Genetics and Genomics Commons^™

The Principal Genetic Determinants For Nasopharyngeal Carcinoma In China Involve The Hla Class I Antigen Recognition Groove, Minzhong Tang, J. A. Lautenberger, Xiaojiang Gao, Efe Sezgin, Sher L. Hendrickson, Jennifer L. Troyer, Victor A. David, Li Guan, Carl Mcintosh, Xiuchan Guo, Yuming Zheng, Jian Liao, Hong Deng, Michael Malasky, Bailey Kessing, Cheryl Winkler, Mary Carrington, Guy De The, Yi Zeng, Stephen J. O'Brien

Biology Faculty Articles

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (P_{HLA-A-aa-site-62}= 7.4×10⁻²⁹; P _{HLA-B-aa-site-116}= 6.5×10⁻¹⁹; P _{HLA-C-aa-site-156} = 6.8×10 …

Inla Promotes Dissemination Of Listeria Monocytogenes To The Mesenteric Lymph Nodes During Food Borne Infection Of Mice, Elsa N. Bou Ghanem, Grant S. Jones, Tanya Myers-Morales, Pooja D. Patil, Achmad N. Hidayatullah, Sarah E. F. D'Orazio

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Intestinal Listeria monocytogenes infection is not efficient in mice and this has been attributed to a low affinity interaction between the bacterial surface protein InlA and E-cadherin on murine intestinal epithelial cells. Previous studies using either transgenic mice expressing human E-cadherin or mouse-adapted L. monocytogenes expressing a modified InlA protein (InlA(m)) with high affinity for murine E-cadherin showed increased efficiency of intragastric infection. However, the large inocula used in these studies disseminated to the spleen and liver rapidly, resulting in a lethal systemic infection that made it difficult to define the natural course of intestinal infection. We describe here a …

Multifactorial Patterns Of Gene Expression In Colonic Epithelial Cells Predict Disease Phenotypes In Experimental Colitis, Aubrey Leigh Frantz, Maria E. C. Bruno, Eric William Rogier, Halide Tuna, Donald A. Cohen, Subbarao Bondada, Ralph Lakshman Chelvarajan, J. Anthony Brandon, C. Darrell Jennings, Charlotte S. Kaetzel

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Background— The pathogenesis of inflammatory bowel disease (IBD) is complex and the need to identify molecular biomarkers is critical. Epithelial cells play a central role in maintaining intestinal homeostasis. We previously identified five “signature” biomarkers in colonic epithelial cells (CEC) that are predictive of disease phenotype in Crohn's disease. Here we investigate the ability of CEC biomarkers to define the mechanism and severity of intestinal inflammation.

Methods— We analyzed the expression of RelA, A20, pIgR, tumor necrosis factor (TNF), and macrophage inflammatory protein (MIP)-2 in CEC of mice with dextran sodium sulfate (DSS) acute colitis or T-cell-mediated chronic colitis. …

Escherichia Coli Recg Functionally Suppresses Human Bloom Syndrome Phenotypes, Michael W. Killen, Dawn M. Stults, William A. Wilson, Andrew J. Pierce

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Defects in the human BLM gene cause Bloom syndrome, notable for early development of tumors in a broad variety of tissues. On the basis of sequence similarity, BLM has been identified as one of the five human homologs of RecQ from Escherichia coli. Nevertheless, biochemical characterization of the BLM protein indicates far greater functional similarity to the E. coli RecG protein and there is no known RecG homolog in human cells. To explore the possibility that the shared biochemistries of BLM and RecG may represent an example of convergent evolution of cellular function where in humans BLM has evolved to …

Gene Expression Analysis Of A Murine Model With Pulmonary Vascular Remodeling Compared To End-Stage Ipah Lungs, Kayoko Shimodaira, Yoichiro Okubo, Eri Ochiai, Haruo Nakayama, Harutaka Katano, Megumi Wakayama, Minoru Shinozaki, Takao Ishiwatari, Daisuke Sasai, Naobumi Tochigi, Tetsuo Nemoto, Tsutomu Saji, Katsuhiko Kamei, Kazutoshi Shibuya

