Genetics and Genomics Commons^™

Understanding Huntington's Disease Using Machine Learning Approaches, Sonali Lokhande

KGI Theses and Dissertations

Huntington’s disease (HD) is a debilitating neurodegenerative disorder with a complex pathophysiology. Despite extensive studies to study the disease, the sequence of events through which mutant Huntingtin (mHtt) protein executes its action still remains elusive. The phenotype of HD is an outcome of numerous processes initiated by the mHtt protein along with other proteins that act as either suppressors or enhancers of the effects of mHtt protein and PolyQ aggregates. Utilizing an integrative systems biology approach, I construct and analyze a Huntington’s disease integrome using human orthologs of protein interactors of wild type and mHtt protein. Analysis of this integrome …

Comparative Molecular Characterization Of Typical And Exceptional Responders In Glioblastoma, Kristin Wipfler

Theses & Dissertations

Glioblastoma (GBM) is the most common and the deadliest type of primary brain tumor, with a median survival time of only 15 months despite aggressive treatment. Although most patients have an extremely poor prognosis, a small number of patients survive far beyond the median survival time. Investigation of these “exceptional responders” has sparked a great deal of interest and is becoming an important focus in the field of cancer research. To investigate the molecular differences between typical and exceptional responders in GBM, comparative analyses of copy number, methylation, gene expression, miRNA expression, and protein expression data sets from The Cancer …

Knowledge Driven Approaches And Machine Learning Improve The Identification Of Clinically Relevant Somatic Mutations In Cancer Genomics, Benjamin John Ainscough

Arts & Sciences Electronic Theses and Dissertations

For cancer genomics to fully expand its utility from research discovery to clinical adoption, somatic variant detection pipelines must be optimized and standardized to ensure identification of clinically relevant mutations and to reduce laborious and error-prone post-processing steps. To address the need for improved catalogues of clinically and biologically important somatic mutations, we developed DoCM, a Database of Curated Mutations in Cancer (http://docm.info), as described in Chapter 2. DoCM is an open source, openly licensed resource to enable the cancer research community to aggregate, store and track biologically and clinically important cancer variants. DoCM is currently comprised of 1,364 variants …

Dna Barcoding Of Quercus Falcata, Quercus Palustris, Quercus Rubra, And Their Hybrids Using Rbcl, Matk, And Ycf1, Mckinzie Johnson, Tim Trott

Research in Biology

No abstract provided.

Integrative Cancer Immunogenomic Analysis Of Serial Melanoma Biopsies Reveals Correlates Of Response And Resistance To Sequential Ctla-4 And Pd-1 Blockade Treatment, Whijae Roh

Dissertations & Theses (Open Access)

Melanoma is the most malignant form of skin cancer. The five-year survival rate for metastatic melanoma is 19.9%. Although targeted therapy of BRAF and MEK inhibitors were developed for melanoma, resistance to therapy is inevitable. Immune checkpoint blockade, which reverses the suppression of the immune system, on the other hand, has shown a durable response in 20-30% of patients with metastatic melanoma. However, more predictive and robust biomarkers of response to this therapy are still needed, and resistance mechanisms remain incompletely understood. To address this, we examined a cohort of metastatic melanoma patients treated with sequential checkpoint blockade against cytotoxic …

Bioinformatic And Experimental Approaches For Deeper Metaproteomic Characterization Of Complex Environmental Samples, Ramsunder Mahadevan Iyer

Doctoral Dissertations

The coupling of high performance multi-dimensional liquid chromatography and tandem mass spectrometry for characterization of microbial proteins from complex environmental samples has paved the way for a new era in scientific discovery. The field of metaproteomics, which is the study of protein suite of all the organisms in a biological system, has taken a tremendous leap with the introduction of high-throughput proteomics. However, with corresponding increase in sample complexity, novel challenges have been raised with respect to efficient peptide separation via chromatography and bioinformatic analysis of the resulting high throughput data. In this dissertation, various aspects of metaproteomic characterization, including …

Transcriptome-Based Gene Networks For Systems-Level Analysis Of Plant Gene Functions, Chirag Gupta

