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At a fundamental level most genes, signaling pathways, biological functions and organ systems are highly conserved between man and all vertebrate species. Leveraging this conservation, researchers are increasingly using the experimental advantages of the amphibian Xenopus to model human disease. The online Xenopus resource, Xenbase, enables human disease modeling by curating the Xenopus literature published in PubMed and integrating these Xenopus data with orthologous human genes, anatomy, and more recently with links to the Online Mendelian Inheritance in Man resource (OMIM) and the Human Disease Ontology (DO). Here we review how Xenbase supports disease modeling and report on a meta-analysis of the published Xenopus research providing an overview of the different types of diseases being modeled in Xenopus and the variety of experimental approaches being used. Text mining of over 50,000 Xenopus research articles imported into Xenbase from PubMed identified approximately 1,000 putative disease- modeling articles. These articles were manually assessed and annotated with disease ontologies, which were then used to classify papers based on disease type. We found that Xenopus is being used to study a diverse array of disease with three main experimental approaches: cell-free egg extracts to study fundamental aspects of cellular and molecular biology, oocytes to study ion transport and channel physiology and embryo experiments focused on congenital diseases. We integrated these data into Xenbase Disease Pages to allow easy navigation to disease information on external databases. Results of this analysis will equip Xenopus researchers with a suite of experimental approaches available to model or dissect a pathological process. Ideally clinicians and basic researchers will use this information to foster collaborations necessary to interrogate the development and treatment of human diseases.
FIGURE 1. Xenbase Gene Page for zic3. Gene-disease annotations are located below Interactants on the Summary tab of the Xenbase Gene Page. Disease Ontology (DO) annotations (red arrowhead) are made via DO-OMIM cross reference or manual curation. OMIM annotations (blue arrowhead) are imported from the National Center for Biotechnology Information (NCBI). DO and OMIM terms link to Xenbase Disease Pages.
FIGURE 2. Xenbase Disease Page for “DOID:0050545: visceral heterotaxy.†An example of a new Disease Page with disease-specific supporting information including associated human and model organism resource links. The representative disease and its descendants are displayed in a Disease Hierarchy with the number of associated Xenbase articles in parentheses. The Literature tab provides a list of all associated Xenbase articles.
FIGURE 3. DO and OMIM references on a Xenbase Article Page. Disease terms link directly to the collated data on a Disease Page for DO (red arrowhead) annotations and OMIM (blue arrowhead) annotations. Multiple disease annotations can be seen by clicking the [+/–] toggle to show more or fewer results. Article Pages also list GO terms as keywords to cover the major topics of an article.
FIGURE 4. Subnetworks from the DO. This figure shows MCL clustered subnetworks from a subset of the DO, consisting of terms annotated during our curation of the Xenbase human disease corpus detailed in the Supplementary Material. Nodes in the network are colored according to the number of direct annotations to the term they represent. Empty nodes have no direct annotations, blue nodes 1–5, yellow nodes 6–14 and purple nodes 15 and higher. Purple nodes and the yellow node(s) with the highest number of annotations for each cluster have been labeled. Cluster regions corresponding to high level DO terms have been highlighted for contrast and labeled. Some small subnetworks and singleton nodes have been moved to proximity with the high level DO term to which they are associated.
FIGURE 5. Human disease-specific Xenopus articles (1990–2017). This chart shows the number of articles published, by year, between 1990 and 2017 that our curation identified as utilizing Xenopus as a model system for studying human disease. Publication dates were obtained from NCBI’s PubMed database.
Ashburner,
Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.
2000, Pubmed
Ashburner,
Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.
2000,
Pubmed Aslan,
High-efficiency non-mosaic CRISPR-mediated knock-in and indel mutation in F0 Xenopus.
2017,
Pubmed Bantle,
Further validation of FETAX: evaluation of the developmental toxicity of five known mammalian teratogens and non-teratogens.
1990,
Pubmed Bell,
A neuroprotective role for polyamines in a Xenopus tadpole model of epilepsy.
2011,
Pubmed Bello,
Disease Ontology: improving and unifying disease annotations across species.
2018,
Pubmed Bhattacharya,
CRISPR/Cas9: An inexpensive, efficient loss of function tool to screen human disease genes in Xenopus.
2015,
Pubmed Blitz,
Biallelic genome modification in F(0) Xenopus tropicalis embryos using the CRISPR/Cas system.
2013,
Pubmed Blum,
Xenopus: An Undervalued Model Organism to Study and Model Human Genetic Disease.
2018,
Pubmed Boskovski,
The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality.
2013,
Pubmed Bronchain,
Implication of thyroid hormone signaling in neural crest cells migration: Evidence from thyroid hormone receptor beta knockdown and NH3 antagonist studies.
