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Identification of genes required for eye development by high-throughput screening of mouse knockouts.

ABSTRACT: Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for every mouse gene. Of 4364 genes evaluated, 347 were identified to influence ocular phenotypes, 75% of which are entirely novel in ocular pathology. This discovery greatly increases the current number of genes known to contribute to ophthalmic disease, and it is likely that many of the genes will subsequently prove to be important in human ocular development and disease.

SUBMITTER: Moore BA

PROVIDER: S-EPMC6303268 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Identification of genes required for eye development by high-throughput screening of mouse knockouts.

Moore Bret A BA Leonard Brian C BC Sebbag Lionel L Edwards Sydney G SG Cooper Ann A Imai Denise M DM Straiton Ewan E Santos Luis L Reilly Christopher C Griffey Stephen M SM Bower Lynette L Clary David D Mason Jeremy J Roux Michel J MJ Meziane Hamid H Herault Yann Y McKerlie Colin C Flenniken Ann M AM Nutter Lauryl M J LMJ Berberovic Zorana Z Owen Celeste C Newbigging Susan S Adissu Hibret H Eskandarian Mohammed M Hsu Chih-Wei CW Kalaga Sowmya S Udensi Uchechukwu U Asomugha Chinwe C Bohat Ritu R Gallegos Juan J JJ Seavitt John R JR Heaney Jason D JD Beaudet Arthur L AL Dickinson Mary E ME Justice Monica J MJ Philip Vivek V Kumar Vivek V Svenson Karen L KL Braun Robert E RE Wells Sara S Cater Heather H Stewart Michelle M Clementson-Mobbs Sharon S Joynson Russell R Gao Xiang X Suzuki Tomohiro T Wakana Shigeharu S Smedley Damian D Seong J K JK Tocchini-Valentini Glauco G Moore Mark M Fletcher Colin C Karp Natasha N Ramirez-Solis Ramiro R White Jacqueline K JK de Angelis Martin Hrabe MH Wurst Wolfgang W Thomasy Sara M SM Flicek Paul P Parkinson Helen H Brown Steve D M SDM Meehan Terrence F TF Nishina Patsy M PM Murray Stephen A SA Krebs Mark P MP Mallon Ann-Marie AM Lloyd K C Kent KCK Murphy Christopher J CJ Moshiri Ala A

Communications biology 20181221

Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for ...[more]

PMID: 30588515

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Project description:BackgroundUnderstanding health risks to embryonic development from exposure to environmental chemicals is a significant challenge given the diverse chemical landscape and paucity of data for most of these compounds. High-throughput screening (HTS) in the U.S. Environmental Protection Agency (EPA) ToxCast™ project provides vast data on an expanding chemical library currently consisting of > 1,000 unique compounds across > 500 in vitro assays in phase I (complete) and Phase II (under way). This public data set can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can aid decision making for assessments of human developmental health and disease.ObjectiveWe mined the ToxCast phase I data set to identify signatures for potential chemical disruption of blood vessel formation and remodeling.MethodsToxCast phase I screened 309 chemicals using 467 HTS assays across nine assay technology platforms. The assays measured direct interactions between chemicals and molecular targets (receptors, enzymes), as well as downstream effects on reporter gene activity or cellular consequences. We ranked the chemicals according to individual vascular bioactivity score and visualized the ranking using ToxPi (Toxicological Priority Index) profiles.ResultsTargets in inflammatory chemokine signaling, the vascular endothelial growth factor pathway, and the plasminogen-activating system were strongly perturbed by some chemicals, and we found positive correlations with developmental effects from the U.S. EPA ToxRefDB (Toxicological Reference Database) in vivo database containing prenatal rat and rabbit guideline studies. We observed distinctly different correlative patterns for chemicals with effects in rabbits versus rats, despite derivation of in vitro signatures based on human cells and cell-free biochemical targets, implying conservation but potentially differential contributions of developmental pathways among species. Follow-up analysis with antiangiogenic thalidomide analogs and additional in vitro vascular targets showed in vitro activity consistent with the most active environmental chemicals tested here.ConclusionsWe predicted that blood vessel development is a target for environmental chemicals acting as putative vascular disruptor compounds (pVDCs) and identified potential species differences in sensitive vascular developmental pathways.

Dataset Information

Identification of genes required for eye development by high-throughput screening of mouse knockouts.

Publications

Identification of genes required for eye development by high-throughput screening of mouse knockouts.

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