Graduate Theses and Dissertations

Present day genomic technologies are evolving at an unprecedented rate, allowing interrogation of

cellular activities with increasing breadth and depth. However, we know very little about how the

genome functions and what the identified genes do. The lack of functional annotations of genes

greatly limits the post-analytical interpretation of new high throughput genomic datasets. For plant

biologists, the problem is much severe. Less than 50% of all the identified genes in the model plant

Arabidopsis thaliana, and only about 20% of all genes in the crop model Oryza sativa have some

aspects of their functions assigned. Therefore, there is an …

Development, Evaluation, And Application Of A Novel Error Correction Method For Next Generation Sequencing Data, Isaac Akogwu

Dissertations

Tremendous evolvement in sequencing technologies and the vast availability of data due to decreasing cost of Next-Generation-Sequencing (NGS) has availed scientists the opportunity to address a wide variety of evolutionary and biological issues. NGS uses massively parallel technology to accelerate the process at the expense of accuracy and read length in comparison to earlier Sanger methods. Therefore, computational limitations exist in how much analysis and information can be gleaned from the data without performing some form of error correction.

Error correction process is laborious and consumes a lot of computational resources. Despite the existence of many NGS data error correction …

Chromatin Accessibility Dynamics In The Arabidopsis Root Epidermis And Endodermis During Cold Acclimation, Shawn Hoogstra

Electronic Thesis and Dissertation Repository

Understanding cell-type specific transcriptional responses to environmental conditions is limited by a lack of knowledge of transcriptional control due to epigenetic dynamics. Additionally, cell-type analyses are limited by difficulties in applying current technologies to single cell-types. A novel DNase-seq protocol and analysis procedure, deemed DNase-DTS, was developed to identify DHSs in the Arabidopsis epidermis and endodermis under control and cold acclimation conditions. Results identified thousands of DHSs within each cell-type and experimental condition. DHSs showed strong association to gene expression, DNA methylation, and histone modifications. A priori mapping of existing DNA binding motifs within accessible genes and the cold C-repeat/dehydration …

Linking Taxonomic Diversity And Trophic Function: A Graph-Based Theoretical Approach, Marcella M. Jurotich, Kaitlyn Dougherty, Barbara Hayford, Sally Clark

Transactions of the Nebraska Academy of Sciences and Affiliated Societies

The purpose of this study is to develop a novel, visual method in analyzing complex functional trait data in freshwater ecology. We focus on macroinvertebrates in stream ecosystems under a gradient of habitat degradation and employ a combination of taxonomic and functional trait diversity analyses. Then we use graph theory to link changes in functional trait diversity to taxonomic richness and habitat degradation. We test the hypotheses that: 1) taxonomic diversity and trophic functional trait diversity both decrease with increased habitat degradation; 2) loss of taxa leads to a decrease in trophic function as visualized using a bipartite graph; and …

Multiple Testing Correction With Repeated Correlated Outcomes: Applications To Epigenetics, Katie Leap

Masters Theses

Epigenetic changes (specifically DNA methylation) have been associated with adverse health outcomes; however, unlike genetic markers that are fixed over the lifetime of an individual, methylation can change. Given that there are a large number of methylation sites, measuring them repeatedly introduces multiple testing problems beyond those that exist in a static genetic context. Using simulations of epigenetic data, we considered different methods of controlling the false discovery rate. We considered several underlying associations between an exposure and methylation over time.

We found that testing each site with a linear mixed effects model and then controlling the false discovery rate …

A Polyglot Approach To Bioinformatics Data Integration: A Phylogenetic Analysis Of Hiv-1, Steven Reisman, Thomas Hatzopoulos, Konstantin Laufer, George K. Thiruvathukal, Catherine Putonti

Konstantin Läufer

As sequencing technologies continue to drop in price and increase in throughput, new challenges emerge for the management and accessibility of genomic sequence data. We have developed a pipeline for facilitating the storage, retrieval, and subsequent analysis of molecular data, integrating both sequence and metadata. Taking a polyglot approach involving multiple languages, libraries, and persistence mechanisms, sequence data can be aggregated from publicly available and local repositories. Data are exposed in the form of a RESTful web service, formatted for easy querying, and retrieved for downstream analyses. As a proof of concept, we have developed a resource for annotated HIV-1 …