Microbiology, Immunology, and Molecular Genetics Faculty Publications

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) continues to be one of the most serious intractable diseases that might start with activation of several triggers representing the genetic susceptibility of a patient. To elucidate what essentially contributes to the onset and progression of IPAH, we investigated factors playing an important role in IPAH by searching discrepant or controversial expression patterns between our murine model and those previously published for human IPAH. We employed the mouse model, which induced muscularization of pulmonary artery leading to hypertension by repeated intratracheal injection of Stachybotrys chartarum, a member of nonpathogenic and ubiquitous fungus in our …

The Search, The Jackson Laboratory

Search Magazine

No abstract provided.

Borrelia Burgdorferi Cp32 Bpab Modulates Expression Of The Prophage Nucp Nuclease And Ssbp Single-Stranded Dna-Binding Protein, Alicia M. Chenail, Brandon L. Jutras, Claire A. Adams, Logan H. Burns, Amy Bowman, Ashutosh Verma, Brian Stevenson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The Borrelia burgdorferi BpaB proteins of the spirochete's ubiquitous cp32 prophages are DNA-binding proteins, required both for maintenance of the bacteriophage episomes and for transcriptional regulation of the cp32 erp operons. Through use of DNase I footprinting, we demonstrate that BpaB binds the erp operator initially at the sequence 5′-TTATA-3′. Electrophoretic mobility shift assays indicated that BpaB also binds with high affinity to sites located in the 5′ noncoding regions of two additional cp32 genes. Characterization of the proteins encoded by those genes indicated that they are a single-stranded DNA-binding protein and a nuclease, which we named SsbP and NucP, …

Mutations In Dmrt3 Affect Locomotion In Horses And Spinal Circuit Function In Mice, Lisa S. Andersson, Martin Larhammar, Fatima Memic, Hanna Wootz, Doreen Schwochow, Carl-Johan Rubin, Kalicharan Patra, Thorvaldur Arnason, Lisbeth Wellbring, Göran Hjälm, Freyja Imsland, Jessica Lynn Petersen, Molly E. Mccue, James R. Mickelson, Gus Cothran, Nadav Ahituv, Lars Roepstorff, Sofia Mikko, Anna Vallstedt, Gabriella Lindgren, Leif Andersson, Klas Kullander

Department of Animal Science: Faculty Publications

Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement. These networks produce left–right alternation of limbs as well as coordinated activation of flexor and extensor muscles. Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favorable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes …

Atlas-Based White Matter Analysis In Individuals With Velo-Cardio-Facial Syndrome (22q11.2 Deletion Syndrome) And Unaffected Siblings, Petya D. Radoeva, Ioana L. Coman, Kevin M. Antshel, Wanda Fremont, Christopher Mccarthy, Ashwini Kotkar, Dongliang Wang, Robert J. Shprintzen, Wendy R. Kates

Communication Disorders Faculty Publications

Background: Velo-cardio-facial syndrome (VCFS, MIM#192430, 22q11.2 Deletion Syndrome) is a genetic disorder caused by a deletion of about 40 genes at the q11.2 band of one copy of chromosome 22. Individuals with VCFS present with deficits in cognition and social functioning, high risk of psychiatric disorders, volumetric reductions in gray and white matter (WM) and some alterations of the WM microstructure. The goal of the current study was to characterize the WM microstructural differences in individuals with VCFS and unaffected siblings, and the correlation of WM microstructure with neuropsychological performance. We hypothesized that individuals with VCFS would have decreased indices …

Hypoxia-Sensitive Gene Expression In The Gastrocnemius Muscle Following Chronic Hind Limb Ischemia, Andrew Tilton

Biological Sciences

Chronic ischemia, caused by the formation atherosclerotic plaque occlusions in major conduit arteries, is the leading cause of morbidity and mortality in western societies. Vascular remodeling can help compensate for the adverse effects of atherosclerotic plaque formation. Vascular remodeling relies heavily on vascular endothelial growth factor (VEGF), a critical protein that contributes to all forms of vascular formation and remodeling including angiogenesis, arteriogenesisand vasculogenesis. VEGF itself is up-regulated by the transcription factor, hypoxia inducible factor 1 alpha (HIF-1α), which becomes activated in low oxygen environments.

