Genetics and Genomics Commons^™

What Lies Beneath? Molecular Evolution During The Radiation Of Caecilian Amphibians, María Torres-Sánchez, David J. Gower, David Alvarez-Ponce, Christopher J. Creevey, Mark Wilkinson, Diego San Mauro

Neuroscience Faculty Publications

Background: Evolution leaves an imprint in species through genetic change. At the molecular level, evolutionary changes can be explored by studying ratios of nucleotide substitutions. The interplay among molecular evolution, derived phenotypes, and ecological ranges can provide insights into adaptive radiations. Caecilians (order Gymnophiona), probably the least known of the major lineages of vertebrates, are limbless tropical amphibians, with adults of most species burrowing in soils (fossoriality). This enigmatic order of amphibians are very distinct phenotypically from other extant amphibians and likely from the ancestor of Lissamphibia, but little to nothing is known about the molecular changes underpinning their radiation. …

Rising Rural Body-Mass Index Is The Main Driver Of The Global Obesity Epidemic In Adults, Con Burns, Tara Coppinger, Janette Walton, Et Al

Publications

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities1,2. This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity3,4,5,6. Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to …

Extracellular Vesicle Encapsulated Micrornas In Patients With Type 2 Diabetes Are Affected By Metformin Treatment., Vikas Ghai, Taek-Kyun Kim, Alton Etheridge, Trine Nielsen, Torben Hansen, Oluf Pedersen, David Galas, Kai Wang

Articles, Abstracts, and Reports

Recently, microRNAs (miRNAs) in circulating extracellular vesicles (EVs), have emerged as a source of potential biomarkers for various pathophysiological conditions, including metabolic disorders such as diabetes. Type 2 diabetes mellitus (T2DM), is the most prevalent form of diabetes in the USA, with 30 million diagnosed patients. Identifying miRNA biomarkers that can be used to assess response to glucose lowering treatments would be useful. Using patient plasma samples from a subset of the Danish Metagenomics of the Human Intestinal Tract (MetaHIT) cohort, we characterized miRNAs from whole plasma, plasma-derived EVs, and EV-depleted plasma by small RNA-sequencing to identify T2DM associated miRNAs. …

Yeast Mitochondrial Protein Pet111p Binds Directly To Two Distinct Targets In Cox2 Mrna, Suggesting A Mechanism Of Translational Activation, Julia L Jones, Katharina B Hofmann, Andrew T Cowan, Dmitry Temiakov, Patrick Cramer, Michael Anikin

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The genes in mitochondrial DNA code for essential subunits of the respiratory chain complexes. In yeast, expression of mitochondrial genes is controlled by a group of gene-specific translational activators encoded in the nucleus. These factors appear to be part of a regulatory system that enables concerted expression of the necessary genes from both nuclear and mitochondrial genomes to produce functional respiratory complexes. Many of the translational activators are believed to act on the 5'-untranslated regions of target mRNAs, but the molecular mechanisms involved in this regulation remain obscure. In this study, we used a combination of in vivo and in …

Times Of Action And Evolutionary Conservation Of Heterochronic Genes, Maria Ivanova, Eric G. Moss

Rowan-Virtua Research Day

Specific genes called heterochronic genes control the timing and sequence of developmental events during larval stages of C. elegans. Mutations in heterochronic genes can cause skipping or reiteration of cell fates associated with certain larval stages. lin-14 and lin-28 are two well-studied heterochronic genes. LIN-14 acts during the first larval stage (L1) and controls events of the L1 and L2 stages, LIN-28 acts during the L2 stage and controls its events.

Acute Promyelocytic Leukemia: A Case Study Correlating Cytogenetic Abnormality With Prognosis, Alyssa Lamond, Theresa Tellier-Castellone

Senior Honors Projects

Advancements in medical technology today have positively impacted the diagnosis, treatment, and prognosis of cancers. Particularly acute promyelocytic leukemia (APL) has completely improved from having the poorest prognosis to one of the best. Acute promyelocytic leukemia is a malignant disease of hematopoietic tissue classified by WHO as leukemia with >20% blasts from the myeloid lineage, specifically promyelocytes. Determined in 1976, FAB classified AML subtypes M1-M7, with APL being M3. Specific characteristics classify the subtype of AML, with each resulting from a different genetic abnormality. The focus of APL diagnosis, treatment, and prognosis occurs around the known PML-RARα fusion gene. Flow …

