Genetics and Genomics Commons^™

Loss-Of-Function Genomic Variants Highlight Potential Therapeutic Targets For Cardiovascular Disease, Jonas B. Nielsen, Oren Rom, Ida Surakka, Sarah E. Graham, Wei Zhou, Tanmoy Roychowdhury, Lars G. Fritsche, Sarah A. Gagliano Taliun, Carlo Sidore, Yuhao Liu, Maiken E. Gabrielsen, Anne Heidi Skogholt, Brooke Wolford, William Overton, Ying Zhao, Jin Chen, He Zhang, Whitney E. Hornsby, Akua Acheampong, Austen Grooms, Amanda Schaefer, Gregory J. M. Zajac, Luis Villacorta, Jifeng Zhang, Ben Brumpton, Mari Løset, Vivek Rai, Pia R. Lundegaard, Morten S. Olesen, Kent D. Taylor, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of …

Epigenetic Regulation Of Prostate Cancer, Ruixin Wang, Xiaoqi Liu

Toxicology and Cancer Biology Faculty Publications

Prostate cancer is (PCa) the second leading cause of cancer death in males in the United State, with 174,650 new cases and 31,620 deaths estimated in 2019. It has been documented that epigenetic deregulation such as histone modification and DNA methylation contributes to PCa initiation and progression. EZH2 (enhancer of zeste homolog 2), the catalytic subunit of the Polycomb Repressive Complex (PRC2) responsible for H3K27me3 and gene repression, has been identified as a promising target in PCa. In addition, overexpression of other epigenetic regulators such as DNA methyltransferases (DNMT) is also observed in PCa. These epigenetic regulators undergo extensive post-translational …

Whole Genome Sequencing Identified A 16 Kilobase Deletion On Eca13 Associated With Distichiasis In Friesian Horses, E. A. Hisey, H. Hermans, Z. T. Lounsberry, F. Avila, R. A. Grahn, K. E. Knickelbein, S. A. Duward-Akhurst, M. E. Mccue, Theodore S. Kalbfleisch, M. E. Lassaline, W. Back, R. R. Bellone

Veterinary Science Faculty Publications

BACKGROUND: Distichiasis, an ocular disorder in which aberrant cilia (eyelashes) grow from the opening of the Meibomian glands of the eyelid, has been reported in Friesian horses. These misplaced cilia can cause discomfort, chronic keratitis, and corneal ulceration, potentially impacting vision due to corneal fibrosis, or, if secondary infection occurs, may lead to loss of the eye. Friesian horses represent the vast majority of reported cases of equine distichiasis, and as the breed is known to be affected with inherited monogenic disorders, this condition was hypothesized to be a simply inherited Mendelian trait.

RESULTS: A genome wide association study (GWAS) …

Genetic-Based Hypertension Subtype Identification Using Informative Snps, Yuanjing Ma, Hongmei Jiang, Sanjiv J. Shah, Donna K. Arnett, Marguerite R. Irvin, Yuan Luo

Epidemiology and Environmental Health Faculty Publications

In this work, we proposed a process to select informative genetic variants for identifying clinically meaningful subtypes of hypertensive patients. We studied 575 African American (AA) and 612 Caucasian hypertensive participants enrolled in the Hypertension Genetic Epidemiology Network (HyperGEN) study and analyzed each race-based group separately. All study participants underwent GWAS (Genome-Wide Association Studies) and echocardiography. We applied a variety of statistical methods and filtering criteria, including generalized linear models, F statistics, burden tests, deleterious variant filtering, and others to select the most informative hypertension-related genetic variants. We performed an unsupervised learning algorithm non-negative matrix factorization (NMF) to identify hypertension …

The P-Glycoprotein Repertoire Of The Equine Parasitic Nematode Parascaris Univalens, Alexander P. Gerhard, Jürgen Krücken, Emanuel Heitlinger, I. Jana I. Janssen, Marta Basiaga, Sławomir Kornaś, Céline Beier, Martin K. Nielsen, Richard E. Davis, Jianbin Wang, Georg Von Samson-Himmelstjerna

Maxwell H. Gluck Equine Research Center Faculty Publications

P-glycoproteins (Pgp) have been proposed as contributors to the widespread macrocyclic lactone (ML) resistance in several nematode species including a major pathogen of foals, Parascaris univalens. Using new and available RNA-seq data, ten different genomic loci encoding Pgps were identified and characterized by transcriptome-guided RT-PCRs and Sanger sequencing. Phylogenetic analysis revealed an ascarid-specific Pgp lineage, Pgp-18, as well as two paralogues of Pgp-11 and Pgp-16. Comparative gene expression analyses in P. univalens and Caenorhabditis elegans show that the intestine is the major site of expression but individual gene expression patterns were not conserved between the two nematodes. In P. …

