Genetics Commons^™

Influence Of Multi-Species Data On Gene-Disease Associations In Substance Use Disorder Using Random Walk With Restart Models, Erich J. Baker, Everest U. Castaneda, Sharon Moore, Jason A. Bubier, Stephen K. Grady, Michael A. Langston, Elissa J. Chessler

Funded Scholarship

A major challenge lies in discovering, emphasizing, and characterizing human gene-disease and gene-gene associations. The limitations of data on the role of human gene products in substance use disorder (SUD) makes it challenging to transition from genetic associations to actionable insights. The integration of data from multiple diverse sources, including information-dense studies in model organisms, has the potential to address this gap. We demonstrate a modified performance of the Random Walk with Restart algorithm when multi-species data is integrated in the heterogeneous network within the context of SUD. Additionally, our approach distinguishes among disparate pathways derived from the Kyoto Encyclopedia …

Beyond Homogeneity: Exploring Causal Heterogeneity In Psychopathology, Philip B. Vinh

Theses and Dissertations

Traditional models in psychiatric research often impose assumptions of causal homogeneity, treating population-level associations as reflective of uniform underlying mechanisms. This dissertation challenges that assumption by introducing statistical and machine learning frameworks designed to detect and model causal heterogeneity in the development of psychopathology. Central to this approach is the advancement of finite mixture structural equation modeling (FM-SEM) to identify latent subgroups characterized by distinct, and sometimes opposing, causal pathways.

The dissertation comprises three integrated empirical studies. The first introduces mixDoC, a finite mixture extension of the classical Direction of Causation (DoC) model applied to twin data, enabling the detection …

Using Abandoned Model Systems And Historical Literature To Teach Modern Concepts And Techniques In Cell Biology, Leocadia V. Paliulis, Gunar Fabig, Sandra Stein, Silke Tulok, Anja Nobst, Chukwuebuka William Okafornta, Thomas Kurth, Thomas Müller-Reichert

Faculty Journal Articles

The cell biology literature of the 19th and early-to-mid 20th centuries is full of the seminal works that were critical for the development of our current understanding of biology but were done using model systems that are no longer commonly used. We argue that these historical papers are ideal for the development of course-based research experiences, both because the background work is conceptually and technically straightforward, and because the study of the abandoned systems stopped prior to the availability of modern techniques. These abandoned systems offer outstanding opportunities for teaching modern light and electron microscopy techniques, thus providing students with …

Functional Characterization Of The Hdt5 Gene In Aspergillus Flavus Morphogenesis, Mycotoxin Production, And Fungal Phytopathogenicity, Brenda Omburo

Graduate Research Theses & Dissertations

The present study aimed at elucidating the role of hdt5 in fungal morphology, mycotoxin production and in plant virulence in Aspergillus flavus. Currently, methodologies to prevent the negative impact of A. flavus are insufficient. It is known that expression of the hdt5 gene is dependent on hbx1, a master regulatory gene that affects expression of hundreds of genes in the A. flavus genome, controlling both development and secondary metabolism. However, while the aflatoxin gene cluster has been elucidated, the genetic regulatory mechanisms controlled by hdt5 are not fully understood. For this study, therefore, a complete strain set composed of a …

Periconceptual Nutrition And The Preimplantation Embryo: Approaches For Intervention And Generational Health, Abigail Klein

Dissertations and Theses

The typical American diet exceeds dietary fat recommendations, contributing to the rising rates of obesity. This negatively impacts fertility, pregnancy and fetal growth, and lifelong offspring health. During pregnancy, this also increases risk of co-morbidities like gestational diabetes. Despite this, lipids are not screened during pregnancy and limited research exists evaluating these co-exposures on offspring health. Our lab used a rat model of maternal high fat (HF) diet with late-gestation diabetes (DM) to demonstrate that mitochondrial dysfunction and oxidative stress incite lifelong cardiometabolic disease risk in offspring. To determine the timing of damage, we hypothesized that maternal overnutrition incites mitochondrial …

Lap-Hsp60 Complex Modulates Epithelial Tight Junction Barrier, Arun Bhunia, Manalee Manalee Samaddar, Chen Sun, Nicholas Gallina, Nicole Irizarry-Tardi, Donqi Liu, Shivendra Tenguria, Rishi Drolia, Anika Jain, Daisuke Kihara, Wen Jiang, Kee-Hong Kim, Abigail Cox, Kurt Ristroph, Gregory Knipp, Nicholas Noinaj

