that a Rad54-like protein, SAD-6 is required for the efficient completion of MSUD and may be necessary for the detection of unpaired DNA. Currently, …

A Mechanistic Study Of An Ipsc Model For Leigh’S Disease Caused By Mtdna Mutataion (8993 T>G), John P. Galdun

Theses and Dissertations

Mitochondrial diseases encompass a broad range of devastating disorders that typically affect tissues with high-energy requirements. These disorders have been difficult to diagnose and research because of the complexity of mitochondrial genetics, and the large variability seen among patient populations. We have devised and carried out a mechanistic study to generate a cell based model for Leigh’s disease caused by mitochondrial DNA mutation 8993 T>G. Leigh’s disease is a multi-organ system disorder that depends heavily on the mutation burden seen within various tissues. Using new reprogramming and sequencing technologies, we were able to show that Leigh’s disease patient fibroblasts …

Power Analysis In Applied Linear Regression For Cell Type-Specific Differential Expression Detection, Edmund Glass

Theses and Dissertations

The goal of many human disease-oriented studies is to detect molecular mechanisms different between healthy controls and patients. Yet, commonly used gene expression measurements from any tissues suffer from variability of cell composition. This variability hinders the detection of differentially expressed genes and is often ignored. However, this variability may actually be advantageous, as heterogeneous gene expression measurements coupled with cell counts may provide deeper insights into the gene expression differences on the cell type-specific level. Published computational methods use linear regression to estimate cell type-specific differential expression. Yet, they do not consider many artifacts hidden in high-dimensional gene expression …

Genomic Comparisons And Genome Architecture Of Divergent Trypanosoma Species, Katie Bradwell

Theses and Dissertations

Virulent Trypanosoma cruzi, and the non-pathogenic Trypanosoma conorhini and Trypanosoma rangeli are protozoan parasites with divergent lifestyles. T. cruzi and T. rangeli are endemic to Latin America, whereas T. conorhini is tropicopolitan. Reduviid bug vectors spread these parasites to mammalian hosts, within which T. rangeli and T. conorhini replicate extracellularly, while T. cruzi has intracellular stages. Firstly, this work compares the genomes of these parasites to understand their differing phenotypes. Secondly, genome architecture of T. cruzi is examined to address the effect of a complex hybridization history, polycistronic transcription, and genome plasticity on this organism, and study its highly …

Functional Consequences Of Mtdna Methylation On Mitochondrial Transcription Factor Binding And Transcription Initiation, Elliot N. Burton

Theses and Dissertations

The role of cytosine modifications on nuclear transcription has been well characterized, but the function of DNA methylation in the mitochondrial genome has not been determined. Previous studies conducted by the Taylor laboratory have shown overexpression of the mitochondrial isoform of DNMT1 leads to strand-specific changes in gene expression. Here, we show that increased mtDNMT1 expression leads to an increase in the polycistronic transcript encoding the ND1 and Cox1 sequences. In order to understand the mechanistic basis of these changes, we investigated the effects of CpG methylation in the heavy strand promoter on transcription initiation and TFAM binding. Methylation was …

Characterizing The Oncogenic Properties Of C-Terminal Binding Protein, Evan T. Sumner

Theses and Dissertations

The paralogous C-terminal binding proteins (CtBP) 1 and 2 are evolutionarily conserved transcriptional coregulators that target and disrupt the expression of several genes essential for multiple cellular processes critical to regulating tumor formation. CtBP’s ability to govern the transcription of genes necessary for apoptosis, tumor suppression, invasion/migration and EMT gives rise to its oncogenic activities. Both isoforms of CtBP are found to be overexpressed in cancers including colorectal, pancreatic, ovarian, and breast, with higher levels correlating to lower overall median survival. Although multiple lines of evidence suggest CtBP plays a role in tumorigenesis, it has never been formally characterized as …

Phylogenetic Analyses Of Andean And Amazonian Tree Communities In Ecuador, Samantha J. Worthy

Theses and Dissertations

The forests of Ecuador are known for their high levels of diversity and endemism, classifying the country as a biodiversity hotspot. Both the western Amazon and Andean montane forests are richly populated with tropical tree species that have been little studied in a community phylogenetic context. The implementation of elevational transects and trait based analyses having proven useful in gaining a better understanding of how environmental factors are affecting the tree community structure in these habitats. The goal of this research was to evaluate the magnitude ofDNA barcode diversity among Amazonian and Andean tree species. Specifically, the objectives were to …

System Genetic Analysis Of Mechanisms Underlying Excessive Alcohol Consumption, Maren L. Smith

Theses and Dissertations

Increased alcohol consumption over time is one of the characteristic symptoms of Alcohol Use Disorder (AUD). The molecular mechanisms underlying this escalation in intake is still the subject of study. However, the mesocortical and mesolimbic dopamine pathways, and the extended amygdala, because of their involvement in reward and reinforcement are believed to play key roles in these behavioral changes. Multiple gene expression studies have shown that alcohol affects the expression of thousands of genes in the brain. The studies discussed in this document use the systems biology technique of co-expression network analysis to attempt to find

patterns within genome-wide expression …