Genome Diversity And The Origin Of The Arabian Horse, Elissa J. Cosgrove, Raheleh Sadeghi, Florencia Schlamp, Heather M. Holl, Mohammad Moradi-Shahrbabak, Seyed Reza Miraei-Ashtiani, Salma Abdalla, Ben Shykind, Mats H. T. Troedsson, Monika Stefaniuk-Szmukier, Anil Prabhu, Stefania Bucca, Monika Bugno-Poniewierska, Barbara Wallner, Joel Malek, Donald C. Miller, Andrew G. Clark, Douglas F. Antczak, Samantha A. Brooks

Veterinary Science Faculty Publications

The Arabian horse, one of the world's oldest breeds of any domesticated animal, is characterized by natural beauty, graceful movement, athletic endurance, and, as a result of its development in the arid Middle East, the ability to thrive in a hot, dry environment. Here we studied 378 Arabian horses from 12 countries using equine single nucleotide polymorphism (SNP) arrays and whole-genome re-sequencing to examine hypotheses about genomic diversity, population structure, and the relationship of the Arabian to other horse breeds. We identified a high degree of genetic variation and complex ancestry in Arabian horses from the Middle East region. Also, …

A Transcriptional Regulatory Network Of Rsv3-Mediated Extreme Resistance Against Soybean Mosaic Virus, Lindsay C. Demers, Neelam R. Redekar, Aardra Kachroo, Sue A. Tolin, Song Li, M. A. Saghai Maroof

Plant Pathology Faculty Publications

Resistance genes are an effective means for disease control in plants. They predominantly function by inducing a hypersensitive reaction, which results in localized cell death restricting pathogen spread. Some resistance genes elicit an atypical response, termed extreme resistance, where resistance is not associated with a hypersensitive reaction and its standard defense responses. Unlike hypersensitive reaction, the molecular regulatory mechanism(s) underlying extreme resistance is largely unexplored. One of the few known, naturally occurring, instances of extreme resistance is resistance derived from the soybean Rsv3 gene, which confers resistance against the most virulent Soybean mosaic virus strains. To discern the regulatory mechanism …

Frontotemporal Dementia Nonsense Mutation Of Progranulin Rescued By Aminoglycosides, Lisha Kuang, Kei Hashimoto, Eric J. Huang, Matthew S. Gentry, Haining Zhu

Molecular and Cellular Biochemistry Faculty Publications

Frontotemporal dementia (FTD) is an early onset dementia and is characterized by progressive atrophy of the frontal and/or temporal lobes. FTD is highly heritable with mutations in progranulin accounting for 5-26% of cases in different populations. Progranulin is involved in endocytosis, secretion and lysosomal processes, but its function under physiological and pathological conditions remains to be defined. Many FTD-causing nonsense progranulin mutations contain a premature termination codon (PTC), thus progranulin haploinsufficiency has been proposed as a major disease mechanism. Currently, there is no effective FTD treatment or therapy.

Aminoglycosides are a class of antibiotics that possess a less known function …

Epigenetic Implications In Inorganic Arsenic-Mediated Carcinogenesis, Meredith Eckstein

Theses and Dissertations--Molecular and Cellular Biochemistry

Chronic, low dose exposure to inorganic arsenic (iAs) is a public health concern throughout the world, contributing to the development of many diseases, including lung cancer. Several mechanisms for iAs-mediated carcinogenesis have been proposed, of which the production of reactive oxygen species and formation of chromosomal aberrations are the most studied. Another equally important, yet less studied mechanism is dysregulation of epigenetic marks. “Epigenetics” refers to changes that occur on the DNA and chromatin that do not alter base pair identity, but alter compaction, expression, and regulation of specific DNA sequences. There are several types of epigenetic marks including histone …

The Roles Of Polar Cell Extensions In Drosophila Micropyle Formation, Bradford Hull

Theses and Dissertations--Biology

The Drosophila micropyle is a conserved formation utilized to allow sperm passage past the robust eggshell structure for fertilization. Micropyle formation follows a unique acellular tubulogenesis method where it is secreted and shaped by specialized follicle cells including the border cells and polar cells. In late oogenesis, the polar cells form extensions that are necessary to create the micropyle pore through which sperm enters. Previous work established that polar cell extension presence is required for micropyle pore formation. We investigated temporal requirements of extensions throughout chorion deposition and found extensions are required during the beginning and middle of choriogenesis, but …

Combination Of Investigational Cell-Based Therapy And Deep Brain Stimulation To Alter The Progression Of Parkinson’S Disease, Nader El Seblani

Theses and Dissertations--Pharmacy

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the motor symptoms are caused by progressive loss of midbrain dopamine neurons. There is no current treatment that can slow or reverse PD. Our current “DBS-Plus” clinical trial (NCT02369003) features the implantation in vivo of autologous Schwann cells (SCs) derived from a patient’s sural nerve into the substantia nigra pars compacta (SNpc) in combination with Deep Brain Stimulation (DBS) therapy for treating patients with advanced PD.

