Genetics and Genomics Commons^™

50 Whys To Look For Genes: Pros And Complications, Peter J. Taylor

Working Papers on Science in a Changing World

“Treating the audience as capable of thinking about the complexities that surround the application of genetic knowledge” was the tagline of a series of daily blog posts made over seven weeks in the fall of 2014, posts that included extended quotes from the recently published Nature-Nurture? No (Taylor 2014). This working paper is a compilation of those posts.

Spectral Gene Set Enrichment (Sgse), H Robert Frost, Zhigang Li, Jason H. Moore

Dartmouth Scholarship

Gene set testing is typically performed in a supervised context to quantify the association between groups of genes and a clinical phenotype. In many cases, however, a gene set-based interpretation of genomic data is desired in the absence of a phenotype variable. Although methods exist for unsupervised gene set testing, they predominantly compute enrichment relative to clusters of the genomic variables with performance strongly dependent on the clustering algorithm and number of clusters. We propose a novel method, spectral gene set enrichment (SGSE), for unsupervised competitive testing of the association between gene sets and empirical data sources. SGSE first computes …

Highly Constrained Intergenic Drosophila Ultraconserved Elements Are Candidate Ncrnas, Andrew D. Kern, Daniel A. Barbash, Joshua Chang Mell, Daniel Hupalo, Amanda Jensen

Dartmouth Scholarship

Eukaryotes contain short (∼80–200 bp) regions that have few or no substitutions among species that represent hundreds of millions of years of evolutionary divergence. These ultraconserved elements (UCEs) are candidates for containing essential functions, but their biological roles remain largely unknown. Here, we report the discovery and characterization of UCEs from 12 sequenced Drosophilaspecies. We identified 98 elements ≥80 bp long with very high conservation across the Drosophila phylogeny. Population genetic analyses reveal that these UCEs are not present in mutational cold spots. Instead we infer that they experience a level of selective constraint almost 10-fold higher compared with …

Estimation Of Breed-Specific Heterosis Effects For Birth, Weaning, And Yearling Weight In Cattle, Lauren N. Schiermiester, R. M. Thallman, Larry Kuehn, Stephen D. Kachman, Matthew L. Spangler

Department of Animal Science: Faculty Publications

Heterosis, assumed proportional to expected breed heterozygosity, was calculated for 6834 individuals with birth, weaning and yearling weight records from Cycle VII and advanced generations of the U.S. Meat Animal Research Center (USMARC) Germplasm Evaluation (GPE) project. Breeds represented in these data included: Angus, Hereford, Red Angus, Charolais, Gelbvieh, Simmental, Limousin and Composite MARC III. Heterosis was further estimated by proportions of British × British (B × B), British × Continental (B × C) and Continental × Continental (C × C) crosses and by breed-specific combinations. Model 1 fitted fixed covariates for heterosis within biological types while Model 2 fitted …

Systems Level Analysis Of Systemic Sclerosis Shows A Network Of Immune And Profibrotic Pathways Connected With Genetic Polymorphisms, J. Matthew Mahoney, Jaclyn Taroni, Viktor Martyanov, Tammara A. A. Wood, Casey S. Greene, Patricia A. Pioli, Monique E. Hinchcliff, Michael L. Whitfield

Dartmouth Scholarship

Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by skin and organ fibrosis. The pathogenesis of SSc and its progression are poorly understood. The SSc intrinsic gene expression subsets (inflammatory, fibroproliferative, normal-like, and limited) are observed in multiple clinical cohorts of patients with SSc. Analysis of longitudinal skin biopsies suggests that a patient's subset assignment is stable over 6-12 months. Genetically, SSc is multi-factorial with many genetic risk loci for SSc generally and for specific clinical manifestations. Here we identify the genes consistently associated with the intrinsic subsets across three independent cohorts, show the relationship between these genes …

The Role Of Artificial Structures In Facilitating Range Expansion Of The Introduced Barnacle Megabalanus Coccopoma In The Southeastern U.S.A., Alicia M. Reigel

College of Graduate Studies: Theses & Dissertations

The barnacle Megabalanus coccopoma is a recent invader of the southeastern U.S.A. from the tropical eastern Pacific. In Georgia, M. coccopoma populations along the immediate coastline often suffer extensive mortality during the winter, but population rebuilding is common after these events suggesting that there may be nearby larval sources. I investigated the hypothesis that artificial structures (i.e., buoys, towers), occurring far enough offshore of Georgia for water temperatures to be moderated by the Gulf Stream, provide refuges for breeding adults of M. coccopoma and can serve as the larval source. I investigated this hypothesis by first developing thirteen microsatellite primer …