A Polyglot Approach To Bioinformatics Data Integration: Phylogenetic Analysis Of Hiv-1, Steven Reisman, Catherine Putonti, George K. Thiruvathukal, Konstantin Läufer

Konstantin Läufer

RNA-interference has potential therapeutic use against HIV-1 by targeting highly-functional mRNA sequences that contribute to the virulence of the virus. Empirical work has shown that within cell lines, all of the HIV-1 genes are affected by RNAi-induced gene silencing. While promising, inherent in this treatment is the fact that RNAi sequences must be highly specific. HIV, however, mutates rapidly, leading to the evolution of viral escape mutants. In fact, such strains are under strong selection to include mutations within the targeted region, evading the RNAi therapy and thus increasing the virus’ fitness in the host. Taking a phylogenetic approach, we …

G-Onramp: Create Genome Browsers That Enable Undergraduate Students To Participate In Collaborative Genome Annotations, Wilson Leung, Yating Liu, Luke Sargent, Jeremy Goecks, Sarah C.R. Elgin

Annual Symposium on Biomathematics and Ecology Education and Research

No abstract provided.

Chromosome Conformation In Context, James Taylor

Annual Symposium on Biomathematics and Ecology Education and Research

No abstract provided.

A Systems Level Approach To Temporal Expression Dynamics In Drosophila Reveals Clusters Of Long Term Memory Genes, Julianna Bozler, Balint Kacsoh, Giovanni Bosco

Annual Symposium on Biomathematics and Ecology Education and Research

No abstract provided.

Cage: A Tool For Identifying Genes With Correlated Spatiotemporal Expression, Basheer Becerra

Annual Symposium on Biomathematics and Ecology Education and Research

No abstract provided.

Sequence Extension Of The Tryptophan And Shikimate Operons In Clostridium Scatologenes Atcc 25775, Shawn Johnston Smiley

Masters Theses & Specialist Projects

3-Methylindole and 4-methylphenol are cytotoxic and malodorant compounds derived from tryptophan and tyrosine, respectively. Each is present in swine waste lagoons and contributes to malodorous emissions from agricultural facilities. Clostridium scatologenes ATCC 25775 produces both compounds and serves as a model organism to study their metabolism and function. Through the repeated assembly and annotation of the Clostridium scatologenes genome, we propose a novel pathway for tryptophan degradation and 3-methylindole production by this organism. The genome of Clostridium scatologenes was sequenced, and re-assembled into contigs. Key elements of the tryptophan and shikimate pathways were identified. Contigs containing these elements were extracted …

Phagephisher: A Pipeline For The Discovery Of Covert Viral Sequences In Complex Genomic Datasets, Thomas Hatzopoulos, Siobhan C. Watkins, Catherine Putonti

Catherine Putonti

Obtaining meaningful viral information from large sequencing datasets presents unique challenges distinct from prokaryotic and eukaryotic sequencing efforts. The difficulties surrounding this issue can be ascribed in part to the genomic plasticity of viruses themselves as well as the scarcity of existing information in genomic databases. The open-source software PhagePhisher (http://www.putonti-lab.com/phagephisher) has been designed as a simple pipeline to extract relevant information from complex and mixed datasets, and will improve the examination of bacteriophages, viruses, and virally related sequences, in a range of environments. Key aspects of the software include speed and ease of use; PhagePhisher can be used with …

Hash-Map-Eradicator: Filtering Non-Target Sequences From Next Generation Sequencing Reads, Jonathon Brenner, Catherine Putonti

Catherine Putonti

Contemporary DNA sequencing technologies are continuously increasing throughput at ever decreasing costs. Moreover, due to recent advances in sequencing technology new platforms are emerging. As such computational challenges persist. The average read length possible has taken a giant leap forward with the PacBio and Nanopore solutions. Regardless of the platform used, impurities within the DNA preparation of the sample - be it from unintentional contaminants or pervasive symbiots - remains an issue. We have developed a new tool, HAsh-MaP-ERadicator (HAMPER), for the detection and removal of non-target, contaminating DNA sequences. Integrating hash-based and mapping-based strategies, HAMPER is both memory and …

