Genetics and Genomics Commons^™

Uncovering Capillary Endothelial Cells Response During Lung Injury-Repair, Celine Shuet Lin Kong

Dissertations and Theses (Open Access)

Once thought to be a homogenous population, capillary endothelial cells (ECs) have embodied organotypic specialization and heterogenous properties, both during homeostasis and tissue injury. In the lung, capillary ECs consist of two distinct populations, CAP1 and CAP2s; how each population responds to diverse tissue injury is incompletely understood. In this thesis, I report the induction and function of a truncated isoform of Ntrk2, Ntrk2^-tk (lacking the tyrosine kinase domain) in multiple injury models. Using a combinatorial approach of single-cell multiome, mouse genetics and viral infection models, I found that Ntrk2^-tk is broadly induced in CAP1s after the initial …

Epigenetic Modification As A Therapeutic Target In Brafv600e-Mutated Metastatic Colorectal Cancer, Hey Min Lee

Dissertations and Theses (Open Access)

Patients with BRAF^V600E-mutated metastatic colorectal cancer (mCRC) experience a worse prognosis and demonstrate only a 5% response rate to BRAF inhibitor treatment. In this study, adaptive resistance, and a potential combination of standard therapies in BRAF^V600E CRC were unveiled. Intriguingly, a robust association of BRAF^V600E mutation and DNA hypermethylation suggests this is a unique subgroup harboring aberrant epigenetic phenotype. Firstly, DNA methyltransferase (DNMT) inhibitor treatment induced profound DNA hypomethylation in vivo, but minimal change in gene expression due to adaptive elevation of the repressive histone methylation, H3K27me3, leading to compensatory suppression of key tumor suppressor genes, …

Patient Preferences For Ultrasound Soft Sign Disclosure With Prior Negative Cfdna Screening, Disha Patel

Dissertations and Theses (Open Access)

Soft signs are nonstructural fetal anomalies that can be identified by the second-trimester comprehensive ultrasound examination. In isolation, soft signs are insufficient to diagnose chromosome conditions but can adjust an individual's risk for aneuploidy, primarily Down syndrome. In the age of noninvasive cell-free DNA (cfDNA) prenatal screening, which exhibits superior sensitivity and specificity for aneuploidy compared to what can be provided by soft sign risk adjustment, the utility of these soft signs is arguably waning. Thus, this study aimed to establish patient preferences for whether and how soft signs are disclosed in pregnancy to inform recommendations for disclosure. A survey …

Acute Pain Prediction In Oral Cavity And Oropharyngeal Cancer Patients Receiving Radiation Therapy, Vivian Salama

Dissertations and Theses (Open Access)

Oral-Cavity and oropharyngeal cancers (OC/OPC) are types of head and neck cancers that are increasing in incidence domestically. Radiation therapy (RT) is crucial in OC/OPC management. Pain is a common and challenging symptom for most patients during therapy, as nearly all patients undergoing locoregional RT in OC/OPC require analgesia for acute iatrogenic pain. Moreover, about 45% of long-term survivors report chronic pain, with more than 10% exhibiting severe chronic pain. Pain control is challenging due to the multifactorial clinical, molecular, and cellular etiology of cancer/therapy pain, as well as variation in pain assessment and the non-uniform management of pain between …

Patient Understanding Of Fetal Sex Versus Gender In The Context Of Routine Cell-Free Dna Screening, Mindy Kolodziejski

Dissertations and Theses (Open Access)

Non-invasive prenatal testing (NIPT) is the current standard of care to screen for fetal aneuploidy using cell-free DNA (cfDNA). NIPT screens for sex chromosome aneuploidies (SCAs) and in doing so, can predict fetal chromosomal sex. Despite sex and gender being distinct concepts, many patients refer to NIPT as “the gender test” and elect testing in order to find out predicted fetal sex and assume gender. Our study aimed to evaluate and describe patient understanding of sex and gender in the context of receiving routine prenatal genetics education (PGE) on NIPT. A survey was developed with the goal of assessing patient …

Influential Factors For Disclosing A Tuberous Sclerosis Complex Diagnosis To Romantic Partners, Laura Gorecki

Dissertations and Theses (Open Access)

Tuberous sclerosis complex (TSC) is a highly variable genetic condition characterized by multi-organ tumor predisposition. Due to the heritability, variability, and severity of this condition, individuals with TSC may face unique psychosocial challenges in dating and romantic relationships, specifically related to disclosing their diagnosis to romantic partners. Despite disclosure within romantic relationships being explored in the context of other genetic conditions, this area has not yet been explored in the TSC community who face unique challenges related to physical and mental health, educational performance, and overall quality of life. This study surveyed 117 independent adults with TSC regarding the following …

