Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Human and mouse essentiality screens as a resource for disease gene discovery

Pilar Cacheiro, Violeta Muñoz-Fuentes, Stephen A. Murray, Mary E. Dickinson, Maja Bucan, Lauryl M.J. Nutter, Kevin A. Peterson, Hamed Haselimashhadi, Ann M. Flenniken, Hugh Morgan, Henrik Westerberg, Tomasz Konopka, Chih-Wei Hsu, Audrey Christiansen, Denise G. Lanza, Arthur L. Beaudet, Jason D. Heaney, Helmut Fuchs, Valerie Gailus-Durner, Tania Sorg, Jan Prochazka, Vendula Novosadova, Christopher J. Lelliott, Hannah Wardle-Jones, Sara Wells, Lydia Teboul, Heather Cater, Michelle Stewart, Tertius Hough, Wolfgang Wurst, Radislav Sedlacek, David J. Adams, John R. Seavitt, Glauco Tocchini-Valentini, Fabio Mammano, Robert E. Braun, Colin McKerlie, Yann Herault, Martin Hrabě de Angelis, Ann-Marie Mallon, K.C. Kent Lloyd, Steve D.M. Brown, Helen Parkinson, Terrence F. Meehan, Damian Smedley, on behalf of the Genomics England Research Consortium and the International Mouse Phenotyping Consortium
doi: https://doi.org/10.1101/678250
Pilar Cacheiro
Clinical Pharmacology, William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Violeta Muñoz-Fuentes
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephen A. Murray
The Jackson Laboratory, Bar Harbor, ME, 4609, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mary E. Dickinson
Departments of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USADepartments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maja Bucan
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lauryl M.J. Nutter
The Centre for Phenogenomics, The Hospital for Sick Children, Toronto, ON, M5T 3H7, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kevin A. Peterson
The Jackson Laboratory, Bar Harbor, ME, 4609, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hamed Haselimashhadi
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ann M. Flenniken
The Centre for Phenogenomics, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, M5T 3H7, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hugh Morgan
Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire, OX11 0RD, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Henrik Westerberg
Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire, OX11 0RD, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tomasz Konopka
Clinical Pharmacology, William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chih-Wei Hsu
Departments of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Audrey Christiansen
Departments of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Denise G. Lanza
Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Arthur L. Beaudet
Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jason D. Heaney
Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Helmut Fuchs
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Valerie Gailus-Durner
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tania Sorg
Université de Strasbourg, CNRS, INSERM, Institut Clinique de la Souris, PHENOMIN-ICS, Illkirch, 67404, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jan Prochazka
Czech Centre for Phenogenomics, Institute of Molecular Genetics CAS, Vestec, Prague, 252 50, Czech Republic
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vendula Novosadova
Czech Centre for Phenogenomics, Institute of Molecular Genetics CAS, Vestec, Prague, 252 50, Czech Republic
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christopher J. Lelliott
Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hannah Wardle-Jones
Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sara Wells
Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire, OX11 0RD, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lydia Teboul
Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire, OX11 0RD, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Heather Cater
Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire, OX11 0RD, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michelle Stewart
Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire, OX11 0RD, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tertius Hough
Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire, OX11 0RD, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wolfgang Wurst
Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, 85764, GermanyChair of Developmental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Neuherberg, 85764, GermanyDeutsches Institut für Neurodegenerative Erkrankungen (DZNE) Site Munich, Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians Universität München, Munich, 80336, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Radislav Sedlacek
Czech Centre for Phenogenomics, Institute of Molecular Genetics CAS, Vestec, Prague, 252 50, Czech Republic
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David J. Adams
Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John R. Seavitt
Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Glauco Tocchini-Valentini
Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, Monterotondo Scalo, I-00015, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Fabio Mammano
Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, Monterotondo Scalo, I-00015, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert E. Braun
The Jackson Laboratory, Bar Harbor, ME, 4609, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Colin McKerlie
The Centre for Phenogenomics, The Hospital for Sick Children, Toronto, ON, M5T 3H7, CanadaTranslational Medicine, The Hospital for Sick Children, Toronto, ON, M5T 3H7, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yann Herault
Université de Strasbourg, CNRS, INSERM, Institut de Génétique, Biologie Moléculaire et Cellulaire, Institut Clinique de la Souris, IGBMC, PHENOMIN-ICS, Illkirch, 67404, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Hrabě de Angelis
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, GermanyChair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, 85354, GermanyGerman Center for Diabetes Research (DZD), Neuherberg, 85764, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ann-Marie Mallon
Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire, OX11 0RD, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
K.C. Kent Lloyd
Mouse Biology Program, University of California, Davis, CA, 95618, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steve D.M. Brown
Medical Research Council Harwell Institute (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire, OX11 0RD, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Helen Parkinson
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Terrence F. Meehan
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Damian Smedley
Clinical Pharmacology, William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: d.smedley@qmul.ac.uk
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