A Polyglot Approach To Bioinformatics Data Integration: A Phylogenetic Analysis Of Hiv-1, Steven Reisman, Thomas Hatzopoulos, Konstantin Laufer, George K. Thiruvathukal, Catherine Putonti

Catherine Putonti

As sequencing technologies continue to drop in price and increase in throughput, new challenges emerge for the management and accessibility of genomic sequence data. We have developed a pipeline for facilitating the storage, retrieval, and subsequent analysis of molecular data, integrating both sequence and metadata. Taking a polyglot approach involving multiple languages, libraries, and persistence mechanisms, sequence data can be aggregated from publicly available and local repositories. Data are exposed in the form of a RESTful web service, formatted for easy querying, and retrieved for downstream analyses. As a proof of concept, we have developed a resource for annotated HIV-1 …

Clusters Of Alpha Satellite On Human Chromosome 21 Are Dispersed Far Onto The Short Arm And Lack Ancient Layers, William Ziccardi, Chongjian Zhao, Valery Shepelev, Lev Uralsky, Ivan Alexandrov, Tatyana Andreeva, Evgeny Rogaev, Christopher Bun, Emily Miller, Catherine Putonti, Jeffrey Doering

Catherine Putonti

Human alpha satellite (AS) sequence domains that currently function as centromeres are typically flanked by layers of evolutionarily older AS that presumably represent the remnants of earlier primate centromeres. Studies on several human chromosomes reveal that these older AS arrays are arranged in an age gradient, with the oldest arrays farthest from the functional centromere and arrays progressively closer to the centromere being progressively younger. The organization of AS on human chromosome 21 (HC21) has not been well-characterized. We have used newly available HC21 sequence data and an HC21p YAC map to determine the size, organization, and location of the …

Finding Function In The Unknown, Kelly Boyd, Emma Highland, Amanda Misch, Amber Hu, Sushma Reddy, Catherine Putonti

Catherine Putonti

Through high-throughput RNA sequencing (RNAseq), transcriptomes for a single cell, tissue, or organism(s) can be ascertained at a high resolution. While a number of bioinformatic tools have been developed for transcriptome analyses, significant challenges exist for studies of non-model organisms. Without a reference sequence available, raw reads must first be assembled de novo followed by the tedious task of BLAST searches and data mining for functional information. We have created a pipeline, PyRanger, to automate this process. The pipeline includes functionality to assess a single transcriptome and also facilitate comparative transcriptomic studies.

Genomes Of Gardnerella Strains Reveal An Abundance Of Prophages Within The Bladder Microbiome, Kema Malki, Jason W. Shapiro, Travis Kyle Price, Evann Elizabeth Hilt, Krystal Thomas-White, Trina Sircar, Amy B. Rosenfeld, Michael J. Zilliox, Alan J. Wolfe, Catherine Putonti

Catherine Putonti

Bacterial surveys of the vaginal and bladder human microbiota have revealed an abundance of many similar bacterial taxa. As the bladder was once thought to be sterile, the complex interactions between microbes within the bladder have yet to be characterized. To initiate this process, we have begun sequencing isolates, including the clinically relevant genus Gardnerella. Herein, we present the genomic sequences of four Gardnerella strains isolated from the bladders of women with symptoms of urgency urinary incontinence; these are the first Gardnerella genomes produced from this niche. Congruent to genomic characterization of Gardnerella isolates from the reproductive tract, isolates from …

Bacteriophages Isolated From Lake Michigan Demonstrate Broad Host-Range Across Several Bacterial Phyla, Kema Malki, Alex Kula, Katherine Bruder, Emily Sible, Thomas Hatzopoulos, Stephanie Steidel, Siobhan C. Watkins, Catherine Putonti

Catherine Putonti

BACKGROUND:

The study of bacteriophages continues to generate key information about microbial interactions in the environment. Many phenotypic characteristics of bacteriophages cannot be examined by sequencing alone, further highlighting the necessity for isolation and examination of phages from environmental samples. While much of our current knowledge base has been generated by the study of marine phages, freshwater viruses are understudied in comparison. Our group has previously conducted metagenomics-based studies samples collected from Lake Michigan - the data presented in this study relate to four phages that were extracted from the same samples.

