Mouse Tiparp Conditional Knockout Project (CRISPR/Cas9)
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Whole-Genome Microarray Detects Deletions and Loss of Heterozygosity of Chromosome 3 Occurring Exclusively in Metastasizing Uveal Melanoma
Anatomy and Pathology Whole-Genome Microarray Detects Deletions and Loss of Heterozygosity of Chromosome 3 Occurring Exclusively in Metastasizing Uveal Melanoma Sarah L. Lake,1 Sarah E. Coupland,1 Azzam F. G. Taktak,2 and Bertil E. Damato3 PURPOSE. To detect deletions and loss of heterozygosity of disease is fatal in 92% of patients within 2 years of diagnosis. chromosome 3 in a rare subset of fatal, disomy 3 uveal mela- Clinical and histopathologic risk factors for UM metastasis noma (UM), undetectable by fluorescence in situ hybridization include large basal tumor diameter (LBD), ciliary body involve- (FISH). ment, epithelioid cytomorphology, extracellular matrix peri- ϩ ETHODS odic acid-Schiff-positive (PAS ) loops, and high mitotic M . Multiplex ligation-dependent probe amplification 3,4 5 (MLPA) with the P027 UM assay was performed on formalin- count. Prescher et al. showed that a nonrandom genetic fixed, paraffin-embedded (FFPE) whole tumor sections from 19 change, monosomy 3, correlates strongly with metastatic death, and the correlation has since been confirmed by several disomy 3 metastasizing UMs. Whole-genome microarray analy- 3,6–10 ses using a single-nucleotide polymorphism microarray (aSNP) groups. Consequently, fluorescence in situ hybridization were performed on frozen tissue samples from four fatal dis- (FISH) detection of chromosome 3 using a centromeric probe omy 3 metastasizing UMs and three disomy 3 tumors with Ͼ5 became routine practice for UM prognostication; however, 5% years’ metastasis-free survival. to 20% of disomy 3 UM patients unexpectedly develop metas- tases.11 Attempts have therefore been made to identify the RESULTS. Two metastasizing UMs that had been classified as minimal region(s) of deletion on chromosome 3.12–15 Despite disomy 3 by FISH analysis of a small tumor sample were found these studies, little progress has been made in defining the key on MLPA analysis to show monosomy 3. -
Genetic Commonalities in Gynecologic Cancers Using Publicly Available Genome-Wide Association Study Summary Results: an Exploratory Meta-Analysis
Title Page Genetic Commonalities in Gynecologic Cancers Using Publicly Available Genome-Wide Association Study Summary Results: An Exploratory Meta-Analysis by Mark Francis Vater BS Biology, Northern Kentucky University, 2014 Submitted to the Graduate Faculty of the Graduate School of Public Health in partial fulfillment of the requirements for the degree of Master of Science University of Pittsburgh 2021 Committee Membership Page UNIVERSITY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH This thesis was presented by Mark Francis Vater It was defended on August 4, 2021 and approved by Jeanine Buchanich, Associate Professor, Department of Biostatistics Ada Youk, Associate Professor, Department of Biostatistics John Shaffer, Assistant Professor, Department of Human Genetics Thesis Advisor: Jenna Carlson, Assistant Professor, Department of Biostatistics ii Copyright © by Mark Vater 2021 iii Abstract Genetic Commonalities in Gynecologic Cancers Using Publicly Available Genome-Wide Association Study Summary Results: An Exploratory Meta-Analysis Mark Francis Vater, MS University of Pittsburgh, 2021 Abstract Public Health Significance: Gynecologic cancers are responsible for millions of deaths worldwide every year. The goal of this research is to further scientific understanding of such cancers, potentially leading to improved diagnosis and treatment. The public health significance of this project is to uncover potential genetic underpinnings of gynecologic cancers, aiding in efforts to reduce the mortality rate of gynecologic cancers, which is imperative in protecting the health of susceptible persons across the globe. Gynecologic cancers are those which arise in the female reproductive system, chiefly, those of the ovaries, cervix, vulva, endometrium, and vagina. These conditions present a serious threat to the health of susceptible persons, leading to nearly three million deaths worldwide each year. -