Developing A Gene Editing System To Study Haplodiploidy In The Jewel Wasp, Nasonia Vitripennis, Emily A. Muller

Scripps Senior Theses

Hymenopteran insects, which include all ants, bees and wasps, reproduce through a poorly understood form of reproduction known as haplodiploidy. A promising experimental system for understanding this developmental process is the jewel wasp, Nasonia vitripennis. A critical aspect of using Nasonia as a model is establishing an effective means for editing specific genes of interest so that their functions can be studied through genetic means. For my thesis research, I performed a pilot study of the gene editing method known as CRISPR in Nasonia. I targeted the single heterochromatin protein 1 (HP1) gene present in the Nasonia genome …

Increasing Knowledge About Alpha-1 Antitrypsin Deficiency In The Chronic Obstructive Pulmonary Disease Population, Maureen Ann Wentink Barta

Walden Dissertations and Doctoral Studies

The purpose of the project was to increase awareness about alpha-1 antitrypsin deficiency (AATD) in chronic obstructive pulmonary disease (COPD), particularly among those with a familial history of genetic factor AATD; an additional goal was to understand its relationship to COPD. COPD is the third leading cause of death in the United States, with more than half of COPD patients experiencing significant disabilities. Major causes for COPD include smoking, air pollution, secondary smoke, upper respiratory infections, hereditary factors, occupational factors, environmental factors, and socioeconomic factors. Genetic factors, however, also play a significant role in early onset COPD and in those …

Phenotypic Robustness And The Assortativity Signature Of Human Transcription Factor Networks, Dov A. Pechenick, Joshua L. Payne, Jason H. Moore

Dartmouth Scholarship

Many developmental, physiological, and behavioral processes depend on the precise expression of genes in space and time. Such spatiotemporal gene expression phenotypes arise from the binding of sequence-specific transcription factors (TFs) to DNA, and from the regulation of nearby genes that such binding causes. These nearby genes may themselves encode TFs, giving rise to a transcription factor network (TFN), wherein nodes represent TFs and directed edges denote regulatory interactions between TFs. Computational studies have linked several topological properties of TFNs - such as their degree distribution - with the robustness of a TFN's gene expression phenotype to genetic and environmental …

Sheep Updates 2014, James Kynge, David Lindsay, Johan Greeff, John Young, Luke Stephen, Graham Gardner, Stephen Lee, Bindi Murray, James Rowe

Sheep Updates

This session covers nine papers from different authors:

Genetic Research: A brave new world of opportunities

1. "China's Appetite" - The implications for WA, James Kynge, Chairman, FT Confidential Research, Emerging Markets Editor, Financial Times, London.

2. The genetics warm-up - the secret language of genetic research and its impacts on WA's sheep flock, Professor David Lindsay, University of Western Australia, Perth WA

The strength of genetic data: is it really valuable?

3. Genetic research in Western Australia - What have the compromises in production been? Johan Greeff, Senior Geneticist, Department of Agriculture and Food Western Australia

4. Show …

Metagenomic Identification Of A Novel Salt Tolerance Gene From The Human Gut Microbiome Which Encodes A Membrane Protein With Homology To A Brp/Blh-Family Beta-Carotene 15,15'-Monooxygenase, Eamonn P. Culligan, Roy D. Sleator, Julian R. Marchesi, Colin Hill

Department of Biological Sciences Publications

The human gut microbiome consists of at least 3 million non-redundant genes, 150 times that of the core human genome. Herein, we report the identification and characterisation of a novel stress tolerance gene from the human gut metagenome. The locus, assigned brpA, encodes a membrane protein with homology to a brp/blh-family β-carotene monooxygenase. Cloning and heterologous expression of brpA in Escherichia coli confers a significant salt tolerance phenotype. Furthermore, when cultured in the presence of exogenous β-carotene, cell pellets adopt a red/orange pigmentation indicating the incorporation of carotenoids in the cell membrane.

