Genetics and Genomics Commons^™

Predictors Of Response And Genetic Resistance/Susceptibility In Pigs To Infection With Porcine Reproductive And Respiratory Syndrome Virus, Donald G. Levis, Rodger K. Johnson,, Thomas A. Rathje, Fernando A. Osorio

Department of Animal Science: Faculty Publications

The primary objective of this study was to determine differences in growth rate and expression of specific immune function genes and levels of cytokines between pigs that are more resistant and more susceptible to PRRSV infection. The data generated in this replication were combined with data from a previous replication. At 34 ± 5 days of age (8.2 ± 1.8 kg body weight), 220 weaned pigs free of PRRSV were transported from their farm of origin to the wean-to-finish barn at the Haskell Agricultural Laboratory. The pigs were randomly allotted to one of 16 pens (2.4 m x 4.3 m) …

Minimum Criteria For Dna Damage-Induced Phase Advances In Circadian Rhythms, Christian I. Hong, Judit Zámborszky, Attila Csikász-Nagy

Dartmouth Scholarship

Robust oscillatory behaviors are common features of circadian and cell cycle rhythms. These cyclic processes, however, behave distinctively in terms of their periods and phases in response to external influences such as light, temperature, nutrients, etc. Nevertheless, several links have been found between these two oscillators. Cell division cycles gated by the circadian clock have been observed since the late 1950s. On the other hand, ionizing radiation (IR) treatments cause cells to undergo a DNA damage response, which leads to phase shifts (mostly advances) in circadian rhythms. Circadian gating of the cell cycle can be attributed to the cell cycle …

Role Of The Genomics Revolution In Pharmaceutics, Daniel A. Brazeau, Gayle A. Brazeau

Pharmaceutical Sciences Faculty Publications

Highlights the examples of Thiopurine S-methyltransferase (TPMT) and Warfarin as a means of describing some of the problems that are common to many pharmacogenetic cases. The pharmacogenetic literature contains many examples of confusing, or even contradictory, studies that arise due to unknown environmental factors that result in poor outcomes; drugs whose metabolism/transport are affected by multiple genes in multiple pathways; and clinically important genes that have many rare allelic variants with similar phenotypes variation in the frequencies of allelic variants among ethnic groups that mask the role of any one variant. These issues are common to most gene/drug dynamics and …

Multiple Genes On Chromosome 7 Regulate Dopaminergic Amacrine Cell Number In The Mouse Retina, Irene E. Whitney, Mary A. Day, Daniel C. Ciobanu, Robert W. Williams, Benjamin E. Reese

Department of Animal Science: Faculty Publications

Purpose—The size of neuronal populations is modulated by gene variants that influence cell production and survival, in turn influencing neuronal connectivity, function, and disease risk. The size of the dopaminergic amacrine (DA) cell population is a highly heritable trait exhibiting six-fold variation among inbred strains of mice, and is used here to identify genes that modulate the number of DA cells.

Methods—The entire population was counted in retinal wholemounts from 37 genetically defined lines of mice, including six standard inbred strains, 25 recombinant inbred strains (AXB/BXA), reciprocal F1 hybrids, a chromosome (Chr) 7 consomic line, and three additional …

Molecular Analysis Of The Genetic Heterogeneity Between Primary And Recurrent Glioblastoma, Anushi Shah

Renée Crown University Honors Thesis Projects - All

Introduction: Glioblastoma multiforme (GBM) is one of the deadliest forms of brain cancer, and affects more than 18,000 new cases each year in the United States alone. The current standard of treatment for GBM includes surgical removal of the tumor, along with radiation and chemotherapy. Despite these treatments, recurrence of GBM is extremely common, and once it recurs, the life expectancy is measured in weeks or months. One of the reasons for the deadly nature of the recurrent GBM is thought to be selection for therapy-resistant tumor cells. In this project, we sought to characterize the molecular changes in recurrent …

Comparative Genomics And Molecular Evolution: New Genomic Resources For The Hymenoptera And Evolutionary Studies On The Genes Of The Nasonia Vitripennis Hox Complex., Monica Munoz-Torres