Through the use of animal chronic hindlimb ischemia models, these genes can be evaluated as …

Two Boundaries Separate Borrelia Burgdorferi Populations In North America, Gabriele Margos, Jean I. Tsao, Santiago Castillo-Ramirez, Yvette A. Girard, Anne G. Hoen

Dartmouth Scholarship

Understanding the spread of infectious diseases is crucial for implementing effective control measures. For this, it is important to obtain information on the contemporary population structure of a disease agent and to infer the evolutionary processes that may have shaped it. Here, we investigate on a continental scale the population structure of Borrelia burgdorferi, the causative agent of Lyme borreliosis (LB), a tick-borne disease, in North America. We test the hypothesis that the observed d population structure is congruent with recent population expansions and that these were preceded by bottlenecks mostly likely caused by the near extirpation in the 1900s …

The Effect Of Mechanical Force On Gene Expression Of Human Bladder Smooth Muscle Cells, Christopher A. Callan

PCOM Biomedical Studies Student Scholarship

The purpose of this project is to define, at the molecular level, the process by which gene expression of the extracellular matrix is regulated by mechanical forces in the Human Bladder Smooth Muscle cells (BSMCs). The goal is to first localize several functionally distinct transmembrane proteins; Sarcoglycans (α, β, γ, δ and ε), cytoskeletal proteins Vimentin, and Desmin to verify their presence in the cultured BSMCs using fluorescent-labeled antibodies specific for each protein. The sarcoglycans are primarily responsible for transferring intracellular force generated by the interaction of actin and myosin while the extracellular proteins are responsible for linking the cells …

Technical Desiderata For The Integration Of Genomic Data Into Electronic Health Records., Daniel R Masys, Gail P Jarvik, Neil F Abernethy, Nicholas R Anderson, George J Papanicolaou, Dina N Paltoo, Mark A Hoffman, Isaac S Kohane, Howard P Levy

Manuscripts, Articles, Book Chapters and Other Papers

The era of "Personalized Medicine," guided by individual molecular variation in DNA, RNA, expressed proteins and other forms of high volume molecular data brings new requirements and challenges to the design and implementation of Electronic Health Records (EHRs). In this article we describe the characteristics of biomolecular data that differentiate it from other classes of data commonly found in EHRs, enumerate a set of technical desiderata for its management in healthcare settings, and offer a candidate technical approach to its compact and efficient representation in operational systems.

Composition Of The Adult Digestive Tract Bacterial Microbiome Based On Seven Mouth Surfaces, Tonsils, Throat And Stool Samples, Nicola Segata, Susan Kinder Haake, Peter Mannon, Katherine P. Lemon, Levi Waldron, Dirk Gevers, Curtis Huttenhower, Jacques Izard

Department of Food Science and Technology: Faculty Publications

Background: To understand the relationship between our bacterial microbiome and health, it is essential to define the microbiome in the absence of disease. The digestive tract includes diverse habitats and hosts the human body’s greatest bacterial density. We describe the bacterial community composition of ten digestive tract sites from more than 200 normal adults enrolled in the Human Microbiome Project, and metagenomically determined metabolic potentials of four representative sites.

