Life Sciences Commons^™

Grammar And Variation: Understanding How Cis-Regulatory Information Is Encoded In Mammalian Genomes, Dana Michele King

Arts & Sciences Electronic Theses and Dissertations

Understanding how genotype leads to phenotype is key to understand both the development and dysfunction of complex organisms. In the context of regulating the gene expression patterns that contribute to cell identity and function, the goal of my thesis research is to how changes in genome sequence may impact impact gene expression by determining how sequence features contribute to regulatory potential. To accomplish this goal, I first leveraged the key regulatory role of pluripotency transcription factors (TFs) in mouse embryonic stem cells (mESCs) and tested synthetically generated and genomic identified combinations of binding site for four TFs, OCT4, SOX2, KLF4, …

Sequence Analysis Methods For The Design Of Cancer Vaccines That Target Tumor-Specific Mutant Antigens (Neoantigens), Jasreet Hundal

Arts & Sciences Electronic Theses and Dissertations

The human adaptive immune system is programmed to distinguish between self and non-self proteins and if trained to recognize markers unique to a cancer, it may be possible to stimulate the selective destruction of cancer cells. Therapeutic cancer vaccines aim to boost the immune system by selectively increasing the population of T cells specifically targeted to the tumor-unique antigens, thereby initiating cancer cell death.. In the past, this approach has primarily focused on targeted selection of ‘shared’ tumor antigens, found across many patients. The advent of massively parallel sequencing and specialized analytical approaches has enabled more efficient characterization of tumor-specific …

Mechanistic Characterization Of Resistome And Microbiome Dynamics Across Diverse Microbial Habitats, Andrew John Gasparrini

Arts & Sciences Electronic Theses and Dissertations

Increasing antibiotic resistance in pathogens is a serious public health challenge, with over two million antibiotic resistant infections in the United States leading to at least 23,000 deaths and an estimated $55 billion in excess healthcare and societal costs. Antibiotic resistance has risen steadily in both pathogenic and benign bacteria since antibiotics’ introduction to agriculture and medicine 70 years ago. A dramatic reduction in the number of antibiotics approved for human use has accompanied this rise in antibiotic resistance, leading to the alarming prospect of a post-antibiotic era. Understanding the evolutionary origins, genetic contexts, and molecular mechanisms of antibiotic resistance …

Genetic Basis Of Thermal Divergence In Saccharomyces Species, Xueying C. Li

Arts & Sciences Electronic Theses and Dissertations

The genetic architecture of phenotypic divergence is a central question in evolutionary biology. Genetic architecture is impacted by whether evolution occurs through accumulation of many small-effect or a few large-effect changes, the relative contribution of coding and cis-regulatory changes, and the prevalence of epistatic effects. Our empirical understanding of the genetic basis of evolutionary change remains incomplete, largely because reproductive barriers limit genetic analysis to those phenotypes that distinguish closely related species. In this dissertation, I use hybrid genetic analysis to examine the basis of thermal divergence between two post-zygotically isolated species, Saccharomyces cerevisiae and S. uvarum. S. cerevisiae is …

The Role Of Fibrillin-1 In Eye Development And Disease, Wendell Brooks Jones

Arts & Sciences Electronic Theses and Dissertations

The ciliary zonule of the human eye consists of a circumferential array of fibers that connect the ocular lens to the nonpigmented ciliary epithelium (NPCE) located at the inner wall of the eye. Zonular fibers consist of bundles of beaded filaments called microfibrils. Microfibrils are major structural elements of the extracellular matrix and are present in pure form in the ciliary zonule. Microfibrils are composed principally of fibrillin-1 (FBN-1); a large extracellular matrix glycoprotein. In humans, mutations in FBN1 underlie Marfan syndrome; a pleiotropic connective tissue disorder that profoundly affects the eye. Ocular manifestations include ectopia lentis (dislocated lenses), cataracts, …

A Tail Of Two Pancancer Projects: Somatic Variant Identification And Driver Gene Discovery Using Tcga, Matthew Hawkins Bailey

Arts & Sciences Electronic Theses and Dissertations

The implementation of next-generation genomic sequencing has exploded over the past dozen years. Large consortia, such as The Cancer Genome Atlas (TCGA); the International Cancer Genetics Consortium (ICGC); and the Pediatric Cancer Genome Projects (PCGP), made great strides in democratizing big data for the scientific community. These data sets provide a rich resource to build tools for somatic variant discovery and exploratory analysis. Public repositories hold the answer to many novel biological and clinical revelations i.e., the discovery of complex indels, splice creating mutations, alternative super enhancer binding sites, machine learning models to predict mutation impact, and cancer subtype classification …

