Life Sciences Commons^™

Winner's Curse Correction And Variable Thresholding Improve Performance Of Polygenic Risk Modeling Based On Genome-Wide Association Study Summary-Level Data, Jianxin Shi, Ju-Hyun Park, Jubao Duan, Sonja T. Berndt, Winton Moy, Kai Yu, Lei Song, William Wheeler, Xing Hua, Debra Silverman, Montserrat Garcia-Closas, Chao Agnes Hsiung, Jonine D. Figueroa, Victoria K. Cortessis, Nuria Malats, Margaret R. Karagas

Dartmouth Scholarship

Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from the discovery samples. We herein propose modifications to improve the performance of PRS. We introduce threshold-dependent winner’s-curse adjustments for marginal association coefficients that are used to weight the single-nucleotide polymorphisms (SNPs) in PRS. Further, as a way to incorporate external functional/annotation knowledge that could identify subsets of SNPs highly enriched for associations, we propose variable thresholds for SNPs selection. We applied …

Whole Genome Sequencing As A Tool For Identifying Phenotypic Properties And Underlying Genetic Mechanisms In Staphylococcus Pseudintermedius, Matthew C. Riley

Doctoral Dissertations

Staphylococcus pseudintermedius is a Gram-positive bacterial opportunistic pathogen commonly associated with dermal infections in canines, but capable of causing serious disease in other species. Reports of human infections caused by S. pseudintermedius along with an increase in resistance to multiple antibiotics highlights the importance of this organism. Whole genome sequencing can allow large scale investigation of genetic mechanisms underlying phenotypic properties that contribute to the expansion of successful S. pseudintermedius clonal lineages.

The increase in multidrug and methicillin-resistant S. pseudintermedius (MRSP) may result from horizontal transfer of genetic material between bacterial isolates, yet is thought to be rare in Staphylococci …

Promises And Challenges Of Eco-Physiological Genomics In The Field: Tests Of Drought Responses In Switchgrass. Plant Physiology, John T. Lovell, Eugene V. Shakirov, Scott Schwartz, David B. Lowry, Michael J. Aspinwall, Samuel H. Taylor, Jason Bonnette, Juan Diego Palacio-Mejia, Christine V. Hawkes, Philip A. Fay, Thomas E. Juenger

Biological Sciences Faculty Research

Identifying the physiological and genetic basis of stress tolerance in plants has proven to be critical to understanding adaptation in both agricultural and natural systems. However, many discoveries were initially made in the controlled conditions of greenhouses or laboratories, not in the field. To test the comparability of drought responses across field and greenhouse environments, we undertook three independent experiments using the switchgrass reference genotype Alamo AP13. We analyzed physiological and gene expression variation across four locations, two sampling times, and three years. Relatively similar physiological responses and expression coefficients of variation across experiments masked highly dissimilar gene expression responses …

Genomic Variants Associated With Cancer-Related Fatigue: A Systematic Review, Joseph D. Tariman Phd, Sadaf Dhorajiwala Msn

Joseph D Tariman PhD, RN, ANP-BC, FAAN

Gene Discovery In Mendelian And Complex Diseases, Sali Farhan

Electronic Thesis and Dissertation Repository

Through the Finding of Rare Disease Genes in Canada (FORGE Canada) initiative, individuals affected with rare Mendelian diseases were clinically ascertained with a goal of identifying the genetic origin of their disease. Herein, I describe the methods for identifying the genetic basis of four Mendelian diseases. The application of next generation sequencing led to the discovery of non-synonymous variation in the DNA of individuals affected by rare diseases. The effects of the candidate variants were assessed using a series of functional experiments to complement the human genetics data. The variants observed in patients’ cells are extremely rare, were consistently predicted …

Understanding Plant Response To Stress Using Gene Model Quality Evaluation And Transcriptome Analysis, Karthik Ramaswamy Padmanabhan