Population And Demographic Structure Of Ixodes Scapularis Say In The Eastern United States., Joyce M. Sakamoto, Jerome Goddard, Jason L. Rasgon

CALS Publications

INTRODUCTION: The most significant vector of tick-borne pathogens in the United States is Ixodes scapularis Say (the blacklegged tick). Previous studies have identified significant genetic, behavioral and morphological differences between northern vs. southern populations of this tick. Because tick-borne pathogens are dependent on their vectors for transmission, a baseline understanding of the vector population structure is crucial to determining the risks and epidemiology of pathogen transmission. METHODS: We investigated population genetic variation of I. scapularis populations in the eastern United States using a multilocus approach. We sequenced and analyzed the mitochondrial COI and 16S genes and three nuclear genes (serpin2, …

Holding Back The Genes: Limitations Of Research Into Canine Behavioural Genetics, Diane Van Rooy, Elizabeth R. Arnott, Jonathan B. Early, Paul Mcgreevy, Claire M. Wade

Genetics Collection

Canine behaviours that are both desirable and undesirable to owners have a demonstrable genetic component. Some behaviours are breed-specific, such as the livestock guarding by maremmas and flank sucking seen in Dobermanns. While the identification of genes responsible for common canine diseases is rapidly advancing, those genes underlying behaviours remain elusive. The challenges of accurately defining and measuring behavioural phenotypes remain an obstacle, and the use of variable phenotyping methods has prevented meta-analysis of behavioural studies. International standardised testing protocols and terminology in canine behavioural evaluations should facilitate selection against behavioural disorders in the modern dog and optimise breeding success …

A Classification And Characterization Of Two-Locus, Pure, Strict, Epistatic Models For Simulation And Detection, Ryan J. Urbanowicz, Ambrose L. S. Granizo-Mackenzie, Jeff Kiralis, Jason H Moore

Dartmouth Scholarship

BackgroundThe statistical genetics phenomenon of epistasis is widely acknowledged to confound disease etiology. In order to evaluate strategies for detecting these complex multi-locus disease associations, simulation studies are required. The development of the GAMETES software for the generation of complex genetic models, has provided the means to randomly generate an architecturally diverse population of epistatic models that are both pure and strict, i.e. all n loci, but no fewer, are predictive of phenotype. Previous theoretical work characterizing complex genetic models has yet to examine pure, strict, epistasis which should be the most challenging to detect. This study addresses three goals: …

Structural Features Of The Pseudomonas Fluorescens Biofilm Adhesin Lapa Required For Lapg-Dependent Cleavage, Biofilm Formation, And Cell Surface Localization, Chelsea D. Boyd, T. Jarrod Smith, Sofiane El-Kirat-Chatel, Peter D. Newell, Yves F. Dufrêne, George A. O'Toole

Dartmouth Scholarship

The localization of the LapA protein to the cell surface is a key step required by Pseudomonas fluorescens Pf0-1 to irreversibly attach to a surface and form a biofilm. LapA is a member of a diverse family of predicted bacterial adhesins, and although lacking a high degree of sequence similarity, family members do share common predicted domains. Here, using mutational analysis, we determine the significance of each domain feature of LapA in relation to its export and localization to the cell surface and function in biofilm formation. Our previous work showed that the N terminus of LapA is required for …

An Examination Of The Phylogenetic Diversity Of Green Algae (Chlorophyceae) That Symbiose With Spotted Salamanders (Ambystoma Maculatum) In The Egg Stage., Crystal Xue

Honors Scholar Theses

In 1909, the species Oophila amblystomatis Lambert ex Wille was described for green algae that symbiose with salamanders in the egg stage (Wille). There are two hypotheses about the source of algae: 1) that algae enter from the surrounding water once the egg clutch is laid in a pond, and 2) that they are acquired from the maternal reproductive tract. We developed a third hypothesis developed to account for the salamander reproductive cycle. Male salamanders lay spermatophores, which are protein-filled capsules, on plant matter in and around ponds. Spermatophores are exposed to the environment before use by females in internal …

Earthworm Remyelination Gene Expression Analysis, Shelby Shevik

Honors Capstones

Capstone submitted as a graduation requirement for the BSU Honors Program.

Methylation Of Leukocyte Dna And Ovarian Cancer: Relationships With Disease Status And Outcome, Brooke L. Fridley, Sebastian M. Armasu, Mine S. Cicek, Melissa C. Larson, Chen Wang, Stacey J. Winham, Kimberly R. Kalli, Devin C. Koestler

Dartmouth Scholarship

Genome-wide interrogation of DNA methylation (DNAm) in blood-derived leukocytes has become feasible with the advent of CpG genotyping arrays. In epithelial ovarian cancer (EOC), one report found substantial DNAm differences between cases and controls; however, many of these disease-associated CpGs were attributed to differences in white blood cell type distributions. We examined blood-based DNAm in 336 EOC cases and 398 controls; we included only high-quality CpG loci that did not show evidence of association with white blood cell type distributions to evaluate association with case status and overall survival.