Biological Sciences Faculty Publications

During infection, Listeria adhesion protein (LAP), a housekeeping enzyme, acts as a tight junction modulator (TJM) through interaction with Hsp60 to facilitate Listeria monocytogenes translocation across the intestinal epithelial barrier. Here, we used purified LAP as a potential TJM to overcome the limiting and variable effects observed by other agents in the class. We structurally determined the LAP interaction alone and in complex with Hsp60 utilizing cryo-EM and computational analysis. LAP structure resolved at 2.83 Å, forms multimeric interlocking dimers and tetramers, and the N-domain interacts with Hsp60, while the C-domain bridges the bacterial surface receptor InlB. The structural studies …

Role Of Chemotype In Aggressiveness, Toxicity, And Competitive-Ness Of Fusarium Graminearum On Wheat, Simran Goyal

Theses and Dissertations--Plant Pathology

Fusarium Head Blight (FHB) of wheat, caused by the fungus Fusarium graminearum, is a devastating disease that led to epidemics in the U.S. during the 1990s, resulting in economic losses exceeding $2.6 billion. Typical symptoms include bleached spikelets and shriveled grains, often contaminated with trichothecene mycotoxins that make them unsafe for food or feed. FHB severity and mycotoxin production are influenced by a complex interplay between host genotype, environmental factors, and pathogen genotype. Integrated management practices that include the use of more resistant cultivars, crop rotation, and fungicide applications help to reduce disease incidence and severity. Disease forecasting models …

‘Who’S Your Daddy?’: Ddradseq Parentage In Broodstock-Offspring Pairs Of Diadema Antillarum In A Population Restoration Initiative, Bianca R. Rosendahl

Undergraduate Scholarship and Creative Works

In the early 1980s Diadema antillarum, or the long-spined urchin, was hit by a catastrophic mass mortality event across the western Atlantic and Gulf of Mexico, inclusive of the Florida Keys. The cause of this die-off event was likely triggered by a pathogen or environmental stressor that decimated native populations by up to 98%. The species has not yet fully recovered and is struggling with recruitment success which is why it may benefit from an ex-situ recovery program. In this study, I used single nucleotide polymorphisms (SNPs) to identify genetic variation and analyze parentage in a captive population of …

Impacts Of Multiple Coastal Stressors Across Life-History Stages In The Eastern Oyster, Amaelia Zyck

Open Access Dissertations

Urbanized estuaries are characterized as a complex of biotic and abiotic stressors, which currently challenge marine life and are expected to intensify and become increasingly unpredictable under the ongoing impacts of climate change. The persistence of coastal species that inhabit these stressful environments will ultimately depend on their ability to adapt. Many of these species have complex life cycles, featuring distinct morphological and physiological developmental stages that can exhibit unique responses to environmental pressures. However, since all stages share the same genome, selective pressures acting on one stage can have cascading effects throughout the life cycle. The larval stage, being …

Using Genetically Heterogenous Mice To Identify Regulators Of Immune Checkpoint Blockade Response, Justin Hackett

Wayne State University Dissertations

Immune Checkpoint Inhibitors (ICI) have dramatically improved patient outcomes in metastatic lung cancer, metastatic melanoma, subtypes of renal cancer and others. However, despite the clinical success, most patients still fail to have a durable response. Understanding what determines response and predicting who will respond to therapy is essential to improving patient outcomes. To investigate genetic underpinnings of ICI response we utilized F1 crosses of C57Bl/6 with Diversity Outbred mice (DOB6F1) and multiple Collaborative Cross (CC) strains to identify and validate (respectively) genetic loci that associated with response to ICI. The genomic data suggested that the lactation and immunomodulatory peptide prolactin …

Assessing Genetic Diversity And Population Structure In The Imperiled Aconitum Reclinatum (White Monkshood), An Endemic Wildflower Of Central Appalachia, Diamanda A. Zizis

