Life Sciences Commons^™

The Evolution Of Transposable Elements As Cis-Regulatory Elements In Mammals, Alan Y. Du

Arts & Sciences Electronic Theses and Dissertations

Transposable elements (TEs) are mobile genetic elements that make up a large proportion of mammalian genomes. Although TEs are highly prevalent genomic sequences, they have been understudied as they were once labeled as “junk DNA.” Despite their initial status as simple genomic parasites, recent studies have implicated TEs as cis-regulatory elements, supplying promoters, enhancers, and boundary elements. Functional testing of regulatory activity, however, remains a significant bottleneck. Nonetheless, due to their repetitive nature, TEs provide a unique model to examine the evolution of cis-regulatory elements, which has traditionally been difficult to study due to lack of homology at the sequence …

Analysis Of Structural Variation And Mtdna Copy Number In Finns, Liron Ganel

Arts & Sciences Electronic Theses and Dissertations

Cardiovascular disease (CVD) is a complex disease responsible for more deaths worldwide than any other cause according to the World Health Organization. Genetic association studies for CVD and related risk factors have successfully identified hundreds of loci associated with these complex diseases and traits, although much of their heritability remains unexplained. Structural variants (SVs) - including insertions, deletions, duplications, and inversions - are an understudied class of genomic variation that have the potential to explain much of the missing heritability of CVD and other complex traits. Here, we discuss advances emerging from the study of SVs in the context of …

Genetics Of Pediatric Musculoskeletal Disorders, Lilian Antunes

Arts & Sciences Electronic Theses and Dissertations

Pediatric musculoskeletal disorders are an extremely broad category of diseases that are often inherited. While individually rare, collectively these disorders are common, affecting around 3% of live births in the US. Despite the mounting clinical and molecular evidence for a genetic etiology, the cause for many patients with pediatric musculoskeletal disorders remain largely unknown. Major challenges in rare pediatric diseases include recruiting large numbers of patients and determining the significance and functional impacts of variants associated with disease within individuals or families. Whole exome sequencing (WES) is a powerful tool to identify coding variants that are associated with rare pediatric …

A Mechanistic And Genomic Analysis Of Molluscum Contagiosum Virus Immune Evasion, Ian Benjamin Harvey

Arts & Sciences Electronic Theses and Dissertations

Molluscum contagiosum virus (MCV) is a common human-specific poxvirus with a proclivity for

infecting children and the immune-compromised. A characteristic MCV infection is restricted to

the epidermal layers of the skin and can persist for weeks to years in an otherwise healthy

individual. The high clinical burden of MCV is at odds with our limited knowledge regarding how

it successfully evades the human immune response, which is in part due to the lack of an animal

model or cell line to propagate the virus. Through this dissertation, we have uncovered and

characterized a novel mechanism by which MC80, a protein …

Multi-Omics Integration For Gene Fusion Discovery And Somatic Mutation Haplotyping In Cancer, Steven Mason Foltz

Arts & Sciences Electronic Theses and Dissertations

Cancer is a disease caused by changes to the genome and dysregulation of gene expression. Among many types of mutations, including point mutations, small insertions and deletions, large scale structural variants, and copy number changes, gene fusions are another category of genomic and transcriptomic alteration that can lead to cancer and which can serve as therapeutic targets. We studied gene fusion events using data from The Cancer Genome Atlas, including over 9,000 patients from 33 cancer types, finding patterns of gene fusion events and dysregulation of gene expression within and across cancer types. With data from the CoMMpass study (Multiple …

Physiologic And Pathologic Profiling Of Clonal Variations, Wing Hing Wong

Arts & Sciences Electronic Theses and Dissertations

This thesis sought to provide a better understanding of clonality in various malignant and non-malignant settings using a variety of genomic analytical tools. Clonality is pre-defined as the presence of a mixed population of cells in which each sub-population has distinct somatic mutation profile. It is a common feature in cancers where subpopulations of cells arise as a result of independent, yet continual acquisition of somatic mutations. The clonal architecture of cancers can be used as a diagnostic and prognostic biomarker as well as to monitor disease progression or resolution. Besides cancer, clonal variability and expansion is also implicated in …

Multi-Omic Understanding Of The Evolution Of Xenobiotic Tolerance In Bacterial Isolates And Communities, Tayte Paul Campbell

Arts & Sciences Electronic Theses and Dissertations

Xenobiotic compounds are any chemicals that are released into an environment by human action and that occur at concentrations higher than found naturally. Xenobiotics, including aromatic compounds and antibiotics, are recalcitrant to degradation because they are often toxic or mutagenic. Despite this toxicity, bacteria account for a large portion of xenobiotic degradation in the environment. Bacteria are able to adapt to these foreign chemicals, gaining increased levels of tolerance and increased rates of xenobiotic degradation. On the strain level, increased tolerance can be caused by mutations in individual cells or through the acquisition of genes from other cells. At the …

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, …

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 …

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 …

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 …

The Mechanism Of Hyper Daptomycin Resistance In Corynebacterium Striatum And Daptomycinճ Mechanism Of Action, Nicholas Kevork Goldner

Arts & Sciences Electronic Theses and Dissertations

Daptomycin, a last line-of-defense antibiotic for treating Gram-positive infections, is experiencing clinical failure against important infectious agents, including Corynebacterium striatum. The recent transition of daptomycin to generic antibiotic status is projected to dramatically increase availability, use, and clinical failure. Despite daptomycinճ more than 30-year history as an important antibiotic, four major questions were left unanswered. 1) How do bacteria become hyper-resistant to daptomycin? 2) What is the in vivo membrane target of daptomycin? 3) How does daptomycin interact with the membrane? 4) What is daptomycinճ mechanism of killing? These four questions have plagued the daptomycin field, and even now conflicting …