Naturalized Offspring From An 85-Year-Old Chinese Chestnut (Castanea Mollissima) Planting: Stand Dynamics And Genetic Relationships, Amy Christel Miller

Open Access Theses

Chestnuts, members of the genus Castanea , family Fagaceae, are valuable worldwide, and all species have noteworthy ecological, economic, and cultural importance in their native ranges. Historically, American chestnut (Castanea dentata (Marshall) Borkh.) was an abundant tree species in eastern North America until its decimation in the early 20 th century by chestnut blight, caused by the fungus Cryphonectria parasitica . To regain the benefits of this prized species in North America, efforts are ongoing to produce and introduce blight-resistant hybrids of C. dentata and the blight-resistant Chinese chestnut ( C. mollissima Blume). It is important that the C. …

Deletion Mutant Library For Investigation Of Functional Outputs Of Cyclic Diguanylate Metabolism In Pseudomonas Aeruginosa Pa14, Dae-Gon Ha, Megan E. Richman, George A. O'Toole

Dartmouth Scholarship

We constructed a library of in-frame deletion mutants targeting each gene in Pseudomonas aeruginosa PA14 predicted to participate in cyclic di-GMP (c-di-GMP) metabolism (biosynthesis or degradation) to provide a toolkit to assist investigators studying c-di-GMP-mediated regulation by this microbe. We present phenotypic assessments of each mutant, including biofilm formation, exopolysaccharide (EPS) production, swimming motility, swarming motility, and twitch motility, as a means to initially characterize these mutants and to demonstrate the potential utility of this library.

How To Get The Most From Microarray Data: Advice From Reverse Genomics, Ivan P. Gorlov, Ji-Yeon Yang, Jinyoung Byun, Christopher Logothetis, Olga Y. Gorlova, Kim-Anh Do, Christopher Amos

Dartmouth Scholarship

Whole-genome profiling of gene expression is a powerful tool for identifying cancer-associated genes. Genes differentially expressed between normal and tumorous tissues are usually considered to be cancer associated. We recently demonstrated that the analysis of interindividual variation in gene expression can be useful for identifying cancer associated genes. The goal of this study was to identify the best microarray data–derived predictor of known cancer associated genes. We found that the traditional approach of identifying cancer genes—identifying differentially expressed genes—is not very efficient. The analysis of interindividual variation of gene expression in tumor samples identifies cancer-associated genes more effectively. The results …

Responsible Integration Of Biological And Psychosocial Models: Comments On “Genetic Associations With Intimate Partner Violence In A Sample Of Hazardous Drinking Men In Batterer Intervention Programs”, Antonia Abbey

Psychology Faculty Research Publications

Despite research demonstrating that gene expression differs in response to social environmental circumstances, deterministic views of biology are common. Stuart and colleagues (this issue) encourage readers to think about genetic factors in the same dynamic and probabilistic manner that they consider other causes of intimate partner violence. Given that participants had co-occurring alcohol problems, future studies should evaluate how different genetic polymorphisms uniquely and synergistically contribute to heavy drinking and aggression under different socio-environmental conditions. Psychological expectancies have a powerful impact on behavior, thus extreme caution is required before labeling people as genetically predisposed to violence.

Gene And Protein Sequence Optimization For High-Level Production Of Fully Active And Aglycosylated Lysostaphin In Pichia Pastoris, Hongliang Zhao, Kristina Blazanovic, Yoonjoo Choi, Chris Bailey-Kellogg, Karl E. Griswold

Dartmouth Scholarship

Lysostaphin represents a promising therapeutic agent for the treatment of staphylococcal infections, in particular those of methicillin-resistant Staphylococcus aureus (MRSA). However, conventional expression systems for the enzyme suffer from various limitations, and there remains a need for an efficient and cost-effective production process to facilitate clinical translation and the development of nonmedical applications. While Pichia pastoris is widely used for high-level production of recombinant proteins, there are two major barriers to the production of lysostaphin in this industrially relevant host: lack of expression from the wild-type lysostaphin gene and aberrant glycosylation of the wild-type protein sequence. The first barrier can …

Trip/Nopo E3 Ubiquitin Ligase Promotes Ubiquitylation Of Dna Polymerase Η, Heather A. Wallace, Julie A. Merkle, Michael C. Yu, Taloa G. Berg, Ethan Lee, Giovanni Bosco, Laura A. Lee

Dartmouth Scholarship

We previously identified a Drosophila maternal effect-lethal mutant named ‘no poles’ (nopo). Embryos from nopo females undergo mitotic arrest with barrel-shaped, acentrosomal spindles during the rapid cycles of syncytial embryogenesis because of activation of a Chk2-mediated DNA checkpoint. NOPO is the Drosophila homolog of human TNF receptor associated factor (TRAF)-interacting protein (TRIP), which has been implicated in TNF signaling. NOPO and TRIP contain RING domains closely resembling those of known E3 ubiquitin ligases. We herein sought to elucidate the mechanism by which TRIP/NOPO promotes genomic stability by performing a yeast two-hybrid screen to identify potential substrates/interactors. We identified members of …