Results: The microbiota of these diverse habitats formed four groups based on similar community compositions: buccal mucosa, keratinized gingiva, hard palate; saliva, tongue, tonsils, throat; sub- and supra-gingival plaques; …

Metabolic Reconstruction For Metagenomic Data And Its Application To The Human Microbiome, Sahar Abubucker, Nicola Segata, Johannes Goll, Alyxandria M. Schubert, Jacques Izard, Brandi L. Cantarel, Beltran Rodriguez-Mueller, Jeremy Zucker, Mathangi Thiagarajan, Bernard Henrissat, Owen White, Scott T. Scott, Barbara Methé, Patrick D. Schloss, Dirk Gever, Makedonka Mitreva, Curtis Huttenhower

Department of Food Science and Technology: Faculty Publications

Microbial communities carry out the majority of the biochemical activity on the planet, and they play integral roles in processes including metabolism and immune homeostasis in the human microbiome. Shotgun sequencing of such communities’ metagenomes provides information complementary to organismal abundances from taxonomic markers, but the resulting data typically comprise short reads from hundreds of different organisms and are at best challenging to assemble comparably to single-organism genomes. Here, we describe an alternative approach to infer the functional and metabolic potential of a microbial community metagenome. We determined the gene families and pathways present or absent within a community, as …

Dna Methylation Arrays As Surrogate Measures Of Cell Mixture Distribution, Eugene Houseman, William P. Accomando, Devin C. Koestler, Brock C. Christensen, Carmen J. Marsit

Dartmouth Scholarship

There has been a long-standing need in biomedical research for a method that quantifies the normally mixed composition of leukocytes beyond what is possible by simple histological or flow cytometric assessments. The latter is restricted by the labile nature of protein epitopes, requirements for cell processing, and timely cell analysis. In a diverse array of diseases and following numerous immune-toxic exposures, leukocyte composition will critically inform the underlying immuno-biology to most chronic medical conditions. Emerging research demonstrates that DNA methylation is responsible for cellular differentiation, and when measured in whole peripheral blood, serves to distinguish cancer cases from controls.

An Integrated Bioinformatics And Computational Biology Approach Identifies New Bh3-Only Protein Candidates, Robert G. Hawley, Yuzhong Chen, Irene Riz, Chen Zeng

Anatomy and Regenerative Biology Faculty Publications

FoxD4L1 is a forkhead transcription factor that expands the neural ectoderm by down-regulating genes that promote the onset of neural differentiation and up-regulating genes that maintain proliferative neural precursors in an immature state. We previously demonstrated that binding of Grg4 to an Eh-1 motif enhances the ability of FoxD4L1 to down-regulate target neural genes but does not account for all of its repressive activity. Herein we analyzed the protein sequence for additional interaction motifs and secondary structure. Eight conserved motifs were identified in the C-terminal region of fish and frog proteins. Extending the analysis to mammals identified a high scoring …

Knowledge, Attitudes, And Utilization Of Brca Testing Among Obstetricians And Gynecologists, Salma Nassef

Dissertations and Theses (Open Access)

Hereditary breast and ovarian cancer (HBOC) is an inherited cancer syndrome that is associated with mutations in the BRCA1 and BRCA2 genes. Carriers of BRCA mutations, both men and women, are at an increased risk for developing certain cancers. Carriers are most notably at an increased risk to develop breast and ovarian cancers; however an increased risk for prostate cancer, melanoma, and pancreatic cancers has also been associated with these mutations. In 2009 the American Congress of Obstetricians and Gynecologists (ACOG) released a practice bulletin stating that evaluating a patient’s risk for HBOC should be a routine part of obstetric …

Fzd6, Matn2 And Slc25a32, Possible Candidate Genes In Nonsyndromic Cleft Lip And Palate, Nevena Cvjetkovic

Dissertations and Theses (Open Access)

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect with a multifactorial etiology. Despite decades of research, the genetic underpinnings of NSCLP still remain largely unexplained. A genome wide association study (GWAS) of a large NSCLP African American family with seven affected individuals across three generations found evidence for linkage at 8q21.3-24.12 (LOD = 2.98). This region contained three biologically relevant candidate genes: Frizzled-6 (FZD6) (LOD = 2.8), Matrilin-2 (MATN2) (LOD = 2.3), and Solute Carrier Family 25, Member 32 (SLC26A32) (LOD = 1.6). Sequencing of the coding regions and the 5’ and 3’ …