All Dissertations

Research on insects, the most successful group from all metazoans on earth, has important societal, as well as scientific benefits. Insects occupy a wide range of roles, which have an effect on human life either because the former pose serious threats to public health and commercial crops as well as in some cases represent the only way to propagate food resources. Despite their tremendous importance, insect genomics remained an uneven territory dominated by studies in the Drosophila group and the mosquitoes. This dissertation attempts to: 1) report on advances in the development and characterization of genomic tools for species of …

Application Of Microsatellite/Ssr Markers For The Identification Of Peach Rootstocks And Chromosomal Regions Associated With The Response To Peach Tree Short Life Syndrome, Xiaoyu Liu

All Dissertations

Peach Tree Short Life (PTSL) is a complicated disease syndrome involving nematodes, temperature, soil conditions, pruning and secondary pathogens. The disease occurs commonly in the southeastern U.S., and possibly in other areas of the U.S., Europe, South America and South Africa as the related Bacterial Canker Complex. PTSL causes premature tree death during the 3rd or 4th year after planting, resulting in large economic losses for growers. Recently, Guardian® &lsquo BY520-9&rsquo rootstock was selected for its tolerance to PTSL; however, the genetic basis for this tolerance remains unknown.
Nemaguard, a PTSL susceptible rootstock, and Guardian® selection 3-17-7 were crossed. Each …

Resampling-Based Multiple Hypothesis Testing With Applications To Genomics: New Developments In The R/Bioconductor Package Multtest, Houston N. Gilbert, Katherine S. Pollard, Mark J. Van Der Laan, Sandrine Dudoit

U.C. Berkeley Division of Biostatistics Working Paper Series

The multtest package is a standard Bioconductor package containing a suite of functions useful for executing, summarizing, and displaying the results from a wide variety of multiple testing procedures (MTPs). In addition to many popular MTPs, the central methodological focus of the multtest package is the implementation of powerful joint multiple testing procedures. Joint MTPs are able to account for the dependencies between test statistics by effectively making use of (estimates of) the test statistics joint null distribution. To this end, two additional bootstrap-based estimates of the test statistics joint null distribution have been developed for use in the …

Sitehound-Web: A Server For Ligand Binding Site Identification In Protein Structures, Marylens Hernandez, Dario Ghersi, Roberto Sanchez

Interdisciplinary Informatics Faculty Publications

SITEHOUND-web (http://sitehound.sanchezlab.org) is a binding-site identification server powered by the SITEHOUND program. Given a protein structure in PDB format SITEHOUND-web will identify regions of the protein characterized by favorable interactions with a probe molecule. These regions correspond to putative ligand binding sites. Depending on the probe used in the calculation, sites with preference for different ligands will be identified. Currently, a carbon probe for identification of binding sites for drug-like molecules, and a phosphate probe for phosphorylated ligands (ATP, phoshopeptides, etc.) have been implemented. SITEHOUND-web will display the results in HTML pages including an interactive 3D representation of …

Evaluation Of Statistical Methods For Normalization And Differential Expression In Mrna-Seq Experiments, James H. Bullard, Elizabeth A. Purdom, Kasper D. Hansen, Sandrine Dudoit

U.C. Berkeley Division of Biostatistics Working Paper Series

The focus of this article is on the design and analysis of mRNA-Seq experiments, with the aim of inferring transcript levels and identifying differentially expressed genes. We investigate two mRNA-Seq datasets obtained using Illumina's Genome Analyzer platform to measure transcript levels in reference samples considered in the MicroArray Quality Control (MAQC) Project. We address the following four main issues: (1) exploratory data analysis for mapped reads, relating read counts to variables describing input samples and genomic regions of interest; (2) assessment and quantitation of biological effects (e.g., expression levels in Brain vs. UHR) and nuisance experimental effects (e.g., library preparation, …

Gene Set Enrichment Analysis Made Simple, Rafael A. Irizarry, Chi Wang, Yun Zhou, Terence P. Speed

Johns Hopkins University, Dept. of Biostatistics Working Papers

Among the many applications of microarray technology, one of the most popular is the identification of genes that are differentially expressed in two conditions. A common statistical approach is to quantify the interest of each gene with a p-value, adjust these p-values for multiple comparisons, chose an appropriate cut-off, and create a list of candidate genes. This approach has been criticized for ignoring biological knowledge regarding how genes work together. Recently a series of methods, that do incorporate biological knowledge, have been proposed. However, many of these methods seem overly complicated. Furthermore, the most popular method, Gene Set Enrichment Analysis …