Enhancing Face Validity Of Mouse Models Of Alzheimer's Disease With Natural Genetic Variation., Kristen D Onos, Asli Uyar, Kelly J Keezer, Harriet M Jackson, Christoph Preuss, Casey J Acklin, Rita O'Rourke, Rebecca Buchanan, Travis L Cossette, Stacey J Sukoff Rizzo, Ileana Soto Reyes, Gregory W Carter, Gareth R Howell

College of Science & Mathematics Departmental Research

Classical laboratory strains show limited genetic diversity and do not harness natural genetic variation. Mouse models relevant to Alzheimer's disease (AD) have largely been developed using these classical laboratory strains, such as C57BL/6J (B6), and this has likely contributed to the failure of translation of findings from mice to the clinic. Therefore, here we test the potential for natural genetic variation to enhance the translatability of AD mouse models. Two widely used AD-relevant transgenes, APPswe and PS1de9 (APP/PS1), were backcrossed from B6 to three wild-derived strains CAST/EiJ, WSB/EiJ, PWK/PhJ, representative of three Mus musculus subspecies. These new AD strains were …

A Dedicated Chaperone Mediates The Safe Transfer Of Mitoribosomal Proteins To Their Site Of Assembly, Gabrielle Ashley Hillman

Graduate School of Biomedical Sciences Theses and Dissertations

Mitochondrial ribosomes are functionally specialized for the synthesis of several essential inner membrane proteins of the respiratory chain. While remarkable progress has recently been made towards understanding the structure of mitoribosomes, the unique pathways and factors that facilitate their biogenesis remain largely unknown. This dissertation defines the physiological role of an evolutionarily conserved yeast protein called Mam33 in mitochondrial ribosome assembly. The biomedical relevance of this finding stems from the fact that mutations or changes in its expression of the human ortholog p32 result in mitochondrial dysfunction. In human patients, bi-allelic mutations cause severe multisystemic defects in mitochondrial energy metabolism, …

Detection Of Genetic Thrombophilia (Fa V Leiden & Pt20210 Mutation) Using Genexpert Technology With Iqcp Implementation, Mariegrace Saquilayan

Natural Sciences and Mathematics | Clinical Laboratory Sciences

Abstract

Individuals having Genetic Thrombophilia pose a higher risk of having a thrombotic event. It is crucial to determine these gene variants to prevent a possible episode of thromboembolism. With the current PCR method, it involves individual processing of DNA isolation, amplification, and detection using three (3) different instruments resulting to an increased turnaround time of 5 to 7 days and additional staff utilization. It is performed by repetitive manual sample pipetting and preparation of reagent master mixes in small vials. Results interpretations are entered manually to a worklist built initially for final verification. These processes increase the risk of …

Notch Inhibitors And The Bet Inhibitor Jq-1 Decrease The Growth Of Primary Tumor Cells Derived From A Novel Mouse Model Of C11orf95-Rela Induced Brain Tumor, Ericka Randazzo, Jesse Dunnack, Justin Fang, Joseph Loturco Phd

University Scholar Projects

Brain tumors are the most common childhood solid malignancy, and because of remarkable advances in treating many cancers outside of the brain, they have become the leading cause of cancer mortality in children. Ependymomas are a class of brain tumors which can be further subdivided into three groups based upon their location and genetic features. Of the three classes, supratentorial ependymomas are the only subgroup known to be marked by an oncogenic driver gene, which consists of a fusion mutation between the C11orf95 and RELA genes. C11orf95-RELA positive tumors are the most aggressive and lethal of …

Quantifying Expression Of Interneuron Subtype Markers For Dlx-2 Transfected Ng2 Cells, Timothy Nolan

Honors Scholar Theses

Neurons are a post-mitotic cell population, and therefore, they are not able to regenerate in vivo after a traumatic injury. Because inhibitory GABAergic interneurons and oligodendrocyte precursor cells (OPCs) are derived from the same precursor, recent studies have focused on transforming these OPCs into GABAergic neurons. However, there are different types of GABAergic interneurons that have different electrophysiological responses, which can lead to functional differences. The Nishiyama laboratory had already used a key gene in GABAergic interneuron and OPC differentiation, Distal-less homeobox 2 (Dlx-2), to transfect OPCs; early electrophysiology tests showed most of these transfected cells behaved like immature neurons, …

Platiscity Of C. Elegans Germline Stem Cells Under Nutritional And Metabolic Stress, Kenneth Trimmer

Dissertations and Theses (Open Access)

