Genetics and Genomics Commons^™

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 …

Dna Methylation Variation In Eastern Diamondback Rattlesnakes (Crotalus Adamanteus) On A Georgia Barrier Island, Megan Hoog

College of Graduate Studies: Theses & Dissertations

The Eastern Diamondback Rattlesnake (Crotalus adamanteus, EDB) is the largest rattlesnake in the world and is thought to be declining in many portions of its range. Genetic venom studies in the Southeast United States have shown evidence of fine-scale differences within two main geographic groups on Jekyll Island. My objective is to expand on this finding to determine if epigenetic mechanisms, specifically DNA methylation, varies among different populations of EDB in similar environments, age classes, and sexes. I collected EDB blood samples through a partnership with the Jekyll Island Authority and screened 44 individuals for epigenetic variation from …

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) …

A Tail Of Two Fishes: Exploring Population Structure In Two Species Of Fishes Across The Galápagos Islands, Hillary Quach

Honors Undergraduate Theses

The Galápagos Islands, a UNESCO World Heritage Site and a biodiversity hotspot with high levels of endemism, is home to over 440 species of fishes. Marine conditions across the Archipelago are greatly influenced by ocean currents in the region. The Pacific Equatorial Undercurrent, South Equatorial Current, and the Humboldt Current deliver waters rich in nutrients across the three major regions within the Galápagos (central, north, and west). These conditions create a dynamic environment close to the equator, enabling diverse species to thrive in distinct parts of the Galápagos. Despite the rich biodiversity in the region and diverse oceanographic conditions, there …

Genomic Epidemiology Of Staphylococcus Aureus Sequence-Type 72, Sachitaa Senthilkumar

Honors Undergraduate Theses

Staphylococcus aureus (S. aureus, SA) is a gram-positive bacterial colonizer and pathogen commonly carried on the skin and in the anterior nares of humans. SA colonization may lead to a variety of non-invasive (e.g., skin and soft tissue infections, SSTIs) and invasive (e.g., bacteremia and osteomyelitis) infections. The SA population is comprised of multiple lineages that can be delineated through multi-locus sequence typing (MLST), which compares nucleotide sequences within seven housekeeping genes. Strains belonging to an MLST share a common evolutionary history and phenotypic characteristics like antibiotic resistance or virulence. As a result, the epidemiology of lineages can be …

“Regression To The Mean”: The Confluence Of Eugenics And Statistics In The 19th And 20th Centuries, Emrys G. King

Pomona Senior Theses

The work of this thesis is twofold — first, qualitatively characterizing the confluence between the British eugenics and statistics movements in the late 19th and early 20th centuries, and second, quantitatively analyzing the effect of this foundation on pedagogical materials in the growing field of statistics between 1880 and 1970. Towards the first goal, the history of the method of least squares, state statistics, and positive and negative eugenics are outlined, followed by a close reading of the foundational texts authored by Francis Galton and Karl Pearson that introduced linear regression. Towards the latter goal, English-language statistics textbooks published between …

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 …

Characterizing Somatic Variants In Nanopore Data With Machine Learning, Shwethal Sayeeram Trikannad

Master's Projects

Oxford Nanopore Technology (ONT) is a popular long-read sequencer in genomics. However, its high base-calling error rate produces several sequencing artifacts. Detection of somatic variants in ONT sequenced tumor-normal samples remains challenging due to low frequencies. In this study, machine learning was applied to a dataset created by benchmarking ClairS output against HCC1395 and colo829 truth sets to classify variants and artifacts. Relevant features were engineered from sequence context and variant site characteristics to model artifact profiles. HistGradientBoostingClassifier achieved 0.876950 accuracy, outperforming all other models. Variant quality was the top predictor with an aggregate accuracy of over 85%. This work …

Revolutionizing Grapevine Breeding Programs: A Mobile Genome Editing System For Perennial Crops, Bridget Bolt

Theses and Dissertations--Plant and Soil Sciences

Grapevine (Vitis vinifera) faces unprecedented challenges from climate change, with up to 90% of current growing regions potentially becoming unsuitable for production within decades. Traditional breeding approaches require 25-30 years for variety development, creating a time constraint incompatible with the pace of environmental change. This research establishes the approach for a novel mobile RNA-based gene editing platform that addresses longstanding bottlenecks in grapevine improvement while preserving cultivar identity and reducing breeding timelines.