Correcting The Site Frequency Spectrum For Divergence-Based Ascertainment, Andrew D. Kern

Dartmouth Scholarship

Comparative genomics based on sequenced referenced genomes is essential to hypothesis generation and testing within population genetics. However, selection of candidate regions for further study on the basis of elevated or depressed divergence between species leads to a divergence-based ascertainment bias in the site frequency spectrum within selected candidate loci. Here, a method to correct this problem is developed that obtains maximum-likelihood estimates of the unascertained allele frequency distribution using numerical optimization. I show how divergence-based ascertainment may mimic the effects of natural selection and offer correction formulae for performing proper estimation into the strength of selection in candidate regions …

The C. Elegans Snail Homolog Ces-1 Can Activate Gene Expression In Vivo And Share Targets With Bhlh Transcription Factors, John S. Reece-Hoyes, Bart Deplancke, M. Inmaculada Barrasa, Julia Hatzold, Ryan B. Smit, H Efsun Arda, Patricia A. Pope, Jeb Gaudet, Barbara Conradt, Albertga J.M. Walhout

Dartmouth Scholarship

Snail-type transcription factors (TFs) are found in numerous metazoan organisms and function in a plethora of cellular and developmental processes including mesoderm and neuronal development, apoptosis and cancer. So far, Snail-type TFs are exclusively known as transcriptional repressors. They repress gene expression by recruiting transcriptional co-repressors and/or by preventing DNA binding of activators from the basic helix-loop-helix (bHLH) family of TFs to CAGGTG E-box sequences. Here we report that the Caenorhabditis elegans Snail-type TF CES-1 can activate transcription in vivo. Moreover, we provide results that suggest that CES-1 can share its binding site with bHLH TFs, in different tissues, …

Generalized Liquid Association, Yen-Yi Ho, Leslie Cope, Thomas A. Louis, Giovanni Parmigiani

Johns Hopkins University, Dept. of Biostatistics Working Papers

The analysis of interactions among a group of genes is fundamental to fur- ther our understanding of their biological interactions in a cell. Several studies suggested that the co-expression relationship of two genes can be modulated by a third controller gene. These controller genes and the corresponding modulated co-expressed gene pairs are the subjects of interests in this study. This described \controller-modulated genes" three-way interactions is referred as liquid association in the literature. Analysis of gene expression data has suggested that these interactions are present in many biological systems.

To quantify the magnitude of liquid association for a given gene …

Characterization Of Conserved Properties Of Hemagglutinin Of H5n1 And Human Influenza Viruses: Possible Consequences For Therapy And Infection Control, Veljko Veljkovic, Nevena Veljkovic, Claude P. Muller, Sybille Müller, Sanja Glisic, Vladimir Perovic, Heinz Köhler

Microbiology, Immunology, and Molecular Genetics Faculty Publications

BACKGROUND: Epidemics caused by highly pathogenic avian influenza virus (HPAIV) are a continuing threat to human health and to the world's economy. The development of approaches, which help to understand the significance of structural changes resulting from the alarming mutational propensity for human-to-human transmission of HPAIV, is of particularly interest. Here we compare informational and structural properties of the hemagglutinin (HA) of H5N1 virus and human influenza virus subtypes, which are important for the receptor/virus interaction.

RESULTS: Presented results revealed that HA proteins encode highly conserved information that differ between influenza virus subtypes H5N1, H1N1, H3N2, H7N7 and defined an …

Joint Multiple Testing Procedures For Graphical Model Selection With Applications To Biological Networks, Houston N. Gilbert, Mark J. Van Der Laan, Sandrine Dudoit

