Genomics Commons^™

Genomic Determinants Of Appetite Regulation And Their Role In Obesity Risk, Timothy J. Renier

Dartmouth College Ph.D Dissertations

Over 40% of US adults and 20% of children live with obesity. It is related to increased risks of diseases including type II diabetes and cancer, is a source of harmful stigma, and impairs child development. Appetitive traits describing patterns of food approach and avoidance behaviors may serve as windows into the underlying pathophysiology of obesity. As both obesity and appetitive traits are heritable, common genetic drivers of obesity may lead to phenotypic obesity through appetitive traits as a disease mechanism. Additionally, GLP-1 receptor agonists (GLP-1RAs) have been shown to exert their profound clinical effects in part by modulating appetite. …

Hierarchical Lineage Tracing To Unravel Mechanisms Of Cancer Treatment Resistance, Rachel Danielle Saxe

Dartmouth College Ph.D Dissertations

Cancer cells adapt to treatment, leading to the emergence of clones that are more aggressive and resistant to anti-cancer therapies. We have a limited understanding of the development of treatment resistance as we lack technologies to map the evolution of cancer under the selective pressure of treatment. To address this, we developed a hierarchical, dynamic lineage tracing method called FLARE (Following Lineage Adaptation and Resistance Evolution). We use this technique to track the progression of acute myeloid leukemia (AML) cell lines through exposure to Cytarabine (AraC), a front-line treatment in AML, in vitro and in vivo. We map distinct cellular …

Evolution And Adaptation To Temperature In Thermotogota, Anne Amelia Farrell

Dartmouth College Ph.D Dissertations

Life thrives across incredibly diverse environmental conditions, yet most organisms are restricted to growing within a narrow range around their optimum growth temperature (OGT). The evolutionary events leading to changes in OGT are poorly understood, and it is uncertain if specific genes are required to thrive at a particular temperature. The bacterial phylum Thermotogota is an excellent model for the evolution of OGT. It comprises mesophilic, thermophilic, and hyperthermophilic members that collectively grow between 20°C and 90°C.

In this work, I analyze the history of OGT in the Thermotogota phylum and show how horizontal gene transfer contributes to the evolution …

Identifying Environmental And Genetic Risk Factors Of Diseases In Case-Control Studies, Siting Li

Dartmouth College Ph.D Dissertations

In response to the increasing efforts in disease prevention and treatment, this thesis applies statistical methods to investigate environmental and genetic risk factors associated with two diseases: bladder cancer and amyotrophic lateral sclerosis (ALS). For bladder cancer, we investigated the association between toenail metal mixture and bladder cancer risk, along with gene expression levels associated with bladder cancer risk. For ALS, our investigation involves identifying genetic variants and gene expression levels associated with ALS risk and exploring gene-smoking interactions linked to ALS risk.

In chapter two, we developed an adaptive-mixture-categorization (AMC)-based g-computation method combining g-computation with optimized exposure categorization. We …

Exploring 3d Genome Interaction And Epigenetic Regulation Via Swi/Snf Complex And Deep Learning Models, Ruoyun Wang

Dartmouth College Ph.D Dissertations

The three-dimensional organization of the genome is fundamental in regulating gene expression and maintaining cellular function. This organization's complexities, influenced by epigenetic marks and chromatin remodeling complexes, are crucial for understanding genomic regulation. Among these, the SWI/SNF complexes are key, facilitating chromatin accessibility and regulating gene activity across cell types. The first part of my dissertation focuses on SWI/SNF complexes, exploring their role in chromatin remodeling and their impact on 3D genome architecture. Utilizing next-generation sequencing (NGS) techniques, this section investigates the interplay between these complexes and chromatin structure. During my research on the SWI/SNF complex, I was intrigued by …

Chromatin Regulation By Swi/Snf Remodelers In Somatic Stem Cell Maintenance And Transformation, Luke Thomas Deary

Dartmouth College Ph.D Dissertations

Cell identity is defined by the epigenome, whereby chromatin regulators work in concert to promote gene expression programs that serve a cell’s specialized purpose. Mutations in chromatin regulators are amongst the most frequent drivers of human disease, underscoring the importance of understanding their activities in maintaining cell identity and tissue function. In particular, mutations in subunits of the evolutionarily conserved SWI/SNF chromatin remodeling complexes drive diseases across human tissues in both development and adult tissue maintenance5. Three major SWI/SNF complexes exist: BAF, PBAF, and GBAF, which differ in their composition and genomic targeting but share an ATP-dependent catalytic activity to …

Dna Methylation-Based Epigenetic Biomarkers In Cell-Type Deconvolution And Tumor Tissue Of Origin Identification, Ze Zhang

Dartmouth College Ph.D Dissertations

DNA methylation is an epigenetic modification that regulates gene expression and is essential to establishing and preserving cellular identity. Genome-wide DNA methylation arrays provide a standardized and cost-effective approach to measuring DNA methylation. When combined with a cell-type reference library, DNA methylation measures allow the assessment of underlying cell-type proportions in heterogeneous mixtures. This approach, known as DNA methylation deconvolution or methylation cytometry, offers a standardized and cost-effective method for evaluating cell-type proportions. While this approach has succeeded in discerning cell types in various human tissues like blood, brain, tumors, skin, breast, and buccal swabs, the existing methods have major …

Tracing Evolution Of Gene Transfer Agents Using Comparative Genomics, Roman Kogay

Dartmouth College Ph.D Dissertations

The accumulating evidence suggest that viruses and their components can be domesticated by their hosts, equipping them with convenient molecular toolkits for various functions. One of such domesticated system is Gene Transfer Agents (GTAs) that are produced by some bacteria and archaea. GTAs morphologically resemble small phage-like particles and contain random fragments of their host genome. They are produced only by a small fraction of the microbial population and are released through a lysis of the host cell. Bioinformatic analyses suggest that GTAs are especially abundant in the taxonomic class of Alphaproteobacteria, where they are vertically inherited and evolve …

Genome-Scale Methylation Analysis In Blood And Tumor Identifies Immune Profile, Age Acceleration, And Dna Methylation Alterations Associated With Bladder Cancer Outcomes, Ji-Qing Chen

Dartmouth College Ph.D Dissertations

Bladder cancer patients receive frequent screening due to the high tumor recurrence rate (more than 60%). Nowadays, the conventional monitoring method relies on cystoscopy which is highly invasive and increases patient morbidity and burden to the health care system with frequent follow-up. As a result, it is urgent to explore novel markers related to the outcomes of bladder cancer. Immune profiles have been associated with cancer outcomes and may have the potential to be biomarkers for outcomes management. However, little work has been conducted to investigate the associations of immune cell profiles with bladder cancer outcomes. Here, I utilized the …