Efficacy Of Genetic Testing Methodologies For Prenatal Detection Of Skeletal Anomalies And Craniosynostosis Syndromes, Nicolette Murphey

Dissertations and Theses (Open Access)

Prenatal ultrasound findings suggestive of skeletal dysplasia often have a wide differential with over 450 skeletal dysplasia syndromes described to date. Specific phenotypic features on ultrasound provide guidance, though we noted in this study that molecular testing is most informative in making a diagnosis. Prenatal genetic testing ranges from screening tests using cell-free fetal DNA to diagnostic tests which include next generation sequencing panels and whole exome or genome sequencing. We aimed to determine which prenatal genetic tests were capable of identifying disease causing variants in pregnancies suspected to have skeletal dysplasia and craniosynostosis syndromes. This multi-center retrospective chart review …

The In4mer Crispr/Cas12a Multiplex Knockout Platform And Its Applications, Nazanin Esmaeili Anvar

Dissertations and Theses (Open Access)

Discovering synthetic lethal interactions between genes holds the key to uncovering cancer vulnerabilities, enabling the development of more effective drugs for patients. However, identifying these vulnerabilities in the complex genome of human, which comprises thousands of genes, poses a significant challenge. One alternative approach to investigate these interactions involves exploring enriched sources of synthetic lethal interactions, such as paralog pairs. In recent years, a couple of studies have conducted dual-gene knockout experiments on paralog pairs using different approaches to identify synthetic lethal interactions. In this study, we conducted a meta-analysis of CRISPR genetic interaction screens. We identified a candidate set …

Dysmorphology Training And Utility In Genetic Counseling, Maria G. Hernandez

Dissertations and Theses (Open Access)

Before the availability of comprehensive genetic testing, dysmorphology was critical for developing a differential for individuals suspected of having a genetic disorder. Literature suggests that the availability of whole exome and whole genome sequencing (ES/GS) has shifted the use of dysmorphology from a forward to backward approach. There is no literature describing the continued use of dysmorphology within the genetic counseling field or the training that genetic counseling students receive. The study aims to describe the dysmorphology training that genetic counselors (GC) and GC students reported receiving, to explore the involvement of GCs in evaluating dysmorphic features and identify factors …

Inclusion Of Adoption As A Pregnancy Management Option In Prenatal Genetic Counseling Practice, Emma Billings

Dissertations and Theses (Open Access)

Prenatal genetic counselors are essential to providing education, psychosocial support, and guidance on pregnancy options to patients who receive a fetal diagnosis of an anomaly or genetic condition. Therefore, genetic counselors should be well-educated on comprehensive pregnancy management options consisting of parenting, abortion, and adoption. The landscape of adoption education in genetic counseling practice was last characterized in 2010 by Perry and Henry, revealing substantial variability in both the inclusion of adoption-specific education in genetic counseling program (GCP) curricula and the discussion of pregnancy options with patients in prenatal practice. As a result, the authors published a call to action …

Fraud In Genetic Testing: Swindling The System, Rachel Notestine, Rachel Notestine, Claire N. Singletary

Dissertations and Theses (Open Access)

Healthcare fraud comprises a sizable portion of the United States healthcare expenditure and inflicts strain on payors, patients, and the healthcare system overall. The genetic testing industry is rapidly growing which provides a multitude of fraud opportunities. There is limited research exploring genetic testing fraud, although federal organizations have highlighted it as an issue. In this study, a retrospective review of federal websites, news articles, and a legal database identified 42 cases of fraud involving outpatient genetic testing published between February 2019 and December 2023. These cases were analyzed for themes via inductive conventional content analysis. Themes of fraudulent activity …

Dysmorphology Training And Utility In Genetic Counseling, Maria Hernandez, Maria Hernandez

Dissertations and Theses (Open Access)

Before the availability of comprehensive genetic testing, dysmorphology was critical for developing a differential for individuals suspected of having a genetic disorder. Literature suggests that the availability of whole exome and whole genome sequencing (ES/GS) has shifted the use of dysmorphology from a forward to backward approach. There is no literature describing the continued use of dysmorphology within the genetic counseling field or the training that genetic counseling students receive. The study aims to describe the dysmorphology training that genetic counselors (GC) and GC students reported receiving, to explore the involvement of GCs in evaluating dysmorphic features and identify factors …