Stem cells are integral for tissue maintenance and fertility. Therefore, understanding how stem cells are regulated under stress is imperative. When confronted with acute starvation, stem cells must conserve energy and metabolites to cope with the lack of an external source. Caenorhabditis elegans germline stem cells (GSCs) are an excellent model for studying stem cell properties and regulation as they can divide throughout the life of the organism. While GSCs are an adult stem cell population, their cell cycle structure more closely mimics mouse and human embryonic stem cells with short G1 and long S phases. In this thesis, I …

Identifying Interest In And Barriers To Psychiatric Genetic Counseling, Samantha Montgomery

Dissertations and Theses (Open Access)

Mental illness is common in the United States and genetic counseling for psychiatric indications can help individuals understand multifactorial inheritance, recurrence risk estimates, and identify ways to protect their future mental health. Despite interest in and efficacy of the service documented in populations outside of the United States, individuals with personal and/or family histories of psychiatric conditions are very rarely accessing psychiatric genetic counseling services. The purpose of our study was to identify interest in and barriers to psychiatric genetic counseling with the hopes of better characterizing this population and improving access to this beneficial service in the future. An …

The Relationship Between Uncertainty Tolerance And Oncologists’ Perceptions Of Large-Panel Genomic Tumor Testing, Eric Anderson, Alexandra Hinton, Christine Lary, Kimberly Murray, Leo Waterson, Paul Han, Maine Cancer Genomics Initiative

MaineHealth Maine Medical Center

Introduction:

Large-panel genomic tumor testing (GTT) is a new technology that promises to make cancer treatment more precise, but that currently poses many uncertainties regarding its clinical value and appropriate use. Uncertainty Tolerance (UT), a psychological construct that describes trait-level differences in individuals’ responses to uncertainty, may influence oncologists’ perceptions and attitudes regarding GTT.

Community Oncology Clinicians’ Knowledge, Beliefs, And Attitudes Regarding Genomic Tumor Testing, Eric Anderson, Alexandra Hinton, Kimberly Murray, Hayley Mandeville, Caitlin Gutheil, Leo Waterston, Lee Lucas, Christine Duarte, Christian Thomas, Susan Miesfeldt, Petra Helbig, Andrey Antov, Jens Rueter, Paul Han

MaineHealth Maine Medical Center

Introduction: Genomic tumor testing (GTT) is a new technology that promises to make cancer treatment more precise. However, little is known about clinicians’ knowledge, beliefs, and attitudes regarding GTT, particularly in community oncology settings.

Physician-Patient Communication About Genomic Tumor Testing: Perceptions Of Oncology Providers, Hayley Mandeville, Eric Anderson, Kimberly Murray, Caitlin Gutheil, Leo Waterston, Lee Lucas, Christine Duarte, Christian Thomas, Susan Miesfeldt, Petra Helbig, Andrey Antov, Jens Rueter, Paul Han

MaineHealth Maine Medical Center

Background:

• Genomic tumor testing (GTT) is a new technology and a cornerstone of the “precision medicine” movement in cancer care.

• GTT uses next-generation genome sequencing technology to identify somatic variants in tumor cells.

• By identifying somatic variants that predict responses to cancer therapies, GTT can help tailor therapy to individual patients, making them more effective.

• However, due to the fact that GTT also detects many variants of uncertain significance, its clinical value is currently unproven.

• When using GTT, physicians counsel patients about both its benefits and its limitations, but the ideal goals and content of …

Hypoglycemia In Mitochondrial Disorders, Allison Moats

Dissertations and Theses (Open Access)

INTRODUCTION: The electron transport chain (ETC) in mitochondria functions to produce energy in the form of adenosine triphosphate (ATP). Defects in the mitochondrial or nuclear DNA that codes for components of the ETC lead to mitochondrial disorders (MTDs). MTDs are multi-system conditions affecting the heart, muscles, and especially brain. The endocrine system is commonly affected in MTDs, and diabetes and hyperglycemia are established secondary diagnoses. Rates of non-iatrogenic hypoglycemia have not been studied in individuals with MTDs. This study aims to investigate the frequency of hypoglycemia in patients with MTDs.