Master’s Theses

Aconitum reclinatum, white monkshood (Ranunculaceae), is a Pennsylvania critically imperiled plant species found in five states of the Appalachian region of the United States: Pennsylvania, West Virginia, Virginia, North Carolina, and Tennessee. This plant is adapted to cool, moist environments but faces threats from increasing habitat loss, deer browse, logging, and changes in rainfall and temperature associated with climate change. Comprehensive knowledge of A. reclinatum genetic population structure remains limited. To address this, we collaborated with Natural Heritage programs within the range of A. reclinatum to sample populations across the species distribution and generate a genotyping-by-sequencing data set of …

Codon Composition In Human Oocyters Reveals Age-Associated Defects In Mrna Decay, Pavla Brachova, Lane K. Christenson, Nehemiah S. Alvarez

Department of Biomedical and Translational Sciences Faculty Publications

Oocytes from women of advanced reproductive age exhibit diminished developmental potential, but the underlying mechanisms remain incompletely defined. Oocyte maturation depends on translational control of maternal mRNA synthesized during growth. We performed a computational analysis on human oocytes from women < 30 versus ≥40 years and observed that mRNA GC content correlates negatively with half-life in oocytes from young (< 30 yr) but positively with oocytes from aged (>40 yr) women. In young oocytes, longer mRNA half-life is associated with lower protein abundance, whereas in aged oocytes GC content correlates positively with protein abundance. During the GV-to-MII transition, codon composition stratifies stability: codons that support rapid translation (optimal) stabilize mRNA, while slow-translating codons (non-optimal) promote decay. With reproductive aging, GC-containing codons become more optimal and align with increased …

Methods In Statistics, Machine Learning, And Deep Learning For Combining Multi-Omics Dataset, Md Mutasim Billah

Dissertations, Master's Theses and Master's Reports

Transcriptome-wide association studies (TWAS) have emerged as a powerful strategy to bridge genome-wide association studies (GWAS) with gene regulatory mechanisms by integrating genotypic data with gene expression data. While early TWAS methods typically rely on linear models and single-tissue expression references, recent advances underscore the need for flexible, multi-tissue approaches that can capture heterogeneous regulatory architectures and tissue-specific expression patterns. This dissertation introduces a three‑part research project that advances multi‑tissue transcriptome‑wide association studies (TWAS) along complementary axes of methodology, statistical power, and modelling flexibility.

In chapter One, TWAS‑CTL introduces a two‑stage cross‑tissue learner that trains any user‑chosen single‑tissue imputers (STLs) …

An Edna Assessment Of The Diamond Darter (Crystallaria Cincotta) In Its Current And Historic Distribution Range, Cameron Moore Layne

Graduate Theses, Dissertations, and Problem Reports (ETD)

Environmental DNA (eDNA) can serve as a useful monitoring tool for cryptic and imperiled freshwater stream fishes. eDNA can fill knowledge gaps regarding species’ distribution, site abundance, and habitat usage. The last known stronghold of the Diamond Darter (Crystallaria cincotta) in the Elk River of West Virginia provides an excellent test case to examine the utility of this non-invasive method of surveying rare species. Diamond Darters are one of the most newly recognized freshwater fishes in North America and are among the most imperiled U.S. fishes, having been federally listed as endangered in 2013. The cryptic behavior and limitations of …

Temporal Dynamics Of Programmed Genome Rearrangement In Sea Lamprey Embryogenesis: A Deep Learning & Lightsheet Imaging Approach To Studying Early Developmental Transitions, Kasturi Rajandran

Theses and Dissertations--Biology

Programmed genome rearrangement (PGR) in the sea lamprey (Petromyzon marinus) leads to the elimination of ~0.5Gb (20%) of the germline genome during early embryogenesis, yet its timing relative to the maternal-to-zygotic transition (MZT) remains unclear. In this study, we imaged embryos cleared at 3-hour intervals (up to 72 hours post fertilization (hpf)) using high-resolution lightsheet fluorescence microscopy and a custom deep-learning image-analysis pipeline (~80% accuracy) to quantify nuclei and micronuclei counts. Micronuclei, which are the hallmarks of PGR first appear between 24 to 27hpf (vs ~36hpf previously reported) indicating PGR starts earlier than previously reported in the sea …