Impact Of Genetic Counseling On Patient Empowerment After Diagnosis Of Fetal Anomaly, Carley Brueckner

Dissertations and Theses (Open Access)

Approximately 3-5% of pregnancies are affected by fetal anomalies, often leading to structural and functional differences that impact infant health and mortality. When anomalies are identified on prenatal ultrasound, genetic counseling (GC) and genetic testing may be offered to investigate the potential for a possible syndromic cause. Genetic counselors provide education on the chance for a genetic etiology, available testing options, potential changes in medical intervention related to an identified etiology, and psychosocial counseling and resources. Regardless of a patient’s testing decision, genetic counseling should include psychosocial counseling to support and empower patients in a time of prognostic uncertainty and …

Histone Lysine Methyltransferase Nsd3 Governs Transcriptional Programs That Drive Pancreatic Neuroendocrine Tumors (Pannets), Mary Esmeralda Fuentes

Dissertations and Theses (Open Access)

Pancreatic Neuroendocrine Tumors (PanNETs) are the most common and lethal neuroendocrine malignancies where treatments used in advanced patients have limited efficacy, adverse side effects, and acquire resistance. Thus, there is a critical need to uncover novel precision therapeutics for PanNET patients. Additionally, pre-clinical models that more accurately represent disease are an urgent necessity for translational studies.

This dissertation directly addresses these challenges by identifying histone lysine methyltransferase (KMT) NSD3 as a critical oncogenic driver of PanNETs through di-methylation of histone H3K36 (H3K36me2).

The findings shown in this body of work indicate that H3K36 methylation by NSD3 functions as a transcriptional …

Motivations And Attitudes For Pursuing Anonymous Genetic Testing For Huntington’S Disease, Jordan Steffen

Dissertations and Theses (Open Access)

Huntington’s disease (HD) is a progressive neurodegenerative disorder for which predictive and confirmatory testing is available. However, only a small portion of at-risk individuals complete predictive testing. Concerns of privacy and genetic discrimination have been cited as reasons testing is declined. This leads some to seek anonymous testing, a process in which measures are taken to exclude identifying information, thereby preventing results from being linked to legal names, medical records, or health insurance. Previous research suggests anonymous testing is not widely favored amongst healthcare providers, but patient perspectives have not been described. These studies also precede the implementation of the …

A Continuous Local Ancestry Measure For Efficient Local-Ancestry-Aware Association Tests, Hanxiao Sun

Dissertations and Theses (Open Access)

Genetic association tests have enabled people to identify susceptible loci and broadened our understanding of complex diseases. However, the GWAS (Genome-wide Association Studies) results are probably confounded by population stratification thus leading to potential false-positive findings. This problem is pronounced particularly in admixed populations, a group of populations with multiple ancestries whose local genetic ancestry may drastically vary at local genomic positions (local ancestry) compared to the overall genetic ancestral composition (global ancestry). It is insufficient to only account for global population structure in admixed populations. Methods have been developed to account for local population stratification but followed by subsequent …

Characterizing The Regulation Of Candida Albicans Hyphal Morphogenesis In The Context Of Host Macrophages, Hannah Wilson

Dissertations and Theses (Open Access)

Candida albicans is a commensal fungus that resides on the skin, mucosal surfaces, and in the gut of an estimated 80% of individuals. Though generally harmless, C. albicans is capable of causing uncomfortable mucosal infections as well as deadly disseminated infections depending on the immune status of the host. Although antifungal therapeutics exist, the mortality rate associated with disseminated disease still lingers around 50%. Further, C. albicans is the fourth most common cause of all bloodstream infections and continues to present as a major clinical issue with less than satisfactory treatment options. For this reason, it is imperative to understand …

A Study Of The Snd1/Prmt5 Axis In Liver Cancer By Genetic Mouse Models, Tanner Wright, Tanner Wright

Dissertations and Theses (Open Access)

Arginine methylation is an essential post-translational modification (PTM) in cells. Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme that catalyzes symmetric dimethyl arginine (SDMA) and requires methylosome protein 50 (MEP50) for stability and enzymatic activity which are necessary for life and development. Effector proteins bind different types of PTM’s to facilitate signaling. Staphylococcal nuclease Tudor domain containing 1 (SND1) is an effector that specifically binds SDMA via its single C-terminal Tudor domain. Both SND1 and PRMT5 have been implicated in hepatocellular carcinoma (HCC). SND1 has been confirmed as a driver of HCC using genetically engineered mouse models (GEMMs), though, …