Supplemental Materials and Methods Page
1 2 Supplementary Information for 3 4 5 Vertebrate adaptive radiation is assembled from an ancient and disjunct spatiotemporal 6 landscape 7 8 Emilie J. Richards, Joseph A. McGirr, Jeremy R. Wang, Michelle E. St. John, Jelmer W. 9 Poelstra, Maria J. Solano, Delaney C. O’Connell, Bruce J. Turner, Christopher H. Martin* 10 11 *Correspondence to: [email protected] 12 13 14 15 This PDF file includes: 16 17 Supplementary text 18 Figures S1 to S17 19 Tables S1 to S19 20 SI References 21 22 Other supplementary materials for this manuscript include the following: 23 24 Datasets S1 to S9 25 26 27 28 29 30 31 32 33 34 35 36 37 1 38 Table of Contents 1. Supplemental Materials and Methods Page 1.1 Sampling 4 1.2 Genomic Library Prep 5 1.3 De novo genome assembly and annotation 5 1.4 Population genotyping. 6 1.5 Population genetic analyses 8 1.6 Mutation rate estimation. 10 1.7 Demographic Inferences 12 1.8 Introgression in SSI specialists 13 1.9 Search for candidate adaptive alleles in SSI specialists 15 1.10 Introgression in outgroup generalist populations 18 1.11. Characterization of adaptive alleles through GO analysis 19 1.12 Characterization of adaptive alleles through genome-wide association mapping 19 1.13 Characterization of adaptive alleles through differential gene expression and QTL 22 analysis from previous studies 1.14 Timing of divergence among adaptive alleles 23 1.15 Timing of selective sweeps on adaptive alleles 26 2. Supplementary Results and Discussion 31 2 2.1 Spatiotemporal stages of adaption based on timing of divergence among adaptive alleles 31 2.2 Spatiotemporal stages of adaptation based on timing of selection on adaptive alleles 35 3. -
Signatures of Adaptive Evolution in Platyrrhine Primate Genomes 5 6 Hazel Byrne*, Timothy H
1 2 Supplementary Materials for 3 4 Signatures of adaptive evolution in platyrrhine primate genomes 5 6 Hazel Byrne*, Timothy H. Webster, Sarah F. Brosnan, Patrícia Izar, Jessica W. Lynch 7 *Corresponding author. Email [email protected] 8 9 10 This PDF file includes: 11 Section 1: Extended methods & results: Robust capuchin reference genome 12 Section 2: Extended methods & results: Signatures of selection in platyrrhine genomes 13 Section 3: Extended results: Robust capuchins (Sapajus; H1) positive selection results 14 Section 4: Extended results: Gracile capuchins (Cebus; H2) positive selection results 15 Section 5: Extended results: Ancestral Cebinae (H3) positive selection results 16 Section 6: Extended results: Across-capuchins (H3a) positive selection results 17 Section 7: Extended results: Ancestral Cebidae (H4) positive selection results 18 Section 8: Extended results: Squirrel monkeys (Saimiri; H5) positive selection results 19 Figs. S1 to S3 20 Tables S1–S3, S5–S7, S10, and S23 21 References (94 to 172) 22 23 Other Supplementary Materials for this manuscript include the following: 24 Tables S4, S8, S9, S11–S22, and S24–S44 1 25 1) Extended methods & results: Robust capuchin reference genome 26 1.1 Genome assembly: versions and accessions 27 The version of the genome assembly used in this study, Sape_Mango_1.0, was uploaded to a 28 Zenodo repository (see data availability). An assembly (Sape_Mango_1.1) with minor 29 modifications including the removal of two short scaffolds and the addition of the mitochondrial 30 genome assembly was uploaded to NCBI under the accession JAGHVQ. The BioProject and 31 BioSample NCBI accessions for this project and sample (Mango) are PRJNA717806 and 32 SAMN18511585. -
New Genetic Loci Link Adipose and Insulin Biology to Body Fat Distribution