This research developed a three-component system for transgene-free gene editing in grapevine. First, a mobile CRISPR/Cas9 system was established using Agrobacterium rhizogenes transformation and the cut-and-dip …

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 …

Phylogenetic Analysis Of Metabolic Enzymes In Hypoxic/Anoxic Conditions In Cetaceans And Cancer, Samerna A. Masih

Electronic Theses & Dissertations (2024 - present)

Cancer cells often exhibit a Warburg-like metabolism, which includes increased fatty acid synthesis and storage that help them survive in hypoxic conditions. This shift is marked by the heightened synthesis and accumulation of fatty acids, acting as a survival mechanism in low-oxygen environments (Baumann et al., 2016). Interestingly, deep-diving whales may utilize a similar metabolic pathway to produce wax esters during their prolonged dives.

Our study focused on exploring the genetic and metabolic similarities between breast cancer cells and deep-diving whales, using computational analyses to investigate lipid metabolism genes. We looked for evolutionarily conserved variations that might reveal adaptive mechanisms …

Polygenic Risk Scores Of Grip Strength In Men And Women With Or At Risk For Hiv, Sreevidya Sadananda Sadasiva Rao

Electronic Theses & Dissertations (2024 - present)

Background: Adequate hand function among older adults is necessary for the successful completion of activities of daily living and can affect whether an older adult is able to live independently. Current research highlights grip strength, the strength people have in their hands, as a robust predictor of morbidity and mortality, and explores the decline in grip strength over time. A person’s family history and genes (DNA) affect how much grip strength they have. Previous studies have identified genes that affect grip strength, mainly in European ancestry populations. In this study, we examined whether these genetic elements predict grip strength in …

Dna And Protein Determinants For P63 Transcriptional Activity, Abigail Mccann

Electronic Theses & Dissertations (2024 - present)

The transcription factor p63 is critical for development of the epidermis and other epithelial-related structures. Mutations in the DNA-binding domain of p63 lead to a range of human developmental disorders characterized by symptoms such as ectrodactyly, painful skin dysplasia, and cleft lip and palate. The TP63 gene is also amplified in squamous cell carcinomas, contributing to tumor pathogenesis. While the importance of p63 in human health is well established, the mechanisms underlying its control of an essential gene network remain unclear. TP63 encodes multiple isoforms with distinct N- and C-terminal domains. The ∆Np63α isoform is directly linked to epidermal development …

Accurate Body Weight Class Prediction From Mirna And Gene Expression In Blood And Saliva Samples, Kimberly Lettner

Master of Science in Forensic Science Directed Research Projects

miRNA interference on protein abundance related to glucose uptake and lipid production has been evaluated in biomedical research and linked to metabolic disorders like severe obesity. The direct regulation of protein abundance caused by miRNAs on a person’s metabolism can lead to an increased weight and overall size. Body size, measured by BMI, provides additional physical descriptions that can be combined with hair color, eye color, age, and skin pigment to aid investigations of unidentified remains or unknown suspects not found in a database. The purpose of this project was to evaluate the miRNA expression of target biomarkers in dried …

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 …

Gadd34 And Crep Regulation In The Unfolded Protein Response, Comparing Molecular Mechanisms In Humans And Zebrafish, Angela Adams

University of the Pacific Theses and Dissertations

In eukaryotic cells, many newly synthesized proteins are sent to the endoplasmic reticulum (ER) of a cell to be folded into the proper conformation for functionality. When proteins get misfolded, or cannot be folded fast enough, these proteins accumulate in the ER which causes the cell to become stressed. This leads to a process known as the Unfolded Protein Response (UPR). Once UPR has been initiated, the α subunit of eukaryotic initiation factor 2 (eIF2α) becomes phosphorylated to inhibit global protein synthesis within the cell, while simultaneously activating the expression of several genes to either aid in cell recovery or …