Open Access Dissertations

The overall aim of the project was to understand how plants reacted to environmental stress and evolved to overcome it. The land plants that we see today evolved from a green algal ancestor around 510 million years ago. Plants had to make significant changes to their cellular, morphological, regulatory and physiological processes during their adaptation to the terrestrial environment from an aquatic environment. The first part of the project was to find out how these changes were reflected on the protein makeup of the early land plants. The gene model sequence data of two early land plants, Physcomitrella patens (moss) …

Development Of An In Silico Kir Genotyping Algorithm And Its Application To Population And Cancer Immunogenetic Analyses, Howard Rosoff

Dissertations & Theses (Open Access)

Gene content determination and variant calling in the complex KIR genomic region are useful for immune system function analysis, pathogenesis and disease risk factor elucidation, immunotherapy development, evolutionary investigations, and human migration modeling. Sequence-specific oligonucleotide and sequence-specific primer PCR methods are the de facto standards for KIR presence/absence identification, but the current platforms are unsuitable for SNP calling, impractical for KIR typing large cohorts of DNA samples, and inapplicable for typing repositories in which sequence data, but not cells or cell analytes, are available. Alternative typing methods, such as in silico sequence-based typing, can address the problems associated with amplicon-based …

Distribution Of Genomic Variation In The Usda Soybean Germplasm Collection And Relationship With Phenotypic Variation, Nonoy Batiller Bandillo

Department of Agronomy and Horticulture: Dissertations, Theses, and Student Research

The USDA Soybean Germplasm Collection harbors a large stock of genetic diversity with potential to accelerate soybean cultivar development. The extent and nature of favorable alleles contained in the collection are not well known nor is the distribution of genetic variation and how it relates to phenotypic variation. The genotyping of the entire USDA Soybean Germplasm Collection marked the beginning of a systematic exploration of genetic diversity for genetic research and breeding. In this research, we conducted the first comprehensive analysis of population structure on the collection of ~14,400 soybean accessions [Glycine max (L.) Merr. and G. soja Siebold …

Confirmation Of The Function Of Mrub1080 As Γ-Glutamyl Kinase (Prob) In Meiothermus Ruber, Cale J. Mccormick, Dr. Lori Scott

Celebration of Learning

This project is part of the Meiothermus ruber genome analysis project, which uses wet lab procedures and computational analysis to gather evidence of orthologous genes between Escherichia coli and Meiothermus ruber. In previous work, bioinformatics evidence supported the hypothesis that the gene Mrub1080 was an ortholog of E. coli proB. We investigated the biological function of Meiothermus ruber genes proB and proBA using the complementation assay. However, functional analysis proved inconclusive. For this particular research project, we confirmed that weakly complementing E. coli proB- null strains actually contained the desired M. ruber proB and proBA genes (inserted into a pKt1 …

Characterization Of The Marine Sponge Amphimedon Compressa Microbiome Across A Spatial Gradient, Renee Michelle Potens

HCNSO Student Theses and Dissertations

Diverse and ecologically important microbial communities (microbiomes) are symbiotic within marine sponges. In this study, the microbiome of Amphimedon compressa from three sample locations (Broward and Dade Counties, Southeast Florida, USA and the Southern Caribbean, Bocas del Toro, Panama) is characterized using 16S rRNA Illumina sequencing. The predominant taxa are Proteobacteria and Cyanobacteria, as expected for Low Microbial Abundance sponges, accounting for over 53% of the total microbiome community. The numbers of Operational Taxonomic Units (OTUs) decrease from Broward County (2,900) to Dade County (2,300) and then Bocas del Toro (1,200). The correlates to a decreasing north-south gradient of …

Life In The Underworld: Anchialine Cave Biology In The Era Of Speleogenomics, Jorge L. Pérez-Moreno, Thomas M. Iliffe, Heather D. Bracken-Grissom

