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 …

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 …

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 …

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 …

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 …

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. …

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 …