Europe PMC Funders Group Author Manuscript Nature. Author manuscript; available in PMC 2015 August 12. Published in final edited form as: Nature. 2015 February 12; 518(7538): 187–196. doi:10.1038/nature14132. Europe PMC Funders Author Manuscripts New genetic loci link adipose and insulin biology to body fat distribution A full list of authors and affiliations appears at the end of the article. # These authors contributed equally to this work. Abstract Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms. Europe PMC Funders Author Manuscripts Depot-specific accumulation of fat, particularly in the central abdomen, confers an elevated risk of metabolic and cardiovascular diseases and mortality1. An easily accessible measure of body fat distribution is waist-to-hip ratio (WHR), a comparison of waist and hip circumferences. -
Identification of PARP-7 Substrates Reveals a Role for Marylation
RESEARCH ARTICLE Identification of PARP-7 substrates reveals a role for MARylation in microtubule control in ovarian cancer cells Lavanya H Palavalli Parsons1,2,3†‡, Sridevi Challa1,2†, Bryan A Gibson1,2†§, Tulip Nandu1,2, MiKayla S Stokes1,2, Dan Huang1,2,4, Jayanthi S Lea3, W Lee Kraus1,2* 1Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, United States; 2Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, United States; 3Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, United States; 4Department of Cardiology, Clinical Center for Human Gene Research, *For correspondence: Union Hospital, Tongji Medical College, Huazhong University of Science and [email protected] Technology, Wuhan, China †These authors contributed equally to this work ‡ Present address: Department Abstract PARP-7 (TiPARP) is a mono(ADP-ribosyl) transferase whose protein substrates and of Obstetrics, Gynecology, and biological activities are poorly understood. We observed that PARP7 mRNA levels are lower in Reproductive Sciences, ovarian cancer patient samples compared to non-cancerous tissue, but PARP-7 protein nonetheless University of Texas Health contributes to several cancer-related biological endpoints in ovarian cancer cells (e.g. growth, Science Center at Houston, McGovern Medical -
Cross-Species Transcriptomic Analysis Elucidates Constitutive Aryl
Sun et al. BMC Genomics 2014, 15:1053 http://www.biomedcentral.com/1471-2164/15/1053 RESEARCH ARTICLE Open Access Cross-species transcriptomic analysis elucidates constitutive aryl hydrocarbon receptor activity Ren X Sun1, Lauren C Chong1, Trent T Simmons1, Kathleen E Houlahan1, Stephenie D Prokopec1, John D Watson1, Ivy D Moffat2, Sanna Lensu3,4, Jere Lindén5, Christine P'ng1, Allan B Okey2, Raimo Pohjanvirta6 and Paul C Boutros1,2,7,8* Abstract Background: Research on the aryl hydrocarbon receptor (AHR) has largely focused on variations in toxic outcomes resulting from its activation by halogenated aromatic hydrocarbons. But the AHR also plays key roles in regulating pathways critical for development, and after decades of research the mechanisms underlying physiological regulation by the AHR remain poorly characterized. Previous studies identified several core genes that respond to xenobiotic AHR ligands across a broad range of species and tissues. However, only limited inferences have been made regarding its role in regulating constitutive gene activity, i.e. in the absence of exogenous ligands. To address this, we profiled transcriptomic variations between AHR-active and AHR-less-active animals in the absence of an exogenous agonist across five tissues, three of which came from rats (hypothalamus, white adipose and liver) and two of which came from mice (kidney and liver). Because AHR status alone has been shown sufficient to alter transcriptomic responses, we reason that by contrasting profiles amongst AHR-variant animals, we may elucidate effects of the AHR on constitutive mRNA abundances. Results: We found significantly more overlap in constitutive mRNA abundances amongst tissues within the same species than from tissues between species and identified 13 genes (Agt, Car3, Creg1, Ctsc, E2f6, Enpp1, Gatm, Gstm4, Kcnj8, Me1, Pdk1, Slc35a3,andSqrdl) that are affected by AHR-status in four of five tissues. -