Analyzing Extracellular Vesicles For Disease Monitoring In Metastatic Colorectal Cancer Patients, Vahid Bahrambeigi

Dissertations and Theses (Open Access)

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Metastases are the main cause of cancer-related death, and the most frequent metastatic sites in patients with CRCs are liver and lung. To confirm the diagnosis of metastatic CRC (mCRCs) and to classify mCRCs, tumor biopsy of a suspected metastasis is often required. The consensus molecular subtype (CMS) classification which is based on gene expression profiles of CRC tumor specimens, is a predictive factor for treatment outcomes of standard chemotherapies for mCRCs. The practicality of repeated tumor biopsies for disease monitoring in mCRC patients is …

Genomic Characterization Of Adolescent And Young Adult Cancers: Investigation Of Ewing Sarcoma Susceptibility And Chornobyl Thyroid Tumors, Olivia Lee

Dissertations and Theses (Open Access)

Adolescent and young adult (AYA) cancers, diagnosed between the ages of 15 and 39, can exhibit distinctive genetic and molecular characteristics. Reported epidemiologic findings and treatment outcomes based on pediatric and adult cancer studies are often not suitable for application to the AYA population, underscoring the need for more thorough genomic research. Advances in sequencing technologies have enabled comprehensive analyses of complex genomic characteristics of AYA cancers, crucial for understanding the underlying biology of these malignancies. Here, I have utilized advanced sequencing techniques and integrated analytic approaches to describe important genomic features in two different AYA cancer types: Ewing Sarcoma …

Identifying Functional Enhancers For Fibrotic Gene Regulation In Liver Fibrosis, Parnaz Merikhian

Dissertations and Theses (Open Access)

Liver fibrosis is characterized by progressive activation of proliferating and migrating myofibroblasts that lead to accumulation of extracellular matrix (ECM). These myofibroblasts most arise from activated liver-resident hepatic stellate cells (HSCs). There is an increasing number of patients suffering from liver fibrosis in developed countries including the United States, which is anticipated to continue to grow during 2023-2033 period. TGF-β1 is a key cytokine with a significant role in regulating cell differentiation and adhesion in liver fibrosis. TGF-β signaling triggers gene expression changes in HSCs, including that of fibrotic and EMT-related genes, which then functionally promote HSCs activation and fibrogenesis. …

Genetic Analysis Of Crossover Defective Mouse Spermatocytes Reveals Discrete Crossover Precursor Intermediates, Tolkappiyan Prem Kumar

Dissertations and Theses (Open Access)

In healthy, non-replicating somatic cells of diploid organisms, like humans and mice, there are two copies of each chromosome, one from each parent. However, the germ cells of these organisms, the oocytes, and the sperm, have only one copy of each chromosome, thus ensuring that when haploid oocytes and sperm fuse to form a zygote, a diploid number of chromosomes is restored. The reduction of a diploid number of chromosomes to a haploid number of chromosomes takes place during meiosis. The meiotic cell cycle consists of two rounds of cell division, Meiosis I and Meiosis II. Meiosis I create haploid …

Landscape Of Ecdna-Borne Non-Coding Rnas In Glioblastoma, Dexin Yang

Dissertations and Theses (Open Access)

Recent advances in cancer genetics found that strong oncogene transcription can occur on a form of non-chromosome DNAs that is often amplified to tens or hundreds of copies, and that can exist in more than half of cancer types. This type of genetic material was termed extrachromosomal DNA (ecDNA). ecDNA appears to be epigenetically highly accessible and transcriptionally active compared with chromosomal DNA, which may partially underlie their critical roles in driving oncogene overexpression and cancer evolution. However, the full molecular mechanisms and regulators that confer the exceptional transcriptional activity of ecDNA-associated genes are incompletely understood.

Enhancers are key genetic …

Molecular Mechanisms Behind Sars-Cov-2 Induced Host Genome Restructuring, Erin Simpson

Dissertations and Theses (Open Access)

Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has caused unprecedented morbidity and mortality worldwide. There are two pathophysiological hallmarks associated with severe patient outcomes after SARS-CoV-2 acute infection, namely delayed/weakened interferon production and overactive inflammatory responses. Our previous work has shown that these altered immune responses are due, at least in part, to significant alterations in 3D genome organization and epigenetic landscape following SARS-CoV-2 infection that are distinct from and more severe than changes caused by other viral infections or immune stimulants. While these changes at the chromatin level are important for understanding the immune dysregulation seen in some cases …

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven By Different P53 Mutants, Dhruv Chachad

Dissertations and Theses (Open Access)