Red Panda: A Novel Method For Detecting Variation In Single-Cell Rna Sequencing, Adam Cornish

Theses & Dissertations

Single-cell sequencing enables the rapid acquisition of genomic and transcriptomic data from individual cells to better understand genetic diseases, such as cancer or autoimmune disorders, which are often affected by changes in rare cells. Currently, no existing software is aimed at identifying single nucleotide variations or micro (1-50bp) insertions and deletions in single-cell RNA sequencing (scRNA-seq) data. However, generating high quality data is vital to the study of the aforementioned diseases, among others. Our goal is to create such a tool and use in-house sequencing to validate its effectiveness. Our software employs the unique information found in scRNA-seq data to …

Accumulation And Transmission Dynamics Of A Naturally-Occurring Mtdna Deletion In Caenorhabditis Briggsae, Jennifer Anne Sullins

Dissertations and Theses

Maintaining mitochondrial genome sequence integrity is essential for preserving normal mitochondrial function. Several human diseases have been associated with heteroplasmic mitochondrial genome mutations, but few genetic systems can simultaneously represent pathogenic mitochondrial genome evolution and inheritance. The nematode Caenorhabditis briggsae is one such model. Natural C. briggsae isolates are globally-distributed and phylogenetically grouped into three distinct clades, with isolates exhibiting varying levels of a large-scale mtDNA deletion, nad5∆. Furthermore, a small subset of clade II isolates exhibits putative compensatory mutations that may reduce the risk of deletion formation and accumulation in those populations. In this thesis, the author characterizes the …

Investigating Autophagy Dysfunction Induced By A Parkinson's Disease-Causing Mutation In Vps35, Abir Ashfakur Rahman

Boise State University Theses and Dissertations

Parkinson’s Disease (PD) is an idiopathic disorder with no known cure. With number of cases steadily rising around the world, it is imperative to turn to the underlying cellular and molecular mechanisms of the disease manifestation and neurodegeneration to craft novel modes of therapy. VPS35 is one of the few genes that have identified and definitively linked to familial PD. The particular mutation that has been associated is known to cause dysfunction of a key cellular process known as autophagy. This process is primarily responsible for clearance of unwanted, damaged or misfolded proteins, among other things. Our study reveals an …

The Evaluation Of Genetic And Phenotypic Differences Associated With Short Term Selection Of Four Different Feed Efficiency Strategies In Japanese Quail, Alex David Gilley

Graduate Theses and Dissertations

The concept of feed efficiency (FE), one unit of feed required to improve one unit of desired output, is relatively simple. However multiple outputs are desired in a commercial poultry breeding program, resulting in the need for nutrients to be partitioned in a particular manner. At the broadest level, nutrients are partitioned between production and maintenance requirements. The requirements for production and maintenance varies between birds. It is the poultry breeder’s responsibility to select individuals most aligned with the breeding objective. Irrespective of the breeding objective, various related and non-related traits influence a bird’s FE. To effectively improve FE, the …

Genetic And Epigenetic Investigations On Pulmonary Hypertension Syndrome In Meat Type- Chickens, Khaloud Alzahrani

Graduate Theses and Dissertations

This dissertation presents a collection of studies that investigate the genetic and epigenetic associations to ascites phenotype in broiler chickens. Ascites is a significant metabolic disease associated with fast-growing meat-type chickens (broilers) and is a terminal result of pulmonary hypertension syndrome PHS. It is a multi-factorial syndrome caused by interactions between genetic, physiological, environmental, and managemental factors. It was estimated that ascites accounts for losses of about US$1 billion annually worldwide and for over 25% of broilers mortality. Although traditional and molecular genetic methods in the selection and in performance improvements, has greatly reduced ascites frequency, yet it has not …

Evaluation Of Genetic And Environmental Influences On Broiler Meat Quality, Sara Katherine Orlowski

Graduate Theses and Dissertations

The effect of both genetic and environmental influences on broiler meat quality were evaluated over three experiments. Selection response was assessed for broiler lines selected for high (HBY4) and low (LBY4) four day percentage breast yield which were formed from a random bred control (RAN). A modern random bred population (MRB) created in 2015 was evaluated for differences in 4 day percentage breast yield and the resulting differences in the incidence and severity of the woody breast and white striping myopathies. Additionally, the use of embryonic thermal manipulation to impact cell division and early caloric feed restriction to slow growth …