The Adiponectin-Pparγ Axis In Hepatic Stellate Cells Regulates Liver Fibrosis, Shangang Zhao, Qingzhang Zhu, Wang-Hsin Lee, Jan-Bernd Funcke, Zhuzhen Zhang, May-Yun Wang, Qian Lin, Bianca Field, Xue-Nan Sun, Guannan Li, Mbolle Ekane, Toshiharu Onodera, Na Li, Yi Zhu, Christine M. Kusminski, Terry D. Hinds Jr., Philipp E. Scherer

Markey Cancer Center Faculty Publications

Hepatic stellate cells (HSCs) are key drivers of local fibrosis. Adiponectin, conventionally thought of as an adipokine, is also expressed in quiescent HSCs. However, the impact of its local expression on the progression of liver fibrosis remains unclear. We recently generated a transgenic mouse line (Lrat-rtTA) that expresses the doxycycline-responsive transcriptional activator rtTA under the control of the HSC-specific lecithin retinol acyltransferase (Lrat) promoter, which enables us to specifically and inducibly overexpress or eliminate genes in these cells. The inducible elimination of HSCs protects mice from methionine/choline-deficient (MCD) diet-induced liver fibrosis, confirming their causal involvement in fibrosis development. We generated …

Urobilin Derived From Bilirubin Bioconversion Binds Albumin And May Interfere With Bilirubin Interacting With Albumin: Implications For Disease Pathology, Kevin I. Williams, Priyanka Suryadevara, Chang-Guo Zhan, Terry D. Hinds Jr., Zachary A. Kipp

Markey Cancer Center Faculty Publications

Background/Objectives: Bilirubin is a hydrophobic molecule that binds the carrier protein albumin for transport through systemic circulation. Bilirubin is cleared from the body through the liver and excreted into the intestines, where the microbiota modifies the chemical structure, forming urobilin, which can be reabsorbed into circulation by the hepatic portal vein. Urobilin has no known function. It is also unknown whether urobilin binds albumin for transport in circulation. We hypothesized that because of the likeness of their chemical structures, urobilin would also bind albumin like bilirubin does. Methods: First, we used in silico docking to predict if urobilin would bind …

Dissecting The Biophysical Mechanisms Of Oleate Hydratase Association With Membranes, William A. Lathram, Robert J. Neff, Ashley N. Zalla, James D. Brien, Vivekanandan Subramanian, Christopher D. Radka

Markey Cancer Center Faculty Publications

This study investigates the dynamics of oleate hydratase (OhyA), a bacterial flavoenzyme from Staphylococcus aureus, and its interactions with lipid membranes, focusing on the factors influencing membrane binding and oligomerization. OhyA catalyzes the hydration of unsaturated fatty acids, playing a key role in bacterial pathogenesis by neutralizing host antimicrobial fatty acids. OhyA binds the membrane bilayer to access membrane-embedded substrates for catalysis, and structural studies have revealed that OhyA forms oligomers on membrane surfaces, stabilized by both protein-protein and protein-lipid interactions. Using fluorescence correlation spectroscopy (FCS), we examined the effects of membrane curvature and lipid availability on OhyA binding to …

Factors Influencing Adherence To Surveillance Guidelines In Individuals With Tuberous Sclerosis Complex, Kashish Khanna

Theses and Dissertations

Tuberous Sclerosis Complex (TSC) is a genetic condition that is caused by pathogenic changes in either the TSC1 or TSC2 gene and is characterized by multiple benign tumors, otherwise known as hamartomas, in various organs such as the brain, skin, lungs, and kidneys. Because of the many different clinical manifestations of TSC, extensive surveillance guidelines are recommended for individuals with TSC. Past studies have shown that there has been a gap in knowledge of these surveillance guidelines. These studies also suggest projects that measure adherence to surveillance guidelines and address specific challenges hindering surveillance guideline adherence. This study aims to …

The Relationship Between Cardiac Patient Beliefs And Experiences With Insurability And Their Decisions On Whether Or Not To Pursue Genetic Testing, Julia Schoeni

Theses and Dissertations

Since the enactment of the Genetic Information Non-Discrimination Act (GINA) in 2008, genetics providers have been incorporating conversations about GINA in pre-test counseling. There is currently limited evidence of the effects of personal or family histories of cardiomyopathy or aortopathy and associated genetic testing on patients seeking insurance policies not protected by GINA, including life, long term care, and disability insurance. This study aimed to determine whether individuals with a personal or family history of cardiomyopathy or aortopathy are having conversations about future insurability with their healthcare providers and how they perceive their ability to get these insurances when deciding …

