Genetics and Genomics Commons^™

Modeling Stochastic Viral Evolution: A Multiscale Wright Fisher Model, Marco Hamins-Puertolas

Biology and Medicine Through Mathematics Conference

No abstract provided.

Floral Symmetry Genes Elucidate The Development And Evolution Of Oil-Bee Pollinated Flowers Of Malpighiaceae And Krameriaceae, Farahnoz N. Khojayori

Theses and Dissertations

Specialization on insect and animal pollinators is thought to be the driving force for the evolution of floral traits. Specifically in the New World (NW), the oil-bee pollination syndrome has led to the convergence of floral characters in two distantly related families of core eudicots, Malpighiaceae and Krameriaceae. Both families display a flag-like structure that establishes a zygomorphic flower and floral oil rewards in epithelial elaiophores. These traits work concomitantly to attract and reward female oil-bees that help fertilize these flowers and in return receive oils. The underlying genetics of floral zygomorphy were studied in several clades of core eudicots, …

Genetic And Environmental Influences Of Bullying Involvement: A Longitudinal Twin Study, Ellyn Dunbar

Theses and Dissertations

Introduction—Bullying involvement is associated with many long-term adverse outcomes. Bullied children are at risk for internalizing disorders including anxiety, depression and suicidal behavior in childhood and adulthood. Bullies are also at risk for psychiatric disorders, specifically externalizing disorders. Bully victims—children who are both bullied and bullies—have a particularly poor prognosis, with a higher risk for internalizing and externalizing disorders. The purpose of this study is to study the epidemiology, risk of psychiatric disorders, and genetic and environmental influences of being bullied, a bully, and a bully victim—in the sample and individually in males and females.

Methods—Twins (N=2,844, aged …

College Student Alcohol Use And Engagement In Prevention Programming, Alexis H. Branch, Shimona Kumar, Christina Mcgrath

UROP Posters

Social problems and adverse consequences have been associated with risky alcohol use (Paschall et al, 2015). Personalized Normative Feedback (PNF) has been utilized to address these problems (White and Hingson, 2014) by comparing students’ alcohol use to campus or national norms (Butler et al, 2009). The current investigation sought to understand differences in alcohol use behaviors in freshmen who did and did not report completion of a personalized feedback intervention (PFI) in a diverse sample of college students from the Spit for Science (S4S) project. S4S is a campus-wide, longitudinal study on the genetic and environmental factors that contribute to …

Quantitative And Molecular Analysis Of Habituation At The Maize R1 Locus, Robert C. Lindsay

Theses and Dissertations

Epigenetics is the study of heritable changes in phenotypes that are not the result of changes in DNA sequence. Examples of epigenetic affecters include methylation changes, chromatin modifications, transcription factors, and RNA-based changes. The molecular mechanisms behind epigenetic changes are not fully understood. Canalization is the buffering of gene expression against environmental changes over time, while habituation is semi-stable expression change over time due to selection. This work characterized the molecular changes associated with the kernel color changes of the R-sc:86-17pale allele at the maize red color1 (r1) locus to determine if the changes are epigenetic in nature. …

Alternative Splicing Of Cytoplasmic Polyadenylation Element Binding Protein 2 Is Modulated Via Serine Arginine Splicing Factor 3 In Cancer Metastasis, James T. Deligio, James Thomas Deligio

Theses and Dissertations

Our laboratory delineated a role for alternative pre-mRNA splicing (AS) in triple negative breast cancer (TNBC). We found the translational regulator cytosolic polyadenylation element binding protein 2 (CPEB2) which has two isoforms, CPEB2A and CPEB2B, is alternatively spliced during acquisition of anoikis resistance (AnR) and metastasis. The splicing event which determines the CPEB2 isoform is via inclusion/ exclusion of exon four in the mature mRNA transcript. The loss of CPEB2A with a concomitant increase in CPEB2B is required for TNBC cells to metastasize in vivo. We examined RNAseq profiles of TNBC cells which had CPEB2 isoforms specifically downregulated to …