U.C. Berkeley Division of Biostatistics Working Paper Series

Gaussian graphical models have become popular tools for identifying relationships between genes when analyzing microarray expression data. In the classical undirected Gaussian graphical model setting, conditional independence relationships can be inferred from partial correlations obtained from the concentration matrix (= inverse covariance matrix) when the sample size n exceeds the number of parameters p which need to estimated. In situations where n < p, another approach to graphical model estimation may rely on calculating unconditional (zero-order) and first-order partial correlations. In these settings, the goal is to identify a lower-order conditional independence graph, sometimes referred to as a ‘0-1 graphs’. For either choice of graph, model selection may involve a multiple testing problem, in which edges in a graph are drawn only after rejecting hypotheses involving (saturated or lower-order) partial correlation parameters. Most multiple testing procedures applied in previously proposed graphical model selection algorithms rely on standard, marginal testing methods which do not take into account the joint distribution of the test statistics derived from (partial) correlations. We propose and implement a multiple testing framework useful when testing for edge inclusion during graphical model selection. Two features of our methodology include (i) a computationally efficient and asymptotically valid test statistics joint null distribution derived from influence curves for correlation-based parameters, and (ii) the application of empirical Bayes joint multiple testing procedures which can effectively control a variety of popular Type I error rates by incorpo- rating joint null distributions such as those described here (Dudoit and van der Laan, 2008). Using a dataset from Arabidopsis thaliana, we observe that the use of more sophisticated, modular approaches to multiple testing allows one to identify greater numbers of edges when approximating an undirected graphical model using a 0-1 graph. Our framework may also be extended to edge testing algorithms for other types of graphical models (e.g., for classical undirected, bidirected, and directed acyclic graphs).

Borrelia Burgdorferi Ebfc Defines A Newly-Identified, Widespread Family Of Bacterial Dna-Binding Proteins, Sean P. Riley, Tomasz Bykowski, Anne E. Cooley, Logan H. Burns, Kelly Babb, Catherine A. Brissette, Amy Bowman, Matthew L. Rotondi, M. Clarke Miller, Edward Demoll, Kap Lim, Michael G. Fried, Brian Stevenson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The Lyme disease spirochete, Borrelia burgdorferi, encodes a novel type of DNA-binding protein named EbfC. Orthologs of EbfC are encoded by a wide range of bacterial species, so characterization of the borrelial protein has implications that span the eubacterial kingdom. The present work defines the DNA sequence required for high-affinity binding by EbfC to be the 4 bp broken palindrome GTnAC, where ‘n’ can be any nucleotide. Two high-affinity EbfC-binding sites are located immediately 5′ of B. burgdorferi erp transcriptional promoters, and binding of EbfC was found to alter the conformation of erp promoter DNA. Consensus EbfC-binding …

Altered Regulation Of Aquaporin Gene Expression In Allergen And Il-13-Induced Mouse Models Of Asthma, Carissa M. Krane, Bijia Deng, Venkateshwar Mutyam, Casey A. Mcdonald, Stephen Pazdziorko, Lawrence Mason, Samuel Goldman, Marion Kasaian, Divya Chaudhary, Cara Williams, Melisa W.Y. Ho

Biology Faculty Publications

IL-13 is known to affect many processes that contribute to an asthmatic phenotype, including inflammation, fibrosis, and mucus production. Members of the aquaporin (AQP) family of transmembrane water channels are targets of regulation in models of lung injury and inflammation. Therefore, we examined AQP mRNA and protein expression in allergen and IL-13-induced mouse models of asthma. Lungs from ovalbumin sensitized and ovalbumin challenged (OVA/OVA) and IL-13 treated mice showed airway thickening, increased mucus production, and pulmonary eosinophilia. Pulmonary function tests showed a significant increase in methacholine-induced airway hyperreactivity in OVA/OVA and IL-13-treated mice as compared with controls. Quantitative PCR analysis …

Velo-Cardio-Facial Syndrome, Doron Gothelf, Amos Frisch, Elena Michaelovsky, Abraham Weizman, Robert J. Shprintzen

Communication Disorders Faculty Publications

Velocardiofacial syndrome (VCFS), also known as DiGeorge, conotruncal anomaly face, and Cayler syndromes, is caused by a microdeletion in the long arm of Chromosome 22. We review the history of the syndrome from the first clinical reports almost half a century ago to the current intriguing molecular findings associating genes from the microdeletion region and the physical and neuropsychiatric phenotype of the syndrome. Velocardiofacial syndrome has a wide spectrum of more than 200 physical manifestations including palate and cardiac anomalies. Yet, the most challenging manifestations of VCFS are the learning disabilities and neuropsychiatric disorders. As VCFS is relatively common and …