Utilizing Evisits To Increase Access To Genetic Services For The Hearing Loss Population: A Tailored Service Delivery Model, Ansley Roberts

Theses and Dissertations

Purpose: Patients referred for genetics services have specific barriers decreasing accessibility, such as communication difficulties, long wait times, and misconceptions about the utility of genetic testing. We assessed a new tailored service delivery model used by the Greenwood Genetic Center to evaluate patients referred for hearing loss to determine if this model increases access to genetics services for individuals with hearing loss. Methods: Data points such as wait times, testing plan, and diagnostic yield were compiled from patient medical records. Comparison and analysis of data was completed by visit type, in-person, virtual, and electronic visits (eVisits), between October 2023 – …

Nature, Nurture, And Serial Murder: A Biocriminological Analysis Of Jeffrey Dahmer And Aileen Wuornos, Dori W. Jal

Honors Thesis

In recent years, there has been an increase in public fascination with serial killers, however current criminological explanations continue to focus on social and psychological factors, lacking commentary on potential biological implications. This thesis addresses a gap in the literature by examining how biological processes, specifically epigenetic, neurobiological, and endocrinological mechanisms, interact with environmental stressors to shape serial homicidal behavior. The goal is to determine whether serial murder can be more effectively understood through a biosocial framework that integrates biological vulnerability with lived experience, rather than relying on singular explanatory models.

Using a qualitative multiple-case study methodology, this research analyzes …

Electrochemical Strategies For Microrna Quantification Leveraging Amplification And Nanomaterials: A Review, Alexander Hunt, Gymama Slaughter

Center for Bioelectronics Publications

MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression and have emerged as critical biomarkers in various diseases, including cancer. Their stability in bodily fluids and role as oncogenes or tumor suppressors make them attractive targets for non-invasive diagnostics. However, conventional detection methods, such as Northern blotting, RT-PCR, and microarrays, are limited by low sensitivity, lengthy protocols, and limited specificity. Electrochemical biosensors offer a promising alternative, providing high sensitivity, rapid response times, portability, and cost-effectiveness. These biosensors translate miRNA hybridization events into quantifiable electrochemical signals, often leveraging redox-active labels, mediators, or intercalators. Recent advancements in nanomaterials and signal amplification …

Weighted Family History Density Of Substance Use: Influence On Participant Substance Use Onset, Escalation, And Duration, Carleigh A. Litteral

Theses and Dissertations--Psychology

Substance use disorders impose a staggering toll on the United States (U.S.), straining healthcare systems, destabilizing communities, and profoundly impacting both individuals and families. Approximately one in six Americans aged 12 and older had a past-year substance use disorder in 2022 (Key Substance Use, 2022), and nearly one-third of adults experience a substance use disorder in their lifetime (Wu, 2010), contributing to an economic burden exceeding $400 billion annually (National Drug Threat Assessment, 2011). Family history of substance use disorders is a key predictor of vulnerability, with individuals who have affected relatives being 2–8 times more …

The Effects Of Plx 3397 On Fentanyl Escalation In Male And Female Sprague-Dawley Rats, Jakob Shaykin

Theses and Dissertations--Psychology

Purpose: A hallmark characteristic of opioid use disorder (OUD) is a persons’ ‘loss of control’, which leads to the compulsion to seek and obtain opioids, resulting in increased consumption. This phenomenon is known as ‘escalation of drug intake’. Chronic opioid use causes microglial reactivity and subsequent release of proinflammatory cytokines leading to neuroinflammation, weakening one’s executive control over drug taking and ultimately leading to greater use. Previous research in our laboratory has explored heterogeneity of fentanyl intake in extended access (6-hr) sessions and identified distinct endophenotypes of fentanyl intake. Moreover, we have observed a positive correlation between Treml1 expression …

Neuroinflammatory Signaling And Immune Cell Infiltration Differ In Brains Of Rats Exposed To Space Radiation And Social Isolation, Austin M. Adkins, Zachary N. M. Luyo, Alea F. Boden, Riley S. Heerbrandt, Richard A. Britten, Laurie L. Wellman, Larry D. Sanford

Center for Integrative Neuroscience and Inflammatory Diseases (CINID) Faculty Publications