Temperature And Polyunsaturated Fatty Acid’S Effect On Daphnia Magna Reproduction, Mark Albright

Electronic Theses and Dissertations

Organisms adapt to their environments by adjusting their biochemistry and physiology; such adaptation is limited by resource availability and physiological constraints. The freshwater crustacean Daphnia magna inhabits a wide range of environments and must survive and reproduce within a range of temperatures. One limit to low-temperature adaptation is thought to be the availability of unsaturated fatty acids necessary to maintain proper fluidity of cellular membranes. D. magna maintained at 10 ºC on a diet poor in unsaturated fatty acids have been observed to produce clutches that fail to develop. However, this has not been observed on a diet rich in …

Thermal And Microbial Effects On Brown Macroalgae: Heat Acclimation And The Biodiversity Of The Microbiome, Charlotte Tc Quigley

Electronic Theses and Dissertations

This dissertation examines effects of stress on brown algal biology from a macroscopic scale by examining the whole aquaculture crops, and at a microscopic level by examining the macroalgal microbiome, across the vertical stress gradient of the intertidal zone and across the latitudes of their biogeographic ranges. Thermal stress negatively affected seedstock gametophytes of the kelp Alaria esculenta isolated from northern and southern locations in Maine. However, previous thermal stress had a positive effect on growth of the next-generation sporophytes. Alaria esculenta has potential as a kelp crop in Maine’s sea vegetable aquaculture sector and implementing this protocol may allow …

Spatial And Temporal Patterns Of Neutral And Adaptive Genetic Variation In The Alpine Butterfly, Parnassius Smintheus, Maryam Jangjoo

Electronic Thesis and Dissertation Repository

Understanding how much genetic diversity exists in populations, and the processes that maintain that diversity, has been a central focus of population genetics. The evolutionary processes that determine patterns of genetic diversity depend on underlying ecological processes such as dispersal and changes in population size. In this thesis, I examine the influence of dispersal and population dynamics on neutral and adaptive genetic variation in a naturally occurring network of populations of the alpine butterfly, Parnassius smintheus.

My first objective was to determine the combined consequences of demographic bottlenecks and dispersal on neutral genetic variation within and among populations. Using …

An Integrative Approach To Understanding Morphological Novelties: Anatomy, Development, Genetics, And Evolution Of An Extreme Craniofacial Trait In East African Cichlids, Moira R. Conith

Doctoral Dissertations

Phenotypic novelties are an important but poorly understood category of morphological diversity that are often associated with elevated rates of diversification and/or ecological success. The aim of this dissertation is to explore a phenotypic novelty at many levels to contribute to our understanding of how these unique traits can arise (e.g., genetically, developmentally, and evolutionarily) as well as their ecological consequences (e.g., trait function). The extreme snout of the Lake Malawi cichlid fish Labeotropheus is used as a case study. The first chapter establishes the Labeotropheus snout as a model of phenotypic novelty by characterizing the gross morphology, genetic architecture, …

Population Genetics Of The Eastern Subterranean Termite, Reticulitermes Flavipes, In The Southern Appalachian Mountains, Lee Ann Passarella

Honors Theses

As an area rich in biodiversity, the Appalachian Mountains are an ideal place for biological research. The pronounced impacts of Pleistocene climatic cycles on forest distributions over time have shaped the evolutionary history of animals that depend on these habitats, underpinning the research that is presented here. The present study on the eastern subterranean termite, Reticulitermes flavipes, was conducted to better understand the spatial distribution of genetic diversity within and among populations of this species in the context of the aforementioned historical climatic changes in the southern Appalachian Mountain region. I hypothesized that there would be geographically localized, distinct genetic …

Variation And Evolution Of Fruit Ripening Traits In Tomato Species, Ian M. Gillis

Doctoral Dissertations

As angiosperm seeds mature within their ovaries, ovary tissue tends to grow and transform itself into fruit, which aids the success of the seeds. Fruits that are fleshy provide numerous ways to aid in the protection and the dispersal of seeds. First, they keep seeds hidden, encased in hard walls, surrounded by poisons and unpalatable compounds, and second, they undergo developmental changes that facilitate seeds’ release. Tomatoes, a model fleshy fruit, have all these protective traits, and over the course of ripening they become the familiar fruit that is a staple crop around the world. The wild relatives of cultivated …

Clpxp-Regulated Proteins Suppress Requirement For Reca In Dam Mutants Of Escherichia Coli K-12, Amie Savakis