Genetic Predictors Of Hyperglycemia Due To Hydrochlorothiazide Therapy, Jorge L. Del Aguila

Dissertations and Theses (Open Access)

Response to pharmacological treatment is variable among individuals. Some patients respond favorably to a drug while others develop adverse reactions. Early investigations showed evidence of variation in genes that code for drug receptors, drug transporters, and drug metabolizing enzymes; and pharmacogenetics appeared as the science that studies the relationship between drug response and genetic variation.

Thiazide diuretics are the recommended first-line monotherapy for hypertension (i.e. SBP>140 or DBP>90). Even so, diuretics are associated with adverse metabolic side effects, such as hyperglycemia, which increase the risk of developing type 2 diabetes. Published approaches testing variation in candidate genes (e.g. …

Effects Of Thymus Size And Involution On The Contribution Of Recent Thymic Emigrants To The Peripheral T Cell Pool, Michelle L. Bolner

Dissertations and Theses (Open Access)

The contribution of recent thymic emigrants (RTEs) to the peripheral naïve T cell population is necessary to maintain diversity of the T cell receptor (TCR) repertoire and produce immune responses against newly encountered antigens.

The thymus involutes with age, after irradiation or chemotherapy, and due to severe viral infections. Thymus involution results in decreased thymopoiesis and RTE output leading to a reduced diversity of peripheral T cells. This increases susceptibility to disease and impairs immune responsiveness to vaccines. Therefore, studies aimed at maintaining or regenerating thymic function are integral for maintaining and restoring peripheral TCR diversity.

Mice that express a …

Predictors Of Contralateral Breast Cancer In Brca Negative Women, Ann E. Simmons

Dissertations and Theses (Open Access)

Breast cancer is the most common cancer diagnosis and second leading cause of death in women. Risk factors associated with breast cancer include: increased age, alcohol consumption, cigarette smoking, white race, physical inactivity, benign breast conditions, reproductive and hormonal factors, dietary factors, and family history. Hereditary breast and ovarian cancer syndrome (HBOC) is caused by mutations in the BRCA1 and BRCA2 genes. Women carrying a mutation in these genes are at an increased risk to develop a second breast cancer. Contralateral breast cancer is the most common second primary cancer in patients treated for a first breast cancer. Other risk …

Heterotopic Ossification: Cellular Basis, Symptoms, And Treatment, Brian Wolfe

Senior Honors Theses

Heterotopic ossification (HO) is the process by which calcified bone develops in soft tissues. Because of the abnormal calcification, complications such as bone deformation, loss of range of motion, and joint immobility adversely affect patients. There are many genetic types of heterotopic ossification, namely fibrodysplasia ossificans progressiva, progressive osseous heteroplasia, and Albright hereditary osteodystrophy. However, this condition can also arise from surgery, burns, or traumatic injuries, so it is seen as an important area for research in the future. There are various treatments available such as non-steroidal anti-inflammatory drugs and radiation therapy, as well as combinations of the two. The …

Resource Availability, Mortality And Fertility: A Path Analytic Approach To Global Life History Variation, Mark A. Caudell, Robert J. Quinlan

Human Biology Open Access Pre-Prints

Humans exhibit considerable diversity in timing and rate of reproduction. Life history theory suggests that ecological cues of resource richness and survival probabilities shape human phenotypes across populations. Populations experiencing high extrinsic mortality due to uncertainty in resources should exhibit faster life histories. Here we use a path analytic approach informed by life history theory to model the multiple pathways between resources, mortality rates, and reproductive behavior in 191 countries. Resources that account for the most variance in population mortality rates are predicted to explain the most variance in total fertility rates. Results indicate that resources (e.g., calories, sanitation, education, …

Association Among Obesity-Related Anthropometric Phenotypes: Analyzing Genetic And Environmental Contribution, Aline Jelenkovic, Esther Rebato