International Journal of Speleology

Anchialine caves contain haline bodies of water with underground connections to the ocean and limited exposure to open air. Despite being found on islands and peninsular coastlines around the world, the isolation of anchialine systems has facilitated the evolution of high levels of endemism among their inhabitants. The unique characteristics of anchialine caves and of their predominantly crustacean biodiversity nominate them as particularly interesting study subjects for evolutionary biology. However, there is presently a distinct scarcity of modern molecular methods being employed in the study of anchialine cave ecosystems. The use of current and emerging molecular techniques, e.g., next-generation sequencing …

Restriction Enzyme Generated Next-Generation Sequencing Libraries And Genetic Risk Modifiers Of Brca1 Mutation Carriers, Bradley Downs

Theses & Dissertations

Next-generation sequencing (NGS) is a high throughput technique used to sequence large amounts of DNA in a short amount of time. However, a limitation to NGS is that the generated data is in a single consensus sequence without distinguishing between variants on homologous chromosomes. Separating or phasing the variants from the maternal and paternal chromosomes can provide information about the genetic origin of disease and information about how DNA nucleotide alterations interact in cis. This dissertation explores a new technical method of using restriction enzymes during NGS library preparation and its ability to increase the amount of phasing information that …

Assessment Of Next Generation Sequencing Technologies For De Novo And Hybrid Assemblies Of Challenging Bacterial Genomes, Sagar Mukund Utturkar

Doctoral Dissertations

In past decade, tremendous progress has been made in DNA sequencing methodologies in terms of throughput, speed, read-lengths, along with a sharp decrease in per base cost. These technologies, commonly referred to as next-generation sequencing (NGS) are complimented by the development of hybrid assembly approaches which can utilize multiple NGS platforms. In the first part of my dissertation I performed systematic evaluations and optimizations of nine de novo and hybrid assembly protocols across four novel microbial genomes. While each had strengths and weaknesses, via optimization using multiple strategies I obtained dramatic improvements in overall assembly size and quality. To select …

The Selective Survival Of Escherichia Coli In Freshwater Beach Sand, Natalie Ann Rumball

Theses and Dissertations

The quantification of Escherichia coli or E. coli is the most common method used to detect recent fecal pollution in recreational water, as this species is known for its high abundance in fecal matter and assumed host-associated nature. However, it has been determined that some strains are capable of long-term survival and potential propagation in non-host environments, such as the beach sand. These long-term environmental survivors are host-independent and are not associated with the same health risks as those E. coli from recent fecal pollution. However, they have been shown to impact how water quality is perceived as they are …

Physiology And Genetics Of Starvation-Selected Drosophila Melanogaster, Christopher Michael Hardy

UNLV Theses, Dissertations, Professional Papers, and Capstones

In nature, organisms have evolved to survive in stressful environments. This has driven organisms to adopt a wide range of unique adaptations. Investigating the mechanistic basis of these adaptations is an important tool for discovery that has led to major advances in science and medicine.

We study how organisms survive life without food, or starvational stress. Environmental stressors have shaped the quantity and quality of food sources across the globe. This has led to vast differences in the ability of some organisms to tolerate starvation over others. Many researchers have used Drosophila melanogaster as a model to study global patterns …

The Genomic Cds Sandbox: An Assessment Among Domain Experts., Ayesha Aziz, Kensaku Kawamoto, Karen Eilbeck, Marc S Williams, Robert R Freimuth, Mark A Hoffman, Luke V Rasmussen, Casey L Overby, Brian H Shirts, James M Hoffman, Brandon M Welch

Manuscripts, Articles, Book Chapters and Other Papers

Genomics is a promising tool that is becoming more widely available to improve the care and treatment of individuals. While there is much assertion, genomics will most certainly require the use of clinical decision support (CDS) to be fully realized in the routine clinical setting. The National Human Genome Research Institute (NHGRI) of the National Institutes of Health recently convened an in-person, multi-day meeting on this topic. It was widely recognized that there is a need to promote the innovation and development of resources for genomic CDS such as a CDS sandbox. The purpose of this study was to evaluate …

Making Sense Of Genomic Variation: Part 1 Snp Annotation, Rolando Garcia-Milian

Rolando Garcia-Milian

Techniques And Approaches To Genetic Analyses In Nephrological Disorders., Laurel K. Willig

Manuscripts, Articles, Book Chapters and Other Papers

Inherited renal disease is a leading cause of morbidity and mortality in pediatric nephrology. High throughput advancements in genomics have led to greater understanding of the biologic underpinnings of these diseases. However, the underlying genetic changes explain only part of the molecular biology that contributes to disease manifestation and progression. Other omics technologies will provide a more complete picture of these cellular processes. This review discusses these omics technologies in the context of pediatric renal disease.