The central hypothesis of our research is that transdifferentiated SCs within conditioned nerve tissue will deliver pro-regenerative factors to enhance the survival of …

Apoe As A Metabolic Regulator In Humans, Mice, And Astrocytes, Brandon C. Farmer

Theses and Dissertations--Physiology

Altered metabolic pathways appear to play central roles in the pathophysiology of late-onset Alzheimer’s disease (AD). Carrier status of the E4 allele of the APOE gene is the strongest genetic risk factor for late-onset AD, and increasing evidence suggests that E4 carriers may be at an increased risk for neurodegeneration based on inherent metabolic impairments. A new appreciation is forming for the role of APOE in cerebral metabolism, and how nutritional factors may impact this role. In chapter 1, the literature on nutritional interventions in E4 carriers aimed at mitigating disease risk is reviewed. Studies investigating the mechanism by which …

Effects Of Thinning Regimes On Genetic Variation Of White Oak (Quercus Alba L.) In Upland Oak Forests Of Eastern Kentucky, Rachel Gayle Thunder

Theses and Dissertations--Forestry and Natural Resources

This research assesses the effects of silvicultural thinnings, varying in residual basal area and number of thinnings, on genetic diversity and relatedness of white oak (Quercus alba L.). The objectives were to (1) develop microsatellite DNA markers (simple sequence repeats, SSRs) for assessing the genetic diversity of white oak and (2) determine if thinnings significantly change the degree of diversity and relatedness in white oak stands. For objective 1, 84 primer pairs from previously predicted genomic SSRs of white oak were evaluated for consistent PCR amplification and polymorphism. Twenty of the 84 primer pairs amplified consistently and were confirmed …

Genetic Analysis Of The Endangered Gray Bat Species (Myotis Grisescens), Emma Fitzgerald

Lewis Honors College Capstone Collection

This study attempts to analyze the genetics using specific haplotype sequences of the endangered gray bat to determine genetic events that have happened in the past as well as determining how the species population has changed over time. We were able to conduct a Tajima’s D test to investigate whether a potential bottleneck has occurred. A linear regression of the genetic vs. geographical distance was produced to investigate the patterns of haplotype distribution. The species past distribution was compared to the current distribution using known collected specimens. A map of future predictions was constructed using present and future climate layers …

From Genes To Species: Ecological Speciation With Gene Flow In Neodiprion Pinetum And N. Lecontei, Emily E. Bendall

Theses and Dissertations--Biology

My dissertation focuses on how differences accumulate across the genome during ecological speciation with geneflow. To do this I used two species of Neodiprionpine sawflies, which are plant-feeding hymenopterans with high host specificity. I used experimental crosses to measure both intrinsic and extrinsic postzygotic isolation and to understand the contribution of specific traits to reproductive isolation. Despite substantial genetic divergence and haploid males in which all recessive incompatibilities should be expressed, I found surprisingly little evidence of intrinsic postzygotic isolation. Recombination in hybrid males may reconstitute viable genotypes and counteract the effects of haploidy in males. Nevertheless, hybrids have …

Predicting Patterns Of Gene Family Evolution In Taxa With Similar Ecological Niches, Kim Vertacnik

Theses and Dissertations--Biology

To fully understand the genetic basis of adaptation, we need to know its predictability—the extent to which specific selective pressures and contexts can yield corresponding genetic changes. In particular, the repeated colonization of similar, specialized environments by different taxa is ideal for assessing the frequency of reoccurring changes in the same genes or functions. But compared to a growing body of literature on the convergent evolution of individual genes, far less is known about the repeatability of gene family evolution, where families (defined here as groups of genes that share sequence and functional similarity from common ancestry) can expand (gain …

Identification And Characterization Of Epigenetic Regulators In The Yellow Fever Mosquito, Aedes Aegypti, Shankar C. R. R. Chereddy

Theses and Dissertations--Entomology

Due to the increased interactions between the sylvatic and urban cycles of Aedes aegypti life cycle, there has been an increase in the incidence of vector-borne diseases. The risk involved through the transmission of viruses like Dengue, Zika, Yellow-fever and Chikungunya calls for an effective control method for the deadly vector. The possibility of pesticide resistance and the costs involved in producing new pesticides have pushed Sterile Insect Technique (SIT) into prominence. However, current methods used to sterize insects for SIT are not highly efficient. This study tackles current issues in mosquito control by identifying and characterizing epigenetic regulators that …

Investigation Into The Roles Of Her9 And Capn5 During Retinal Development And Regeneration, Cagney Coomer

Theses and Dissertations--Biology

The formation of a healthy and functioning eye requires coordinated interactions between numerous signaling pathways and gene regulatory networks within the developing neural retina. Tight regulation of gene expression is required for cell specification and differentiation in this multilayered, light sensitive tissue. The photoreceptors are the light detecting cells of the retina, capable of functioning in both intense sunlight and dim light at night. When pigment cells of the photoreceptor outer segment are activated by light, a complex chain of events called phototransduction leads to the electrical signal cascade that is transmitted through the retina and ultimately to the brain …