Masters Theses

Double strand breaks (DSB) are a common source of DNA damage in both prokaryotes and eukaryotes. If they are not repaired or are repaired incorrectly, they can lead to cell death (bacteria) or cancer (humans). In Escherichia coli, repair of DSB are typically accomplished via homologous recombination and mediated by RecA. This repair pathway, among others, is associated with activation of the SOS response. DNA adenine methyltransferase (dam) mutants have an increased number of DSB and, therefore, are notorious for being RecA-dependent for viability. Here, we show that the synthetic lethality of Δdam/ΔrecA is suppressed when clpP is removed, suggesting …

Myc Distant Enhancers Underlie Ovarian Cancer Susceptibility At The 8q24.21 Locus, Anxhela Gjyshi Gustafson

USF Tampa Graduate Theses and Dissertations

Ovarian cancer is a leading cause of death among women diagnosed with cancer. Mortality rate is high because an overwhelming majority of new cases are diagnosed with late-stage disease when the survival statistics are very poor with an overall 5-year survival rate of less than 40%. Despite the large burden of disease, the etiology of ovarian cancer is not well understood. In addition to linkage studies that have identified highly penetrant cancer susceptibility genes such as BRCA1 and BRCA2, the emergence of Genome Wide Association Studies (GWAS) in the last decade has facilitated the identification of common genetic variants with …

Underlying Contribution Of Executive Functioning To Cognition And Academic Achievement In Individuals With Dystrophinopathy, Robert Fee

Dissertations, Theses, and Capstone Projects

Dystrophinopathy is a genetic disorder that results in the lack of or abnormal expression of the protein dystrophin. It is a disorder that alters cell structure and function, impacts the developing brain and brain function, presents with multi-domain cognitive deficits, and influences both mood and behavior. Cognitive impairments appear to be more localized to specific areas of functioning rather than a global deficit; however, deficits have been identified across multiple cognitive domains including language and aspects of executive functioning. A careful examination of the cognitive phenotype and its association to mutations affecting CNS isoforms is necessary to clarify the neuropsychological …

Integration Of Bmp And Insulin/Igf-1 Signaling Regulates Multiple Homeostatic Functions In Caenorhabditis Elegans, James F. Clark

Dissertations, Theses, and Capstone Projects

The maintenance of homeostatic functions is key to the survival and well-being of an organism. Regulation of homeostasis relies on varied inputs, both intrinsic and extrinsic, to potentiate a web of interconnected signaling relays. Insulin/IGF-1 signaling (IIS) is a well-known regulator of glucose and lipid metabolism, as well as having far reaching effects in other homeostatic mechanisms. On the other hand, bone morphogenetic protein (BMP), a member of the transforming growth factor beta signaling superfamily, is known for its role in differentiation and development, with only recent studies highlighting potential roles in metabolic homeostasis. Here we elucidate new functions for …

Creating Tools To Determine Whether Katanin 60 Affects Female Rejection Of Males In Drosophila, Joshua R. Isaacson

Electronic Thesis and Dissertation Repository

During courtship, it is vital for organisms to recognize conspecifics because of the costs associated with forming interspecies hybrids. Many organisms use species-specific cues to recognize potential mates. These cues are perceived and evaluated via neural pathways. The genetic basis of how species-specific cues are evaluated and processed into receptive or rejection behaviour remains almost entirely unknown. The gene Katanin 60 (Kat60) has previously been identified as contributing to interspecific mate rejection between Drosophila melanogaster and D. simulans. I use the CRISPR/Cas9 system and RNA interference (RNAi) to confirm if Kat60 influences female receptivity between D. melanogaster …

A Mechanism Of Antimicrobial Resistance And A Mitigation Strategy, Christopher Bulow

Arts & Sciences Electronic Theses and Dissertations

ABSTRACT OF THE DISSERTATION

A Mechanism of Antimicrobial Resistance and a Mitigation Strategy

by

Christopher Bulow

Doctor of Philosophy in Biology and Biomedical Sciences

Molecular Genetics and Genomics

Washington University in St. Louis, 2018

Professor Gautam Dantas, Chair

The ability to treat infections, perform surgery, and administer immunosuppressants and chemotherapy depends on effective antibiotics. The emergence and spread of antimicrobial resistance is far outpacing the development of new therapies1-3 threatening to thrust medicine into a post-antibiotic era4. Many mechanisms of antimicrobial action and of antimicrobial resistance remain poorly understood as drug development struggles to keep pace. As resistance develops, the …

Methods To Record Transcription Factor Binding And Enhancer Activity Throughout Cellular Differentiation, Zongtai Qi