Astronauts on the proposed Mars missions will be exposed to extended periods of social isolation (SI) and space radiation (SR). SI and SR-induced immune dysregulation can result in persistent neuroinflammation and neuronal damage which could negatively impact an astronaut’s health and ability to maintain adequate levels of performance. The synergistic effects of combined SI and SR on immune system functionality and the brain remain unknown. Determining how single and combined inflight stressors modulate the immune system is crucial for fully understanding pathways impacting astronaut health and performance. We used ground-based analogs of SI and SR in rodent models to investigate …

Late Diagnosis Of Klinefelter Syndrome: Overcoming Phenotypic Variability And Diagnostic Oversights, Amna Kamran, Chinelo Okigbo

Department of Medicine Faculty Publications

We report a case of Klinefelter syndrome (KS) diagnosed in adulthood, emphasizing the impact of phenotypic variability and the declining reliance on physical examination in delayed recognition. A 27-year-old male with obesity, low libido, and biochemical and clinical primary hypogonadism was found to have 47, XXY karyotype, consistent with KS. His hypogonadism was initially attributed to obesity and overlooked, despite classic signs of a micropenis and small testes. The case highlights the importance of physical examination, comprehensive history, and clinician awareness in diagnosing KS, particularly in atypical presentations. KS is associated with increased risks of osteoporosis, cardiovascular disease, and psychosocial …

Copula-Based Bayesian Model For Detecting Differential Gene Expression, Prasansha Liyanaarachchi, N. Rao Chaganty

Mathematics & Statistics Faculty Publications

Deoxyribonucleic acid, more commonly known as DNA, is a fundamental genetic material in all living organisms, containing thousands of genes, but only a subset exhibit differential expression and play a crucial role in diseases. Microarray technology has revolutionized the study of gene expression, with two primary types available for expression analysis: spotted cDNA arrays and oligonucleotide arrays. This research focuses on the statistical analysis of data from spotted cDNA microarrays. Numerous models have been developed to identify differentially expressed genes based on the red and green fluorescence intensities measured using these arrays. We propose a novel approach using a Gaussian …

Cath-Ddg: Towards Robust Mutation Effect Prediction On Protein-Protein Interactions Out Of Cath Homologous Superfamily, Guanglei Yu, Xuehua Bi, Teng Ma, Yaohang Li, Jianxin Wang

Computer Science Faculty Publications

Motivation: Protein-protein interactions (PPIs) are fundamental aspects in understanding biological processes. Accurately predicting the effects of mutations on PPIs remains a critical requirement for drug design and disease mechanistic studies. Recently, deep learning models using protein 3D structures have become predominant for predicting mutation effects. However, significant challenges remain in practical applications, in part due to the considerable disparity in generalization capabilities between easy and hard mutations. Specifically, a hard mutation is defined as one with its maximum TM-score < 0.6 when compared to the training set. Additionally, compared to physics-based approaches, deep learning models may overestimate performance due to potential data leakage.

Results: We propose new training/test splits that mitigate data leakage according to the CATH homologous superfamily. Under the constraints of physical …

Multi-Locas Gwas Mapping And Candidate Gene Analysis Of Anticancer Peptide Lunasin In Soybean (Glycine Max L. Merr), Rikki Locklear, Jennifer Kusumah, Layla Rashad, Felicia Lugaro, Sonia Viera, Nathan Kipyego, Faith Kipkosgei, Daisy Jerop, Shirley Jacquet, Mythy Addelmajid Kassem, Jiazheng Yuan, Elvira De Mejia, Rouf Mian

Biological Sciences Faculty Publications

Soybean (Glycine max) peptide lunasin exhibits significant cancer-preventive, antioxidant, and hypocholesterolemic effects. This study aimed to identify quantitative trait nucleotides (QTNs) associated with lunasin content and to annotate the candidate genes in the soybean genome. The mapping panel of 144 accessions was gathered from the USDA Soybean Germplasm Collection, encompassing diverse geographical origins and genetic backgrounds, and was genotyped using SoySNP50K iSelect Beadchips. The lunasin content in soybean seeds was measured using the enzyme-linked immunosorbent assay (ELISA) method, with lipid-adjusted soybean flour prepared from seeds obtained from the Germplasm Resource Information Network (GRIN) of USDA-ARS in 2003 and …