Missense mutations in the DNA binding domain of the Trp53 gene are characterized as structural (p53R172H) or contact (p53R245W) mutations based on their effect on the conformation of the protein. These mutations show gain-of-function activities such as increased metastatic incidence as compared to p53 loss, often mediated by their interaction with a repertoire of transcription factors. These interactions are largely context specific. In order to understand the mechanisms by which these mutations drive osteosarcoma progression, we created a mouse model, wherein either the p53 structural mutant p53R172H, or the contact mutant, p53R245W, are expressed specifically in …

P53 Dimers Elicit Unique Tumor Suppressive Activities Through An Altered Metabolic Program, Jovanka Gencel-Augusto

Dissertations and Theses (Open Access)

p53 is the most frequently mutated tumor suppressor in human cancer. As a tetrameric transcription factor, mutation of the p53 Tetramerization Domain (TD) is a mechanism by which cancers abrogate wild-type (WT) p53 function. p53 TD mutations result in a protein that preferentially forms monomers or dimers. These are also normal p53 states under basal cellular conditions. Although it is accepted that tetrameric p53 is required for full tumor suppressive activities, the physiological relevance of monomeric and dimeric states of p53 is not well understood. We have established in vivo models for monomeric and dimeric p53 which model Li-Fraumeni Syndrome …

Reconstructing Mutational Lineages In Breast Cancer By Multi-Patient-Targeted Single Cell Dna Sequencing, Jake Leighton

Dissertations and Theses (Open Access)

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high rates of metastasis and recurrence, where TNBC patients have a poor 5-year survival and ~50% are non-responsive to chemotherapy. Aneuploidy is a cancer hallmark that is pervasive in over 90% of breast cancer patients and is indicative of complex genomic rearrangements that are acquired during tumor initiation. Although copy number aberrations have been extensively studied in relation to aneuploidy and TNBC initiation, little is currently known regarding the timing and impact of single nucleotide variants (SNVs) contributing to these early transformative genomic events. Paramount to novel …

The Diagnostic Odyssey Of Hypermobile Eds Patients: Diagnosis, Clinical Expectations, And Psychosocial Concerns, Madeline Alpar

Dissertations and Theses (Open Access)

Background: Ehlers-Danlos syndrome (EDS) is a highly variable, heritable connective tissue disorder. Hypermobile EDS (hEDS) is the most common subtype of EDS and has no identifiable underlying genetic etiology. Patients with clinical features of hEDS face a long diagnostic odyssey due to lack of genetic testing and wide clinical heterogeneity. Additionally, recent research has shown that genetic institutions limit evaluations for suspected hEDS, adding another barrier to care.

Methods: We developed an online patient survey to explore the diagnostic odyssey of hEDS for those who were diagnosed with or suspicious for hEDS. This survey included sections on demographics, diagnostic information …

Targeting Metabolic Alterations Associated With Smooth Muscle Α-Actin Pathogenic Variant Attenuates Moyamoya-Like Cerebrovascular Disease, Anita Kaw

Dissertations and Theses (Open Access)

Heterozygous pathogenic variants in ACTA2, encoding smooth muscle α-actin (α-SMA), predispose to thoracic aortic aneurysms and dissections. De novo missense variants disrupting ACTA2 arginine 179 (p.Arg179) cause a multisystemic disease termed smooth muscle dysfunction syndrome (SMDS), which is characterized by early onset thoracic aortic disease and moyamoya disease-like (MMD) cerebrovascular disease. The MMD-like cerebrovascular disease in SMDS patients is marked by bilateral steno-occlusive lesions in the distal internal carotid arteries (ICAs) and their branches. To study the molecular mechanisms that underlie the ACTA2 p.Arg179 variants, a smooth muscle-specific Cre-lox knock-in mouse model of the heterozygous Acta2 R179C variant, termed …

Deephtlv: A Deep Learning Framework For Detecting Human T-Lymphotrophic Virus 1 Integration Sites, Johnathan Jia, Johnathan Jia

Dissertations and Theses (Open Access)

In the 1980s, researchers found the first human oncogenic retrovirus called human T-lymphotrophic virus type 1 (HTLV-1). Since then, HTLV-1 has been identified as the causative agent behind several diseases such as adult T-cell leukemia/lymphoma (ATL) and a HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP). As part of its normal replication cycle, the genome is converted into DNA and integrated into the genome. With several hundreds to thousands of unique viral integration sites (VISs) distributed with indeterminate preference throughout the genome, detection of HTLV-1 VISs is a challenging task. Experimental studies typically use molecular biology …