Role of Glycogen Synthase Kinase-3 Beta in the Transition to Excessive Consumption
Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2018 Molecular Brain Adaptations to Ethanol: Role of Glycogen Synthase Kinase-3 Beta in the Transition to Excessive Consumption Andrew D. van der Vaart Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Molecular and Cellular Neuroscience Commons, Pharmacology Commons, and the Psychiatry and Psychology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/5510 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. ©Andrew van der Vaart 2018 All Rights Reserved Molecular Brain Adaptations to Ethanol: Role of Glycogen Synthase Kinase-3 Beta in the Transition to Excessive Consumption A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. by Andrew Donald van der Vaart Bachelor of Arts, University of Virginia, 2009 Director: Michael F. Miles, M.D., Ph.D., Professor, Departments of Pharmacology and Toxicology, Neurology Virginia Commonwealth University, Richmond, Virginia, February 2018 i Acknowledgments I would like to sincerely thank all of the people in my life who have provided support, guidance, and contributions to this endeavor. I thank the VCU M.D.-Ph.D. program and the NIAAA for giving me the opportunity to practice research without fear of mistakes for long enough to learn something. I must thank my mentor Dr. -
Systematic Analysis, Comparison, and Integration of Disease Based Human
Zhang et al. BMC Medical Genomics 2010, 3:1 http://www.biomedcentral.com/1755-8794/3/1 RESEARCH ARTICLE Open Access Systematic analysis, comparison, and integration of disease based human genetic association data and mouse genetic phenotypic information Yonqing Zhang1†, Supriyo De1†, John R Garner1, Kirstin Smith1, S Alex Wang2, Kevin G Becker1* Abstract Background: The genetic contributions to human common disorders and mouse genetic models of disease are complex and often overlapping. In common human diseases, unlike classical Mendelian disorders, genetic factors generally have small effect sizes, are multifactorial, and are highly pleiotropic. Likewise, mouse genetic models of disease often have pleiotropic and overlapping phenotypes. Moreover, phenotypic descriptions in the literature in both human and mouse are often poorly characterized and difficult to compare directly. Methods: In this report, human genetic association results from the literature are summarized with regard to replication, disease phenotype, and gene specific results; and organized in the context of a systematic disease ontology. Similarly summarized mouse genetic disease models are organized within the Mammalian Phenotype ontology. Human and mouse disease and phenotype based gene sets are identified. These disease gene sets are then compared individually and in large groups through dendrogram analysis and hierarchical clustering analysis. Results: Human disease and mouse phenotype gene sets are shown to group into disease and phenotypically relevant groups at both a coarse and fine level based on gene sharing. Conclusion: This analysis provides a systematic and global perspective on the genetics of common human disease as compared to itself and in the context of mouse genetic models of disease. -
HBV DNA Integration and Clonal Hepatocyte Expansion in Chronic Hepatitis B Patients Considered Immune Tolerant
Accepted Manuscript HBV DNA Integration and Clonal Hepatocyte Expansion in Chronic Hepatitis B Patients Considered Immune Tolerant William S. Mason, Upkar S. Gill, Samuel Litwin, Yan Zhou, Suraj Peri, Oltin Pop, Michelle L.W. Hong, Sandhia Naik, Alberto Quaglia, Antonio Bertoletti, Patrick T.F. Kennedy PII: S0016-5085(16)34808-9 DOI: 10.1053/j.gastro.2016.07.012 Reference: YGAST 60585 To appear in: Gastroenterology Accepted Date: 7 July 2016 Please cite this article as: Mason WS, Gill US, Litwin S, Zhou Y, Peri S, Pop O, Hong MLW, Naik S, Quaglia A, Bertoletti A, Kennedy PTF, HBV DNA Integration and Clonal Hepatocyte Expansion in Chronic Hepatitis B Patients Considered Immune Tolerant, Gastroenterology (2016), doi: 10.1053/ j.gastro.2016.07.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT TITLE: HBV DNA Integration and Clonal Hepatocyte Expansion in Chronic Hepatitis B Patients Considered Immune Tolerant SHORT TITLE : Immunopathology in immune tolerant CHB AUTHORS: William S. Mason 1, Upkar S. Gill 2, Samuel Litwin 1, Yan Zhou 1, Suraj Peri 1, Oltin Pop 3, Michelle L.W. Hong 4, Sandhia Naik 5, Alberto Quaglia 3, Antonio Bertoletti 4 & Patrick T.F. -