Snd1-Targeted Gene Therapy For Hepatocellular Carcinoma, Bryan D. Mckiver

Theses and Dissertations

Staphylococcal nuclease and tudor-domain containing 1 (SND1) is an oncogene for a wide variety of cancers, including hepatocellular carcinoma (HCC). SND1 is a multifunctional protein regulating gene expression of proto-oncogenes and tumor suppressor genes, making SND1 a prime target for developing cancer therapeutics. This notion is especially attributed to HCC as most patients are diagnosed in advanced stages and the therapeutic options available for these patients are severely limited. In this study, we evaluated the therapeutic potential of a replication-defective adenovirus vector delivering SND1 shRNA (Ad.SND1sh) to human HCC cell lines, HepG3, HuH-7, and Hep3B. Adenovirus infection in HCC cells …

Processing Of 3′-Blocked Dna Double-Strand Breaks By Tyrosyl-Dna Phosphodiesterase 1, Artemis And Polynucleotide Kinase/ Phosphatase, Ajinkya S. Kawale

Theses and Dissertations

DNA double-strand breaks (DSBs) containing unligatable termini are potent cytotoxic lesions leading to growth arrest or cell death. The Artemis nuclease and tyrosyl-DNA phosphodiesterase (TDP1) are each capable of resolving protruding 3′-phosphoglycolate (PG) termini of DNA double-strand breaks (DSBs). Consequently, a knockout of Artemis and a knockout/knockdown of TDP1 rendered cells sensitive to the radiomimetic agent neocarzinostatin (NCS), which induces 3′-PG-terminated DSBs. Unexpectedly, however, a knockdown or knockout of TDP1 in Artemis-null cells did not confer any greater sensitivity than either deficiency alone, indicating a strict epistasis between TDP1 and Artemis. Moreover, a deficiency in Artemis, but not TDP1, resulted …

Natural And Anthropogenic Drivers Of Tree Evolutionary Dynamics, Brandon M. Lind

Theses and Dissertations

Species of trees inhabit diverse and heterogeneous environments, and often play important ecological roles in such communities. As a result of their vast ecological breadth, trees have become adapted to various environmental pressures. In this dissertation I examine various environmental factors that drive evolutionary dynamics in threePinusspecies in California and Nevada, USA. In chapter two, I assess the role of management influence of thinning, fire, and their interaction on fine-scale gene flow within fire-suppressed populations of Pinus lambertiana, a historically dominant and ecologically important member of mixed-conifer forests of the Sierra Nevada, California. Here, I find evidence …

Using Mathematical Models Of Biological Processes In Genome-Wide Association Studies Of Psychiatric Disorders, Amy Cochran

Biology and Medicine Through Mathematics Conference

No abstract provided.

Hepatocellular Cancer Genome And Transcriptome Analysis Validates Clinically Significant Mutational Signatures With The Tgf-𝛃 Pathway, Shuyun Rao, Jian Chen, Kazufumi Ohshiro, Shoujun Gu, Sobia Zaidi, Wilma S. Jogunoori, Jon White, Nagarajan Pattabiraman, Raja Mazumder, Anelia Horvath, Ray-Chang Wu, Shulin Li, Chuxia Deng, Bibhuti Mishra, Rehan Akbanni, The Tcga Cancer Network, Lopa Mishra

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

Oncogenic Nelfe Enhances Myc-Induced Hepatocellular Carcinogenesis, Hien Dang, Atsushi Takai, Marshonna Forgues, Yosawat Pomyen, Haiwei Mou, Wen Xue, Debashish Ray, Kevn Ha, Quiad Morris, Timothy Hughes, Xin Wei Wang

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

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 …

Separation Of Blood Mixtures Using Fluorescently Labeled Antibodies, Christopher Ehrhardt, Dani Jabado, Emily Brocato

UROP Posters

Identifying and analyzing biological mixture samples at a crime scene are of paramount concern for forensic scientists, especially if that type of evidence contains only one cell type. The presence of multiple contributors in a biological evidence sample reduces the probative value of DNA evidence and can sometimes lead to its eventual loss of value. As such, this study was performed in an attempt to examine and evaluate flow cytometry analysis as a means to separate blood mixture samples labeled with fluorescent antibodies. Fluorescein Isothiocyanate (FITC) antibodies were specifically targeted and bound to HLA (Human Leukocyte Antigens) markers present on …

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 …