Human Biology Open Access Pre-Prints

Obesity has become a public health and policy problem in many parts of the world. Epidemiological and population studies in this field are usually based on different anthropometric measures, however, common genetic and environmental factors between these phenotypes have been scarcely studied. The objective of this work is to assess the strength of these factors on the covariation among a large set of obesity-related traits. The subject group consisted of 533 nuclear families living in the Greater Bilbao (Spain), and included 1702 individuals aged 2-61 years. Detailed anthropometric measurements (stature, breadths, circumferences and skinfolds) were carried out in each subject. …

Characterization Of Species C Human Adenovirus Serotype 6 (Ad6), Eric A. Weaver, Reeti Khare, Mathew L. Hillestad, Donna Palmer, Philip Ng, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

Adenovirus serotype (Ad5) is the most studied Ad. Ad1, 2, and 6 are also members of species C Ad and are presumed to have biologies similar to Ad5. In this work, we have compared the ability of Ad1, 2, 5, and 6 to infect liver and muscle after intravenous and intramuscular injection. We found that Ad6 was surprisingly the most potent at liver gene delivery and that Ad1 and Ad2 were markedly weaker than Ad5 and 6. To understand these differences, we sequenced the Ad6 genome. This revealed that the Ad6 fiber protein is surprisingly three shaft repeats shorter than …

Heme Oxygenase-1 Regulates The Immune Response To Influenza Virus Infection And Vaccination In Aged Mice, Nathan W. Cummins, Eric A. Weaver, Shannon M. May, Anthony J. Croatt, Oded Foreman, Richard B. Kennedy, Gregory A. Poland, Michael A. Barry, Karl A. Nath, Andrew D. Badley

Nebraska Center for Virology: Faculty Publications

Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase-1 (HO-1) expression on vaccine response and outcome of influenza infection. HO-1-deficient and wild-type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adenoviral-based influenza vaccine. A genome-wide association study evaluated the expression of single-nucleotide polymorphisms (SNPs) in the HO-1 gene and the response to influenza vaccination in healthy humans. HO-1-deficient mice had decreased survival after influenza infection compared to WT mice (median …

Dialogues, Dilemmas, And Disclosures: Genomic Research And Incidental Findings, Lynn W. Bush, Karen H. Rothenberg

Faculty Scholarship

No abstract provided.

Genes And Plays: Bringing Elsi Issues To Life, Karen H. Rothenberg, Lynn W. Bush

Faculty Scholarship

Ethical complexities surround the promise of genomic technology and the power of genetic information as they alter conceptions of identity and dynamics within personal and professional relationships. Creative approaches such as dramatic vignettes offer a unique analytical stage for imagining the bioethical past and future. Dramatic narratives can bring to life images of differing perspectives and values when experiencing innovations in medicine. Although the scientific landscape shifts, concerns expressed in theatre from 50 years ago parallel many contemporary ELSI (ethical, legal and social implications) issues, highlighting the ongoing struggle to appreciate the impact of emerging genetic technologies on relationships. To …

Emerging Viruses In The Felidae: Shifting Paradigms, Stephen J. O'Brien, Jennifer L. Troyer, Meredith Brown, Warren E. Johnson, Agostinho Antunes, Melody E. Roelke, Jill Pecon-Slattery

Biology Faculty Articles

The domestic cat is afflicted with multiple viruses that serve as powerful models for human disease including cancers, SARS and HIV/AIDS. Cat viruses that cause these diseases have been studied for decades revealing detailed insight concerning transmission, virulence, origins and pathogenesis. Here we review recent genetic advances that have questioned traditional wisdom regarding the origins of virulent Feline infectious peritonitis (FIP) diseases, the pathogenic potential of Feline Immunodeficiency Virus (FIV) in wild non-domestic Felidae species, and the restriction of Feline Leukemia Virus (FeLV) mediated immune impairment to domestic cats rather than other Felidae species. The most recent interpretations indicate important …