Integrative Multi-Omic Analysis Identifies New Drivers and Pathways
www.nature.com/scientificreports OPEN Integrative multi-omic analysis identifes new drivers and pathways in molecularly distinct subtypes of Received: 16 October 2018 Accepted: 4 June 2019 ALS Published: xx xx xxxx Giovanna Morello1, Maria Guarnaccia1, Antonio Gianmaria Spampinato1, Salvatore Salomone2, Velia D’Agata 3, Francesca Luisa Conforti6, Eleonora Aronica4,5 & Sebastiano Cavallaro1 Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease. Increasing the chances of success for future clinical strategies requires more in-depth knowledge of the molecular basis underlying disease heterogeneity. We recently laid the foundation for a molecular taxonomy of ALS by whole-genome expression profling of motor cortex from sporadic ALS (SALS) patients. Here, we analyzed copy number variants (CNVs) occurring in the same patients, by using a customized exon-centered comparative genomic hybridization array (aCGH) covering a large panel of ALS-related genes. A large number of novel and known disease-associated CNVs were detected in SALS samples, including several subgroup-specifc loci, suggestive of a great divergence of two subgroups at the molecular level. Integrative analysis of copy number profles with their associated transcriptomic data revealed subtype-specifc genomic perturbations and candidate driver genes positively correlated with transcriptional signatures, suggesting a strong interaction between genomic and transcriptomic events in ALS pathogenesis. The functional analysis confrmed our previous pathway-based characterization of SALS subtypes and identifed 24 potential candidates for genomic-based patient stratifcation. To our knowledge, this is the frst comprehensive “omics” analysis of molecular events characterizing SALS pathology, providing a road map to facilitate genome-guided personalized diagnosis and treatments for this devastating disease. -
Supporting Information
Supporting Information Miller et al. 10.1073/pnas.0914257107 SI Materials and Methods files with 20 to 40 samples and 5,629 to 9,731 genes each and 20 Data Set Acquisition and Filtering. All data sets were downloaded mouse expression files with 18 and 44 samples and 5,176 to 6,157 from the GEO database, and consisted of experiments run on genes each. All preprocessed data files (as well as the resulting either mouse or human brain tissue (Fig. 1A). We filtered out all network data and some associated code and support files) are but a core collection of data sets that were similar enough for available at the WGCNA group Web site (www.genetics.ucla.edu/ useful bioinformatic comparison. First, we removed all data sets labs/horvath/CoexpressionNetwork/MouseHumanBrain). that were not run on an Affymetrix platform, leaving three From these preprocessed expression files we created a human platforms in human (HG-U95A, HG-U133A, HG-U133 Plus 2) and a mouse consensus network (method modified from ref. 4). and two in mouse (MG-U74A, MG-U430A). Second, we ex- For each consensus network we first created correlation matrices cluded all samples in each data set that were not taken from from each data set (obtained by calculating the Pearson correla- brain tissue (for example, in one expression atlas study, more tions between all variable probe sets across all subjects in each than 80% of the samples were excluded). Third, to make the data set), and then weighted them based on the number of sam- correlations between genes more comparable across studies, we ples used in that data set.