ABSTRACT

Although genomic sequencing has been transformative in the study of rare genetic diseases, identifying causal variants remains a considerable challenge that can be addressed in part by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from the comprehensive viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and from human cell line essentiality screens. We propose a novel, cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing characteristics in the biological processes they regulate, tissue expression levels and human mutation rates. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented in the developmental lethal category, representing genes not essential for cell survival but required for organism development. Exploiting this finding, we have screened developmental disorder cases from three independent disease sequencing consortia and identified potentially pathogenic, de novo variants shared in different patients for several developmental lethal genes that have not previously been associated with rare disease. We therefore propose FUSIL as an efficient resource for disease gene discovery.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted June 24, 2019.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Human and mouse essentiality screens as a resource for disease gene discovery
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
Share
Human and mouse essentiality screens as a resource for disease gene discovery
Pilar Cacheiro, Violeta Muñoz-Fuentes, Stephen A. Murray, Mary E. Dickinson, Maja Bucan, Lauryl M.J. Nutter, Kevin A. Peterson, Hamed Haselimashhadi, Ann M. Flenniken, Hugh Morgan, Henrik Westerberg, Tomasz Konopka, Chih-Wei Hsu, Audrey Christiansen, Denise G. Lanza, Arthur L. Beaudet, Jason D. Heaney, Helmut Fuchs, Valerie Gailus-Durner, Tania Sorg, Jan Prochazka, Vendula Novosadova, Christopher J. Lelliott, Hannah Wardle-Jones, Sara Wells, Lydia Teboul, Heather Cater, Michelle Stewart, Tertius Hough, Wolfgang Wurst, Radislav Sedlacek, David J. Adams, John R. Seavitt, Glauco Tocchini-Valentini, Fabio Mammano, Robert E. Braun, Colin McKerlie, Yann Herault, Martin Hrabě de Angelis, Ann-Marie Mallon, K.C. Kent Lloyd, Steve D.M. Brown, Helen Parkinson, Terrence F. Meehan, Damian Smedley, on behalf of the Genomics England Research Consortium and the International Mouse Phenotyping Consortium
bioRxiv 678250; doi: https://doi.org/10.1101/678250
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Human and mouse essentiality screens as a resource for disease gene discovery
Pilar Cacheiro, Violeta Muñoz-Fuentes, Stephen A. Murray, Mary E. Dickinson, Maja Bucan, Lauryl M.J. Nutter, Kevin A. Peterson, Hamed Haselimashhadi, Ann M. Flenniken, Hugh Morgan, Henrik Westerberg, Tomasz Konopka, Chih-Wei Hsu, Audrey Christiansen, Denise G. Lanza, Arthur L. Beaudet, Jason D. Heaney, Helmut Fuchs, Valerie Gailus-Durner, Tania Sorg, Jan Prochazka, Vendula Novosadova, Christopher J. Lelliott, Hannah Wardle-Jones, Sara Wells, Lydia Teboul, Heather Cater, Michelle Stewart, Tertius Hough, Wolfgang Wurst, Radislav Sedlacek, David J. Adams, John R. Seavitt, Glauco Tocchini-Valentini, Fabio Mammano, Robert E. Braun, Colin McKerlie, Yann Herault, Martin Hrabě de Angelis, Ann-Marie Mallon, K.C. Kent Lloyd, Steve D.M. Brown, Helen Parkinson, Terrence F. Meehan, Damian Smedley, on behalf of the Genomics England Research Consortium and the International Mouse Phenotyping Consortium
bioRxiv 678250; doi: https://doi.org/10.1101/678250

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genomics
Subject Areas
All Articles
  • Animal Behavior and Cognition (1545)
  • Biochemistry (2500)
  • Bioengineering (1757)
  • Bioinformatics (9729)
  • Biophysics (3929)
  • Cancer Biology (2990)
  • Cell Biology (4235)
  • Clinical Trials (135)
  • Developmental Biology (2653)
  • Ecology (4129)
  • Epidemiology (2033)
  • Evolutionary Biology (6933)
  • Genetics (5243)
  • Genomics (6532)
  • Immunology (2208)
  • Microbiology (7012)
  • Molecular Biology (2784)
  • Neuroscience (17412)
  • Paleontology (127)
  • Pathology (432)
  • Pharmacology and Toxicology (712)
  • Physiology (1068)
  • Plant Biology (2516)
  • Scientific Communication and Education (647)
  • Synthetic Biology (835)
  • Systems Biology (2699)
  • Zoology (439)