Discovering Rare Hematopoietic Clones Harboring Leukemia-Associated Mutations Using Error-Corrected Sequencing, Andrew Lee Young

Arts & Sciences Electronic Theses and Dissertations

Cancer is a heterogeneous group of diseases that currently takes over half a million lives per year in the United States alone. Our understanding of cancer has improved dramatically over the last forty years, beginning with the discovery that cancer is a disease of the genome. Currently, the set of somatic mutations found in malignancy are largely known. The specific somatic mutations driving an individual’s disease can be readily assessed at clinical presentation. Additionally, the functional consequences for many of these mutations are known as well as their role in tumorigenesis. Despite this understanding, a cure for cancer remains elusive. …

Discerning Drivers Of Cancer: Computational Approaches To Somatic Exome Sequencing Data, Runjun Kumar

Arts & Sciences Electronic Theses and Dissertations

Paired tumor-normal sequencing of thousands of patient’s exomes has revealed millions of somatic mutations, but functional characterization and clinical decision making are stymied because biologically neutral ‘passenger’ mutations greatly outnumber pathogenic ‘driver’ mutations. Since most mutations will return negative results if tested, conventional resource-intensive experiments are reserved for mutations which are observed in multiple patients or rarer mutations found in well-established cancer genes. Most mutations are therefore never tested, diminishing the potential to discover new mechanisms of cancer development and treatment opportunities. Computational methods that reliably prioritize mutations for testing would greatly increase the translation of sequencing results to clinical …

Genetic And Genomic Dissections Of Myelinating Glial Cell Development, Breanne Leigh Harty

Arts & Sciences Electronic Theses and Dissertations

Myelin is a multilamellar sheath made by specialized glial cells that iteratively spiral and compact their plasma membranes around axon segments. In vertebrate nervous systems, myelination facilitates rapid action propagation and provides trophic support critical for neuronal survival. In the central nervous system (CNS), oligodendrocytes (OLs) extend many processes to simultaneously ensheath multiple axons, while in the peripheral nervous system (PNS), myelinating Schwann cells (SCs) pair 1:1 with a single axon segment. Elaboration of the myelin sheath is one of the most exquisite and complex examples of massive coordinated cellular shape changes in the vertebrate nervous system. Furthermore, the importance …

A Search For Parent-Of-Origin Effects On Honey Bee Gene Expression, Sarah D. Kocher, Jennifer M. Tsuruda, Joshua D. Gibson, Christine M. Emore, Miguel E. Arechavaleta-Velasco, David C. Queller, Joan E. Strassmann, Christina M. Grozinger, Michael R. Gribskov, Phillip San Miguel, Rick Westerman, Greg J. Hunt

Biology Faculty Publications & Presentations

Parent-specific gene expression (PSGE) is little known outside of mammals and plants. PSGE occurs when the expression level of a gene depends on whether an allele was inherited from the mother or the father. Kin selection theory predicts that there should be extensive PSGE in social insects because social insect parents can gain inclusive fitness benefits by silencing parental alleles in female offspring. We searched for evidence of PSGE in honey bees using transcriptomes from reciprocal crosses between European and Africanized strains. We found 46 transcripts with significant parent-of-origin effects on gene expression, many of which overexpressed the maternal allele. …

Whole Genome Comparison Of A Large Collection Of Mycobacteriophages Reveals A Continuum Of Phage Genetic Diversity, Welkin Pope, Charles Bowman, Daniel Russell, Deborah Jacobs-Sera, David Asai, Steven Cresawn, William Jacobs, Roger Hendrix, Jeffrey Lawrence, Graham Hatfull, Sarah C.R. Elgin

Biology Faculty Publications & Presentations

The bacteriophage population is large, dynamic, ancient, and genetically diverse. Limited genomic information shows that phage genomes are mosaic, and the genetic architecture of phage populations remains ill-defined. To understand the population structure of phages infecting a single host strain, we isolated, sequenced, and compared 627 phages of Mycobacterium smegmatis. Their genetic diversity is considerable, and there are 28 distinct genomic types (clusters) with related nucleotide sequences. However, amino acid sequence comparisons show pervasive genomic mosaicism, and quantification of inter-cluster and intra-cluster relatedness reveals a continuum of genetic diversity, albeit with uneven representation of different phages. Furthermore, rarefaction analysis shows …

Characterizing The Fitness Landscapes Of Gut Symbionts In Defined Community And Diet Contexts, Meng Wu

Arts & Sciences Electronic Theses and Dissertations

A species' niche is the description of all the environmental conditions required to permit a population of that species to persist, including the effects of the population on those conditions. This definition includes the species' resource requirements, as well as stress tolerances and interactions with other species acting as competitors, predators, parasites, and mutualists. The human gut microbiota serves as a microbial `metabolic organ' tasked in part with the biotransformation of many components of our diet. Relatively little is known about the factors that allow members of the human gut microbiota to persist in a habitat that experiences marked changes …

On The Origin Of Phenotypic Variation: Novel Technologies To Dissect Molecular Determinants Of Phenotype, Francesco Vallania

All Theses and Dissertations (ETDs)

This thesis describes the conception, design, and development of novel computational tools, theoretical models, and experimental techniques applied to the dissection of molecular factors underlying phenotypic variation. The first part of my work is focused on finding rare genetic variants in pooled DNA samples, leading to the development of a novel set of algorithms, SNPseeker and SPLINTER, applied to next-generation sequencing data. The second part of my work describes the creation of a reporter system for DNA methylation for the purpose of dissecting the genetic contribution of tissue-specific patterns of DNA methylation across the genome. Finally the last part of …