Arts & Sciences Electronic Theses and Dissertations

The ability to create distinct cell types is fundamental for the development of multicellular organisms. Since all cells in an organism contain the same genes, cellular diversity is achieved through the transcriptional network where transcription factors (TFs) interacts with cis-regulatory elements, leading to the selective transcription of different sets of genes. To better understand the functions of TFs and regulatory elements underlying cell fate decisions, we developed methods that are able to record their activities throughout cellular differentiation. In Chapter 2, we developed a degradation domain based induction system for ҃alling CardsӠmethod which maps the binding sites of TFs using …

Evaluation Of Neurobiological Risk Factors For Alcohol Consumption; Convergent Evidence For Predispositional Effects Of Brain Volume, David Baranger

Arts & Sciences Electronic Theses and Dissertations

Alcohol is one of the most widely used psychoactive substances and accounts for 5% of global disease burden. The goal of the present work is to help advance efforts to both identify prognostic markers of risk, and to understand the mechanisms by which alcohol consumption impacts health. Early life stress is one of the strongest predictors of mental illness, including alcohol dependence, and has been hypothesized to impact risk via modulation of striatal reward functions and reward learning. Studies examined the effect of stress on reward learning and processing, and tested for moderation by genetic and environmental risk. Results were …

Kdm6b Is Required For Self-Renewal Of Normal And Leukemic Mouse Stem Cells Under Proliferative Stress, Cates Mallaney

Arts & Sciences Electronic Theses and Dissertations

KDM6B (JMJD3) is one of two known epigenetic modifiers responsible for the removal of the repressive histone mark, histone-3 lysine-27 trimethylation (H3K27me3), and has been shown to play a role in development, differentiation, and inflammatory stress response. Unlike the other H3K27me3 demethylase, UTX (KDM6A), which is frequently mutated in hematopoietic malignancies, KDM6B is upregulated in a myriad of blood disorders. This suggests that it may have important functions in the pathogenesis of hematopoietic cancers. Here, we examined the role of Kdm6b in hematopoietic stem cell (HSC) fate decisions under normal and malignant conditions to evaluate its potential as a therapeutic …

Characterization Of The Celf6 Rna Binding Protein: Effects On Mouse Vocal Behavior And Biochemical Function, Michael A. Rieger

Arts & Sciences Electronic Theses and Dissertations

Behavior in higher eukaryotes is a complex process which integrates signals in the environment, the genetic makeup of the organism, and connectivity in the nervous system to produce extremely diverse adaptations to the phenomenon of existence. Unraveling the subcellular components that contribute to behavioral output is important for both understanding how behavior occurs in an unperturbed state, as well as understanding how behavior changes when the underlying systems that generate it are altered. Of the numerous molecular species that make up a cell, the regulation of messenger RNAs (mRNAs), the coding template of all proteins, is of key importance to …

The Role Of Mesenchymal Stromal Cells And Classical Dendritic Cells In The Maintenance And Regulation Of The Bone Marrow Niche, Jingzhu Zhang

Arts & Sciences Electronic Theses and Dissertations

The bone marrow niche is an important microenvironment for the regulation of normal and malignant hematopoiesis. The first discovered niche component is mesenchymal stromal cells, which are the major source for the production and secretion of multiple niche factors. Mesenchymal stromal cells are heterogeneous and various transgenes have been used to target non-identical but overlapping subpopulations. To further characterize the heterogeneity of mesenchymal stromal cells, we tested the targeting specificity of three tissue-specific Cre-recombinase transgenes. We show that in addition to osteoblasts, Ocn-Cre targets a majority of Cxcl12-abundant reticular (CAR) cells and arteriolar pericytes. Surprisingly, Dmp1-Cre also targets a subset …

Transcriptional Signatures Of Host Susceptibility In Urinary Tract Infections, Lu Yu

Arts & Sciences Electronic Theses and Dissertations

Urinary tract infections (UTI) caused by uropathogenic Escherichia coli (UPEC) are common and highly recurrent. Two important non-behavioral risk factors for UTI in women are genetics and history of two or more episodes of previous UTI. However, specific mechanisms of how these two factors modulate host susceptibility to UTI remain unclear. Concordantly, inbred mice of various genotypes and with different infection histories exhibit different susceptibilities to acute and chronic bladder infection (cystitis), which recapitulates a range of clinical UTI outcomes observed in women. Early host-pathogen interactions have been shown to determine UTI outcomes in mouse models. Here, we used two …