Long-Term Survival After Multidisciplinary Management Of Resected Pancreatic Adenocarcinoma, Matthew H G Katz, Huamin Wang, Jason B Fleming, Charlotte C Sun, Rosa F Hwang, Robert A Wolff, Gauri Varadhachary, James L Abbruzzese, Christopher H Crane, Sunil Krishnan, Jean-Nicolas Vauthey, Eddie K Abdalla, Jeffrey E Lee, Peter W T Pisters, Douglas B Evans

Faculty, Staff and Student Publications

INTRODUCTION: Actual 5-year survival rates of 10-18% have been reported for patients with resected pancreatic adenocarcinoma (PC), but the use of multimodality therapy was uncommon in these series. We evaluated long-term survival and patterns of recurrence in patients treated for PC with contemporary staging and multimodality therapy.

METHODS: We analyzed 329 consecutive patients with PC evaluated between 1990 and 2002 who underwent resection. Each received a multidisciplinary evaluation and a standard operative approach. Pre- or postoperative chemotherapy and/or chemoradiation were routine. Surgical specimens of 5-year survivors were re-reviewed. A multivariate model of factors associated with long-term survival was constructed.

RESULTS: …

When Old-Order Amish Meet New Order Science: Genetic Maladies And The Amish Dilemma, Kelley Downey

Undergraduate Research Conference

The Old World Amish, an Anabaptist Christian domination in the United States and Canada are know for their plain dress, avoidance of modern technology, and separation from the mainstream society.

A traditional agricultural religious group, the Old World Amish maintains isolation from the rest of the community. Financially well-off, they are homogeneous on education, occupation by gender, age at marriage, religion/ethnicity, and health care.

Although the Amish strongly discourage marriage between close cousins, the Lancaster Amish genealogy is described as mutational - inbreeding from multiple, remote connections rather than close consanguinity (first-cousin marriages).

Amish settlements have been identified with certain …

Comparison Of Replication-Competent, First Generation, And Helper-Dependent Adenoviral Vaccines, Eric A. Weaver, Pramod N. Nehete, Stephanie S. Buchl, Julien S. Senac, Donna Palmer, Philip Ng, K. Jagannadha Sastry, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

All studies using human serotype 5 Adenovirus (Ad) vectors must address two major obstacles: safety and the presence of pre-existing neutralizing antibodies. Helper-Dependent (HD) Ads have been proposed as alternative vectors for gene therapy and vaccine development because they have an improved safety profile. To evaluate the potential of HD-Ad vaccines, we compared replication-competent (RC), first-generation (FG) and HD vectors for their ability to induce immune responses in mice. We show that RC-Ad5 and HD-Ad5 vectors generate stronger immune responses than FG-Ad5 vectors. HD-Ad5 vectors gave lower side effects than RC or FG-Ad, producing lower levels of tissue damage and …

Multifactor Dimensionality Reduction Analysis Identifies Specific Nucleotide Patterns Promoting Genetic Polymorphisms, Eric Arehart, Scott Gleim, Bill White, John Hwa, Jason H. Moore

Dartmouth Scholarship

The fidelity of DNA replication serves as the nidus for both genetic evolution and genomic instability fostering disease. Single nucleotide polymorphisms (SNPs) constitute greater than 80% of the genetic variation between individuals. A new theory regarding DNA replication fidelity has emerged in which selectivity is governed by base-pair geometry through interactions between the selected nucleotide, the complementary strand, and the polymerase active site. We hypothesize that specific nucleotide combinations in the flanking regions of SNP fragments are associated with mutation.