2017,
Pubmed Buchholz,
Xenopus metamorphosis as a model to study thyroid hormone receptor function during vertebrate developmental transitions.
2017,
Pubmed Calo,
Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders.
2018,
Pubmed Chen,
Functional analysis of nonsynonymous single nucleotide polymorphisms in human SLC26A9.
2012,
Pubmed Cossette,
Early expression of thyroid hormone receptor beta and retinoid X receptor gamma in the Xenopus embryo.
2004,
Pubmed Cross,
Learning about cancer from frogs: analysis of mitotic spindles in Xenopus egg extracts.
2009,
Pubmed Dawson,
Developmental toxicity testing with FETAX: evaluation of five compounds.
1989,
Pubmed Devotta,
Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome.
2016,
Pubmed Dickinson,
Using frogs faces to dissect the mechanisms underlying human orofacial defects.
2016,
Pubmed Dominguez-Sola,
Non-transcriptional control of DNA replication by c-Myc.
2007,
Pubmed Dubey,
Modeling human craniofacial disorders in Xenopus.
2017,
Pubmed Duncan,
Xenopus as a model organism for birth defects-Congenital heart disease and heterotaxy.
2016,
Pubmed Dzierzak,
Blood Development: Hematopoietic Stem Cell Dependence and Independence.
2018,
Pubmed Fainsod,
Xenopus embryos to study fetal alcohol syndrome, a model for environmental teratogenesis.
2018,
Pubmed Feehan,
Modeling Dominant and Recessive Forms of Retinitis Pigmentosa by Editing Three Rhodopsin-Encoding Genes in Xenopus Laevis Using Crispr/Cas9.
2017,
Pubmed Felix,
Channelopathies: ion channel defects linked to heritable clinical disorders.
2000,
Pubmed Fort,
Evaluation of the developmental toxicity of five compounds with the frog embryo teratogenesis assay: Xenopus (FETAX) and a metabolic activation system.
1989,
Pubmed Garfinkel,
An interspecies heart-to-heart: Using Xenopus to uncover the genetic basis of congenital heart disease.
2017,
Pubmed Hardwick,
An oncologist׳s friend: How Xenopus contributes to cancer research.
2015,
Pubmed Haynes-Gilmore,
A critical role of non-classical MHC in tumor immune evasion in the amphibian Xenopus model.
2014,
Pubmed Hellsten,
The genome of the Western clawed frog Xenopus tropicalis.
2010,
Pubmed Hertel,
A structural basis for the acute effects of HIV protease inhibitors on GLUT4 intrinsic activity.
2004,
Pubmed Hoff,
ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3.
2013,
Pubmed Hoogenboom,
Xenopus egg extract: A powerful tool to study genome maintenance mechanisms.
2017,
Pubmed Howe,
The Zebrafish Model Organism Database: new support for human disease models, mutation details, gene expression phenotypes and searching.
2017,
Pubmed Howe,
Model organism data evolving in support of translational medicine.
2018,
Pubmed James,
Valproate-induced neurodevelopmental deficits in Xenopus laevis tadpoles.
2015,
Pubmed James-Zorn,
Navigating Xenbase: An Integrated Xenopus Genomics and Gene Expression Database.
2018,
Pubmed
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Echinobase Joukov,
The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly.
2006,
Pubmed Karimi,
Xenbase: a genomic, epigenomic and transcriptomic model organism database.
2018,
Pubmed
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Echinobase Khokha,
Xenopus white papers and resources: folding functional genomics and genetics into the frog.
2012,
Pubmed Kofent,
Xenopus as a model system for studying pancreatic development and diabetes.
2016,
Pubmed Köhler,
The Human Phenotype Ontology in 2017.
2017,
Pubmed Lambert,
Vestibular asymmetry as the cause of idiopathic scoliosis: a possible answer from Xenopus.
2009,
Pubmed Lambert,
Restricted neural plasticity in vestibulospinal pathways after unilateral labyrinthectomy as the origin for scoliotic deformations.
2013,
Pubmed Landais,
Monoketone analogs of curcumin, a new class of Fanconi anemia pathway inhibitors.
2009,
Pubmed Lehmann-Horn,
Voltage-gated ion channels and hereditary disease.
1999,
Pubmed Lienkamp,
Using Xenopus to study genetic kidney diseases.
2016,
Pubmed Limon,
Microtransplantation of neurotransmitter receptors from postmortem autistic brains to Xenopus oocytes.
2008,
Pubmed Ludwig,
Functional evaluation of Dent's disease-causing mutations: implications for ClC-5 channel trafficking and internalization.
2005,
Pubmed Mandel,
The BMP pathway acts to directly regulate Tbx20 in the developing heart.
2010,
Pubmed Miledi,
Microtransplantation of functional receptors and channels from the Alzheimer's brain to frog oocytes.