Finding Fault?: Exploring Legal Duties To Return Incidental Findings In Genomic Research, Elizabeth R. Pike, Karen H. Rothenberg, Benjamin E. Berkman

Faculty Scholarship

The use of whole genome sequencing in biomedical research is expected to produce dramatic advances in human health. The increasing use of this powerful, data-rich new technology in research, however, will inevitably give rise to incidental findings (IFs), findings with individual health or reproductive significance that are beyond the aims of the particular research, and the related questions of whether and to what extent researchers have an ethical obligation to return IFs. Many have concluded that researchers have an ethical obligation to return some findings in some circumstances, but have provided vague or context-dependent approaches to determining which IFs must …

Origins Of The Classical Gene Concept, 1900–1950: Genetics, Mechanistic, Philosophy, And The Capitalization Of Agriculture, Garland E. Allen

Biology Faculty Research

In the period of “classical genetics” (roughly 1915–1950), the common view of the gene was mechanistic—that is, genes were seen as individual, atomistic units, as material components of the chromosomes. Although it was recognized early on that genes could interact and influence each other’s expression, they were still regarded as individually functioning units, much like the chemists’ atoms or molecules. Although geneticists in particular knew the story was more complex, the atomistic gene remained the central view for a variety of reasons. It fit the growing philosophy of mechanistic materialism in the life sciences, as biologists tried to make their …

Phenotypes And Variants In Cases Submitted For X-Linked Intellectual Disability (Xlid) Gene Panel Testing, Michael J. Friez

Theses and Dissertations

Intellectual disability (ID) refers to reduced cognitive function, apparent before the age of 18, that negatively affects a person's learning and adaptive capacity. Approximately 1-3% of the population is affected with ID, males more than females, and most in the mild-to-moderate range. ID creates financial, logistical and psychosocial challenges for affected persons and their families and caregivers. It is estimated that up to 50% of ID has a genetic cause. Molecular genetic diagnosis may help in obtaining services and has important implications for family members, but can be elusive. Genes causing ID are known to be over-represented on the X …

Linking Molecular, Electrical And Anatomical Properties Of Human Epileptic Brain, Shruti Bagla

Wayne State University Dissertations

Epilepsy is a common neurological disorder of recurrent unprovoked seizures. It affects almost 1% of the world population. Although there is a wide range of anti-epileptic drugs (AEDs) available, they only treat the seizure symptoms and do not cure the disease itself. The poor role of AEDs can be attributed to the lack of knowledge of exact mechanisms and networks that produce epileptic activities in the neocortex. At present, the best cure for epilepsy is surgical removal of electrically localized epileptic brain tissue. Surgically removed brain tissue presents an excellent opportunity to discover the molecular and cellular basis of human …

Walking The Edge With Controversial Use Of Preimplantation Genetic Diagnosis (Pgd): Opinions And Attitudes Of Genetic Counselors, Kristen Everton

Theses and Dissertations

Purpose: This study explored opinions and attitudes of genetic counselors regarding three controversial applications of preimplantation genetic diagnosis (PGD): PGD for early-onset Alzheimer, use of embryos that are BRCA positive after PGD revealed no disease-free embryos to be available, and PGD to select against a variant of unknown significance (VUS) for Marfan syndrome. Methods: Genetic counselors were contacted through the National Society of Genetic Counselors (NSGC) electronic mailing list. Inclusion criteria required that a participant was currently practicing as a genetic counselor, was a member of the NSGC, and has counseled patients about PGD. Twenty-nine participants volunteered to participate and …

Understanding Crx-Associated Retinopathies Using Animal Models, Nicholas Minh Abell Tran

All Theses and Dissertations (ETDs)

Cone-rod homeobox: CRX) protein is a "paired-like" homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa: RP), Cone-Rod Dystrophy: CoRD) and Leber Congenital Amaurosis: LCA), with variable severity. The goal of my dissertation project was to develop and characterize animal models to understand genetic mechanisms of phenotypic diversity in CRX-associated disease. Heterozygous Crx Knock-Out: KO) mice: "+/-") have normal vision as adults and fail to model the dominant human disease.

We generated two Crx Knock-IN: K-IN) mouse models: CrxE168d2: "E168d2") and CrxR90W: "R90W"), which …