Comparison Of Gene Ontology Term Annotations Between E.Coli K12 Databases, Reddysailaja Marpuri

Student Research Conference Select Presentations

The objective of this project was to get up-to-date functional information on all genes of E.coli K12 strains based on Genome Ontology terms. Gene Ontology is described by a defined library of terms related the biological process, cellular components and molecular functions of a gene in an organism. The genome sequence of an organism gains its value when it is annotated with gene ontology terms, which bridges the gap from the sequence to the biology of an organism. Since we use annotated gene database in the prediction of the function of newly sequenced genes, it is important to have databases …

A Novel Topology For Representing Protein Folds, Mark R. Segal

COBRA Preprint Series

Various topologies for representing three dimensional protein structures have been advanced for purposes ranging from prediction of folding rates to ab initio structure prediction. Examples include relative contact order, Delaunay tessellations, and backbone torsion angle distributions. Here we introduce a new topology based on a novel means for operationalizing three dimensional proximities with respect to the underlying chain. The measure involves first interpreting a rank-based representation of the nearest neighbors of each residue as a permutation, then determining how perturbed this permutation is relative to an unfolded chain. We show that the resultant topology provides improved association with folding and …

Detection Of Cwd Prions In Urine And Saliva Of Deer By Transgenic Mouse Bioassay, Nicholas J. Haley, Davis M. Seelig, Mark D. Zabel, Glenn C. Telling, Edward A. Hoover

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Chronic wasting disease (CWD) is a prion disease affecting captive and free-ranging cervids (e.g. deer, elk, and moose). The mechanisms of CWD transmission are poorly understood, though bodily fluids are thought to play an important role. Here we report the presence of infectious prions in the urine and saliva of deer with chronic wasting disease (CWD). Prion infectivity was detected by bioassay of concentrated, dialyzed urine and saliva in transgenic mice expressing the cervid PrP gene (Tg[CerPrP] mice). In addition, PrP(CWD) was detected in pooled and concentrated urine by protein misfolding cyclic amplification (PMCA). The concentration of abnormal prion protein …

Fitting Ace Structural Equation Models To Case-Control Family Data, Kristin N. Javaras, James I. Hudson, Nan M. Laird

COBRA Preprint Series

Investigators interested in whether a disease aggregates in families often collect case-control family data, which consist of disease status and covariate information for families selected via case or control probands. Here, we focus on the use of case-control family data to investigate the relative contributions to the disease of additive genetic effects (A), shared family environment (C), and unique environment (E). To this end, we describe a ACE model for binary family data and then introduce an approach to fitting the model to case-control family data. The structural equation model, which has been described previously, combines a general-family extension of …

Ab Initio Exon Definition Using An Information Theory-Based Approach, Peter K. Rogan

Biochemistry Publications

Transcribed exons in genes are joined together at donor and acceptor splice sites precisely and efficiently to generate mRNAs capa ble of being translated into proteins. The sequence variability in individual splice sites can be modeled using Shannon information theory. In the laboratory, the degree of individual splice site use is inferred from the structures of mRNAs and their relative abundance. These structures can be predicted using a bipartite information theory framework that is guided by current knowledge of biological mechanisms for exon recognition. We present the results of this analysis for the complete dataset of all expressed human exons.

Constructing And Using Case Studies In Genetics To Engage Students In Active Learning, Sue Styer

Faculty Publications & Research

One of the national goals in science education is to teach science in a way that mirrors the process of science as inquiry, described by the National Science Education Standards (NSES) Science Teaching Standard B and Content Standard A (NRC, 1996). Inquiry-based learning, including the use of case studies, is one of several types of active learning that allows students to experience critical thinking skills inherent in the science process (Handelsman et al., 2007). Using case studies also develops skills in group learning and personalizes and humanizes science, making it more relevant to students (National Center for Case Study Teaching …

Wnt And Egf Pathways Act Together To Induce C. Elegans Male Hook Development, Hui Yu, Adeline Seah, Michael A. Herman, Edwin L. Ferguson, H. Robert Horvitz, Paul W. Sternberg

School of Biological Sciences: Faculty Publications

Comparative studies of vulva development between Caenorhabditis elegans and other nematode species have provided some insight into the evolution of patterning networks. However, molecular genetic details are available only in C. elegans and Pristionchus pacificus. To extend our knowledge on the evolution of patterning networks, we studied the C. elegans male hook competence group (HCG), an equivalence group that has similar developmental origins to the vulval precursor cells (VPCs), which generate the vulva in the hermaphrodite. Similar to VPC fate specification, each HCG cell adopts one of three fates (1°, 2°, 3°), and 2° HCG fate specification …