METHODS: Individuals diagnosed with a ‘definite’ or ‘probable’ …

Genetic Counselor Utilization And Interpretation Of Somatic Tumor Testing In Evaluation For Lynch Syndrome, Danielle Williams

Dissertations and Theses (Open Access)

Lynch syndrome (LS) is a hereditary cancer predisposition syndrome characterized by increased risk for colorectal and uterine cancers. Individuals with pathogenic variants in the mismatch repair (MMR) genes (MLH1, MSH2/EPCAM, MSH6, PMS2) are diagnosed with LS and subsequently recommended to proceed with high risk screening protocols to increase prevention and early detection of LS-related cancers. Various tumor studies can help identify those at high risk for LS, but sometimes create uncertainty with discordant screening and germline results, leading to unexplained mismatch repair deficiency (UMMRD). Somatic testing of the MMR genes has created opportunities for resolving …

Identifying Pathogenic Variants In Hereditary Cancer Syndrome Genes Via Tumor Molecular Profiling, Carol Nowlen

Dissertations and Theses (Open Access)

Tumor molecular profiling is often performed in order to direct cancer treatment options. However, because many of the genes analyzed on tumor molecular profiling overlap with genes known to be associated in the germline with hereditary cancer predisposition syndromes, tumor molecular profiling can unknowingly uncover germline predisposition to cancer development. In this study, we determined the number of patients with pathogenic variants (PVs) identified in BRCA1 and BRCA2 (BRCA1/2) via tumor molecular profiling at The University of Texas MD Anderson Cancer Center, then performed a retrospective chart review to determine the proportion of such patients that received germline …

Sequence-Specific Gene Correction Of Cystic Fibrosis Airway Basal Cells, Varada Anirudhan

Dissertations and Theses (Open Access)

Cystic fibrosis (CF) is a lethal monogenic disease resulting from mutations in the CFTR gene which encodes a protein involved in regulating anion trans-epithelial transport. A three-base deletion in CFTR (termed as ΔF508 mutation), wherein CFTR protein is misfolded leading to its pre-mature degradation in the endoplasmic reticulum (ER), is the most common cause of this debilitating disease. Since CFTR is expressed in multiple body systems, CF affects different organs, but lung pathology is the greatest cause of death in affected patients. We achieved site-specific gene correction with an efficiency of ~10 % in CF airway basal cells homozygous for …

Computational Genomic Models For Spatio-Temporal Investigation Of Early Lung Cancer Pathology, Smruthy Sivakumar

Dissertations and Theses (Open Access)

Lung cancer, of which non-small cell lung cancer (NSCLC) is the most common form, is the second most prevalent cancer and the leading cause of cancer-related deaths. NSCLCs primarily comprise adenocarcinomas (LUAD) and squamous cell carcinomas (LUSC). Advances in early detection and prevention have been limited by the lack of early-stage biomarkers and targets. A comprehensive molecular characterization of premalignant lesions and tumor-adjacent normal tissue can aid in better understanding NSCLC pathogenesis. However, these investigations are further challenged by limited tissue availability and low cellular fractions of detectable somatic mutations.

Therefore, there is a dearth of knowledge about the pathogenesis …

Cellular Localization Of Rad51d Mutant Proteins And The Application Of Art To Increase Scientific Literacy In America, Claire L. Chabot

Senior Theses

Ovarian cancers are the leading cause of death from cancer of the female reproductive system. Approximately 50% of ovarian cancers have defects in the homologous recombination (HR) DNA repair pathway that is required for the repair of DNA double-stranded breaks. The status of HR genes, such as BRCA1, BRCA2, and the RAD51 family, contributes to ovarian cancer development as well as treatment decisions regarding chemotherapy, radiation, and immunotherapy. The overarching goal of this project is to identify new insights into HR that can integrate with Precision Medicine Initiatives and align with the goals of the Cancer Moonshot 2020 Program. I …

Using Genetic Diversity To Understand Susceptibility To Cognitive Decline In Aging And Alzheimer’S Disease, Sarah M. Neuner

Theses and Dissertations (ETD)

An individual's genetic makeup plays an important role in determining susceptibility to cognitive aging and transition to dementia such as Alzheimer's disease (AD). Identifying the specific genetic variants that contribute to cognitive aging and AD may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we turned to genetically diverse mice from the BXD genetic reference panel (GRP) to overcome some of the …

Genetic Modification Of Animals: Scientific And Ethical Issues, Jarrod Bailey

Genetic Engineering and Cloning Collection

No abstract provided.