2004,
Pubmed Moody,
Fates of the blastomeres of the 16-cell stage Xenopus embryo.
1987,
Pubmed Moody,
Fates of the blastomeres of the 32-cell-stage Xenopus embryo.
1987,
Pubmed Morgan,
Teratogenic potential of atrazine and 2,4-D using FETAX.
1996,
Pubmed Morris,
clusterMaker: a multi-algorithm clustering plugin for Cytoscape.
2011,
Pubmed Mouche,
FETAX Assay for Evaluation of Developmental Toxicity.
2017,
Pubmed Mughal,
Evaluating Thyroid Disrupting Chemicals In Vivo Using Xenopus laevis.
2018,
Pubmed Müller,
Textpresso: an ontology-based information retrieval and extraction system for biological literature.
2004,
Pubmed Neilson,
Pa2G4 is a novel Six1 co-factor that is required for neural crest and otic development.
2017,
Pubmed Nutt,
The Xenopus oocyte: a model for studying the metabolic regulation of cancer cell death.
2012,
Pubmed Pratt,
Modeling human neurodevelopmental disorders in the Xenopus tadpole: from mechanisms to therapeutic targets.
2013,
Pubmed Proks,
A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes.
2006,
Pubmed Robson,
Expression of ribosomopathy genes during Xenopus tropicalis embryogenesis.
2016,
Pubmed Salanga,
Xenopus as a Model for GI/Pancreas Disease.
2015,
Pubmed Sangrithi,
Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome.
2005,
Pubmed Sareen,
Fanconi anemia proteins FANCD2 and FANCI exhibit different DNA damage responses during S-phase.
2012,
Pubmed Sater,
Using Xenopus to understand human disease and developmental disorders.
2017,
Pubmed Shannon,
Cytoscape: a software environment for integrated models of biomolecular interaction networks.
2003,
Pubmed Shi,
Heritable CRISPR/Cas9-mediated targeted integration in Xenopus tropicalis.
2015,
Pubmed Sigel,
The Xenopus oocyte: system for the study of functional expression and modulation of proteins.
2005,
Pubmed Simaite,
Recessive mutations in PCBD1 cause a new type of early-onset diabetes.
2014,
Pubmed Simons,
Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy.
2015,
Pubmed Smith,
Expanding the mammalian phenotype ontology to support automated exchange of high throughput mouse phenotyping data generated by large-scale mouse knockout screens.
2015,
Pubmed Sobeck,
Fanconi anemia proteins are required to prevent accumulation of replication-associated DNA double-strand breaks.
2006,
Pubmed Stäubli,
Abnormal creatine transport of mutations in monocarboxylate transporter 12 (MCT12) found in patients with age-related cataract can be partially rescued by exogenous chaperone CD147.
2017,
Pubmed Steffensen,
High incidence of functional ion-channel abnormalities in a consecutive Long QT cohort with novel missense genetic variants of unknown significance.
2015,
Pubmed Stone,
Identification, developmental expression and regulation of the Xenopus ortholog of human FANCG/XRCC9.
2007,
Pubmed Tandon,
Expanding the genetic toolkit in Xenopus: Approaches and opportunities for human disease modeling.
2017,
Pubmed The Gene Ontology Consortium,
Expansion of the Gene Ontology knowledgebase and resources.
2017,
Pubmed Ullah,
Analyzing and Modeling the Kinetics of Amyloid Beta Pores Associated with Alzheimer's Disease Pathology.
2015,
Pubmed Van Nieuwenhuysen,
TALEN-mediated apc mutation in Xenopus tropicalis phenocopies familial adenomatous polyposis.
2015,
Pubmed Vindas-Smith,
Identification and Functional Characterization of CLCN1 Mutations Found in Nondystrophic Myotonia Patients.
2016,
Pubmed Vize,
Model systems for the study of kidney development: use of the pronephros in the analysis of organ induction and patterning.
1997,
Pubmed Walentek,
ATP4a is required for development and function of the Xenopus mucociliary epidermis - a potential model to study proton pump inhibitor-associated pneumonia.
2015,
Pubmed Walentek,
What we can learn from a tadpole about ciliopathies and airway diseases: Using systems biology in Xenopus to study cilia and mucociliary epithelia.
2017,
Pubmed Wang,
Targeted gene disruption in Xenopus laevis using CRISPR/Cas9.
2015,
Pubmed Willis,
Study of the DNA damage checkpoint using Xenopus egg extracts.
2012,
Pubmed Yaoita,
Xenopus laevis alpha and beta thyroid hormone receptors.
1990,
Pubmed Yelin,
Ethanol exposure affects gene expression in the embryonic organizer and reduces retinoic acid levels.
2005,
Pubmed