FINDINGS:

Four phages were extracted from Lake Michigan …

A Polyglot Approach To Bioinformatics Data Integration: Phylogenetic Analysis Of Hiv-1, Steven Reisman, Catherine Putonti, George K. Thiruvathukal, Konstantin Läufer

Catherine Putonti

RNA-interference has potential therapeutic use against HIV-1 by targeting highly-functional mRNA sequences that contribute to the virulence of the virus. Empirical work has shown that within cell lines, all of the HIV-1 genes are affected by RNAi-induced gene silencing. While promising, inherent in this treatment is the fact that RNAi sequences must be highly specific. HIV, however, mutates rapidly, leading to the evolution of viral escape mutants. In fact, such strains are under strong selection to include mutations within the targeted region, evading the RNAi therapy and thus increasing the virus’ fitness in the host. Taking a phylogenetic approach, we …

A Combined Computational Strategy Of Sequence And Structural Analysis Predicts The Existence Of A Functional Eicosanoid Pathway In Drosophila Melanogaster, Michael Scarpati

Dissertations, Theses, and Capstone Projects

With increased understanding of their roles in signal transduction and metabolism, eicosanoids have emerged as important players in human health and disease. Mammalian prostanoids and related lipid mediators perform varied functions in different tissues and organs. Synthesized through the oxygenation of C20 polyunsaturated fatty acids, mammalian eicosanoids are both pro- and anti-inflammatory. The physiological contexts in which eicosanoid family members act at the cellular level are not well understood. In this study, we examined whether the genome of Drosophila melanogaster, a powerful model for innate immunity and inflammation, codes for the enzymes required for eicosanoid biosynthesis. We report the …

Amelioration Of Prenatal Alcohol Effects By Environmental Enrichment In A Mouse Model Of Fasd, Aniruddho Chokroborty-Hoque

Electronic Thesis and Dissertation Repository

Maternal alcohol consumption during pregnancy results in a spectrum of behavioural and cognitive deficits collectively known as Fetal Alcohol Spectrum Disorders (FASD). Currently, little is know about if and how the external environment may modulate these deficits. I have used C57BL/6 mice to study this interaction between prenatal alcohol exposure and the postnatal environment. Alcohol exposure during synaptogenesis produces high levels of anxiety-like traits and decreased memory performance. Alcohol-exposed mice (and matched unexposed controls) were put in 'environmentally-enriched' conditions of voluntary exercise, physical activities and cognitive stimulation to ascertain the effects of a positive postnatal environment. The results show that …

Robust Algorithms For Detecting Hidden Structure In Biological Data, Roman Sloutsky

Arts & Sciences Electronic Theses and Dissertations

Biological data, such as molecular abundance measurements and protein

sequences, harbor complex hidden structure that reflects its underlying

biological mechanisms. For example, high-throughput abundance measurements

provide a snapshot the global state of a living cell, while homologous

protein sequences encode the residue-level logic of the proteins' function

and provide a snapshot of the evolutionary trajectory of the protein family.

In this work I describe algorithmic approaches and analysis software I

developed for uncovering hidden structure in both kinds of data.

Clustering is an unsurpervised machine learning technique commonly used

to map the structure of data collected in high-throughput experiments,

such …

Unravelling Organelle Genome Transcription Using Publicly Available Rna-Sequencing Data, Matheus Sanita Lima

Electronic Thesis and Dissertation Repository

The study of organelles helped forge theories of genome evolution because of their unconventional genomes and gene expression regimes. The organelle genomics field (~35 years old) has seen the development of next generation sequencing (NGS) techniques and the consequent skyrocketing of genomic and transcriptomic data. However, these data are being underused in the studies of organelle genome transcription. My thesis investigates how NGS has affected the field of organelle genomics at both the DNA and RNA levels. First, I demonstrate that although organelle genomes are being sequenced as never before, they are un-characterized as they are published mostly as “organelle …