Weighted Pathway Genetic Load Analysis Of Hyperbilirubinemic Infants Indicates A Potential Genetic Component For Susceptibility To Bilirubin Neurotoxicity, Sean M. Riordan, Jean-Baptiste Lepichon, Steven Shapiro, John Cowden, Monica Villagullen, Laurence Thielemans, Dina Villanueva Garcia, Jesus Aguirre-Hernandez

Posters

Severe kernicterus spectrum disorder (KSD) is described as motor and auditory deficits resulting from brain damage caused by hyperbilirubinemia. The severity of HB does not always predict the severity of injury. The lack of a strong monogenetic link to susceptibility suggests bilirubin-induced brain damage may be due to impaired bilirubin response pathways. This poster describes work to use a modified pathway genetic load (mPGL) score method to perform a targeted genetic analysis of whole exome data from patients with various degrees of neonatal HB, with an ultimate goal of developing a neonatal screen to susceptibiltiy to bilirubin neurotoxicity.

Developing Technologically Advanced Research In Low- And Middle-Income Countries, Isa Abdulkadir, Tina Slusher, Fidelia Bode-Thomas, Sean Riordan, Jean-Baptiste Lepichon, Laila Hassan, Shehu Abdullahi, Akinyemi Ofakunrin, Stephen Oguche, Steven Shapiro, William Ogala

Posters

This poster presents a collaboration between a group of scientists in Nigeria and the USA in developing a genomic research project and the solutions adopted in tackling the ethical implications and partnership equity and ownership of such a project.

Rediscovering The Axolotl As A Model For Thyroid Hormone Dependent Development, Anne Crowner, Shivam Khatri, Dana Blichmann, S. Randal Voss

Neuroscience Faculty Publications

The Mexican axolotl (Ambystoma mexicanum) is an important model organism in biomedical research. Much current attention is focused on the axolotl's amazing ability to regenerate tissues and whole organs after injury. However, not forgotten is the axolotl's equally amazing ability to thwart aspects of tissue maturation and retain juvenile morphology into the adult phase of life. Unlike close tiger salamander relatives that undergo a thyroid hormone regulated metamorphosis, the axolotl does not typically undergo a metamorphosis. Instead, the axolotl exhibits a paedomorphic mode of development that enables a completely aquatic life cycle. The evolution of paedomorphosis allowed axolotls …

Small Molecule Kras Agonist For Mutant Kras Cancer Therapy., Ke Xu, Dongkyoo Park, Andrew T Magis, Jun Zhang, Wei Zhou, Gabriel L Sica, Suresh S Ramalingam, Walter J Curran, Xingming Deng

Articles, Abstracts, and Reports

BACKGROUND: Lung cancer patients with KRAS mutation(s) have a poor prognosis due in part to the development of resistance to currently available therapeutic interventions. Development of a new class of anticancer agents that directly targets KRAS may provide a more attractive option for the treatment of KRAS-mutant lung cancer.

RESULTS: Here we identified a small molecule KRAS agonist, KRA-533, that binds the GTP/GDP-binding pocket of KRAS. In vitro GDP/GTP exchange assay reveals that KRA-533 activates KRAS by preventing the cleavage of GTP into GDP, leading to the accumulation of GTP-KRAS, an active form of KRAS. Treatment of human lung cancer …

Incorporating Pathway Information Into Feature Selection Towards Better Performed Gene Signatures, Suyan Tian, Chi Wang, Bing Wang

Biostatistics Faculty Publications

To analyze gene expression data with sophisticated grouping structures and to extract hidden patterns from such data, feature selection is of critical importance. It is well known that genes do not function in isolation but rather work together within various metabolic, regulatory, and signaling pathways. If the biological knowledge contained within these pathways is taken into account, the resulting method is a pathway-based algorithm. Studies have demonstrated that a pathway-based method usually outperforms its gene-based counterpart in which no biological knowledge is considered. In this article, a pathway-based feature selection is firstly divided into three major categories, namely, pathway-level selection, …

Male Determining Gene Nix May Bring An End To Transmission Of Diseases Through Mosquitoes, Mohammed Mahdi

Thinking Matters Symposium Archive

Female mosquitoes take blood from humans to gain protein needed to produce eggs, and in the process they can transmit viruses, such as Zika, Dengue, and chikungunya, or parasites, such as malaria. Male mosquitoes do not transmit diseases. This literature review will examine what is known about how sex is determined in mosquitoes and how this can be used to manipulate the females that spread diseases to humans. Using CRISPR Cas9, the lab of Zhijian Tu removed the Nix gene from mosquito embryos; all of these were feminized. Ectopic overexpression of Nix gene product in mosquito embryos caused even genetically …