Comprehensive Genetic Testing Identifies Targetable Genomic Alterations In Most Patients With Non-Small Cell Lung Cancer, Specifically Adenocarcinoma, Single Institute Investigation, Janani Vigneswaran, Yi-Hung Carol Tan, Septimiu D. Murgu, Brian M. Won, Kathryn Alexa Patton, Victoria M. Villaflor, Philip C. Hoffman, Thomas Hensing, D. Kyle Hogarth, Renuka Malik

Dartmouth Scholarship

This study reviews extensive genetic analysis in advanced non-small cell lung cancer (NSCLC) patients in order to: describe how targetable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially targetable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. Thoracic Oncology Research Program Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. 364 patients including 289 adenocarcinoma underwent genotype testing by various platforms such as FoundationOne, Caris Molecular …

Genome-Wide Annotation, Identification, And Global Transcriptomic Analysis Of Regulatory Or Small Rna Gene Expression In Staphylococcus Aureus, Ronan K. Carroll, Andy Weiss, William H. Broach, Richard E Wiemels, Austin B. Mogen, Kelly C. Rice, Lindsey N. Shaw

Molecular Biosciences Faculty Publications

In Staphylococcus aureus, hundreds of small regulatory or small RNAs (sRNAs) have been identified, yet this class of molecule remains poorly understood and severely understudied. sRNA genes are typically absent from genome annotation files, and as a consequence, their existence is often overlooked, particularly in global transcriptomic studies. To facilitate improved detection and analysis of sRNAs in S. aureus, we generated updated GenBank files for three commonly used S. aureus strains (MRSA252, NCTC 8325, and USA300), in which we added annotations for >260 previously identified sRNAs. These files, the first to include genome-wide annotation of sRNAs in S. aureus, were …

Genome To Phenome: Improving Animal Health, Production, And Well-Being – A New Usda Blueprint For Animal Genome Research 2018–2027, Caird Rexroad, Jeffrey Vallet, Lakshmi Kumar Matukumalli, James Reecy, Derek Bickhart, Harvey Blackburn, Mark Boggess, Hans Cheng, Archie Clutter, Noelle Cockett, Catherine Ernst, Janet E. Fulton, John Liu, Joan Lunney, Holly Neibergs, Catherine Purcell, Timothy P. L. Smith, Tad Sonstegard, Jerry Taylor, Bhanu Telugu, Alison Van Eenennaam, Curtis P. Van Tassell, Kevin Wells

Department of Animal Science: Faculty Publications

In 2008, a consortium led by the Agricultural Research Service (ARS) and the National Institute for Food and Agriculture (NIFA) published the “Blueprint for USDA Efforts in Agricultural Animal Genomics 2008–2017,” which served as a guiding document for research and funding in animal genomics. In the decade that followed, many of the goals set forth in the blueprint were accomplished. However, several other goals require further research. In addition, new topics not covered in the original blueprint, which are the result of emerging technologies, require exploration. To develop a new, updated blueprint, ARS and NIFA, along with scientists in the …

Functional Car Models For Spatially Correlated Functional Datasets, Lin Zhang, Veerabhadran Baladandayuthapani, Hongxiao Zhu, Keith A. Baggerly, Tadeusz Majewski, Bogdan Czerniak, Jeffrey S. Morris

Jeffrey S. Morris

We develop a functional conditional autoregressive (CAR) model for spatially correlated data for which functions are collected on areal units of a lattice. Our model performs functional response regression while accounting for spatial correlations with potentially nonseparable and nonstationary covariance structure, in both the space and functional domains. We show theoretically that our construction leads to a CAR model at each functional location, with spatial covariance parameters varying and borrowing strength across the functional domain. Using basis transformation strategies, the nonseparable spatial-functional model is computationally scalable to enormous functional datasets, generalizable to different basis functions, and can be used on …

Can The Insertion Of An E. Coli Shine-Dalgarno Sequence Upstream Of M. Ruber Proa Of The Proba Operon Enhance Its Expression, As Measured By A Complementation Assay Using E. Coli Null Strains?, Matthew D. Murphy, Dr. Lori Scott

Meiothermus ruber Genome Analysis Project

The process by which the thermophilic bacteria Meiothermus ruber (M. ruber) synthesizes the amino acid proline is examined in this paper. In the well-studied E. coli system, proline biosynthesis involves three enzymes ProA, ProB and ProC; proA and proB form the proBA operon and both proA and proB possess an upstream Shine-Delgarno sequence; and ProB is functionally dependent on ProA as components of a ProBA complex. In previous studies in Dr. Scott’s lab, the putative M. ruber proA (locus tag Mrub1079), proB (Mrub1080) and proC (Mrub1345) genes were cloned into the pKt1 expression vector, transformed into the corresponding …

Tick Genome Assembled: New Opportunities For Research On Tick-Host-Pathogen Interactions, Jose De La Fuente, Robert M. Waterhouse, Daniel E. Sonenshine, R. Michael Roe, Jose M. Ribeiro, David B. Sattelle, Catherine A. Hill

Biological Sciences Faculty Publications

As tick-borne diseases are on the rise, an international effort resulted in the sequence and assembly of the first genome of a tick vector. This result promotes research on comparative, functional and evolutionary genomics and the study of tick-host-pathogen interactions to improve human, animal and ecosystem health on a global scale.

Genomic Comparisons And Genome Architecture Of Divergent Trypanosoma Species, Katie Bradwell

Theses and Dissertations

Virulent Trypanosoma cruzi, and the non-pathogenic Trypanosoma conorhini and Trypanosoma rangeli are protozoan parasites with divergent lifestyles. T. cruzi and T. rangeli are endemic to Latin America, whereas T. conorhini is tropicopolitan. Reduviid bug vectors spread these parasites to mammalian hosts, within which T. rangeli and T. conorhini replicate extracellularly, while T. cruzi has intracellular stages. Firstly, this work compares the genomes of these parasites to understand their differing phenotypes. Secondly, genome architecture of T. cruzi is examined to address the effect of a complex hybridization history, polycistronic transcription, and genome plasticity on this organism, and study its highly …

Modeling The Mechanism Underlying Environmental And Genetic Determinants Of Gene Expression And Complex Traits, Gregory Alan Moyerbrailean

Wayne State University Dissertations

Advances in next-generation sequencing technologies and functional genomics strategies have allowed researchers to identify both common and rare genetic variation, to deeply profile gene expression, and even to determine regions of active gene transcription.

While these technologies and strategies have contributed greatly to our understanding of complex traits and diseases, there are many biological questions and analytical issues to be addressed.

Genome-wide association studies (GWAS) have successfully identified large numbers of genetic variants associated with complex traits and diseases. However, in many cases the mechanistic link between the phenotype and associated variant remains unclear. This may be because most variants …

Breeding Objectives Indicate Value Of Genomics For Beef Cattle, M. D. Macneil

Kansas Agricultural Experiment Station Research Reports

Genomics may have much to offer in the implementation of breeding objectives. Advantages of genomic prediction include increased accuracy of expected progeny differences (EPDs) for traits that have been components of routine genetic evaluations. Perhaps more importantly, genomic prediction makes it possible to include traits that are too costly or too difficult to measure, and traits that are measured too late in life or are sex-limited such that candidates for selection cannot have EBV with high accuracy at the time when selection decisions are made. Genomically enhanced EPDs may also allow for a marked reduction in generation interval, thus accelerating …