Human and mouse essentiality screens as a resource for disease gene discovery
Pilar Cacheiro
(1)
,
Violeta Muñoz-Fuentes
(2)
,
Stephen Murray
(3)
,
Mary Dickinson
(4)
,
Maja Bucan
(5)
,
Lauryl Nutter
(6)
,
Kevin Peterson
(3)
,
Hamed Haselimashhadi
(2)
,
Ann Flenniken
(7)
,
Hugh Morgan
(8)
,
Henrik Westerberg
(8)
,
Tomasz Konopka
(1)
,
Chih-Wei Hsu
(4)
,
Audrey Christiansen
(4)
,
Denise Lanza
(4)
,
Arthur Beaudet
(4)
,
Jason Heaney
(4)
,
Helmut Fuchs
(9)
,
Valerie Gailus-Durner
(9)
,
Tania Sorg
(10, 11)
,
Jan Prochazka
(12)
,
Vendula Novosadova
(12)
,
Christopher Lelliott
(13)
,
Hannah Wardle-Jones
(13)
,
Sara Wells
(8)
,
Lydia Teboul
(8)
,
Heather Cater
(8)
,
Michelle Stewart
(8)
,
Tertius Hough
(8)
,
Wolfgang Wurst
(9, 14, 15)
,
Radislav Sedlacek
(12)
,
David Adams
(13)
,
John Seavitt
(4)
,
Glauco Tocchini-Valentini
(16)
,
Fabio Mammano
(16)
,
Robert Braun
(3)
,
Colin Mckerlie
(7)
,
Yann Herault
(17, 11)
,
Martin Hrabě de Angelis
(9, 14, 18)
,
Ann-Marie Mallon
(8)
,
K. Lloyd
(19)
,
Steve Brown
(8)
,
Helen Parkinson
(2)
,
Terrence Meehan
(2)
,
Damian Smedley
(1)
1
QMUL -
Queen Mary University of London
2 EMBL-EBI - European Bioinformatics Institute [Hinxton]
3 JAX - The Jackson Laboratory [Bar Harbor]
4 BCM - Baylor College of Medicine
5 University of Pennsylvania
6 SickKids - The Hospital for sick children [Toronto]
7 MSH - Mount Sinai Hospital [Toronto, Canada]
8 MRC Harwell Institute [UK]
9 HMGU - Helmholtz Zentrum München = German Research Center for Environmental Health
10 ICS - Institut Clinique de la Souris
11 PHENOMIN - French National Infrastructure for Mouse Phenogenomics
12 IMG / CAS - Institute of Molecular Genetics of the Czech Academy of Sciences
13 The Wellcome Trust Sanger Institute [Cambridge]
14 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
15 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
16 CNR - CNR - Italian National Research Council
17 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
18 DZD - German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg]
19 UC Davis - University of California [Davis]
2 EMBL-EBI - European Bioinformatics Institute [Hinxton]
3 JAX - The Jackson Laboratory [Bar Harbor]
4 BCM - Baylor College of Medicine
5 University of Pennsylvania
6 SickKids - The Hospital for sick children [Toronto]
7 MSH - Mount Sinai Hospital [Toronto, Canada]
8 MRC Harwell Institute [UK]
9 HMGU - Helmholtz Zentrum München = German Research Center for Environmental Health
10 ICS - Institut Clinique de la Souris
11 PHENOMIN - French National Infrastructure for Mouse Phenogenomics
12 IMG / CAS - Institute of Molecular Genetics of the Czech Academy of Sciences
13 The Wellcome Trust Sanger Institute [Cambridge]
14 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
15 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
16 CNR - CNR - Italian National Research Council
17 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
18 DZD - German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg]
19 UC Davis - University of California [Davis]
Lauryl Nutter
- Fonction : Auteur
- PersonId : 797881
- ORCID : 0000-0001-9619-146X
Ann Flenniken
- Fonction : Auteur
- PersonId : 797880
- ORCID : 0000-0003-1892-6154
Jason Heaney
- Fonction : Auteur
- PersonId : 797883
- ORCID : 0000-0001-8475-8828
Tania Sorg
- Fonction : Auteur
- PersonId : 760132
- ORCID : 0000-0001-6974-4735
Jan Prochazka
- Fonction : Auteur
- PersonId : 804742
- ORCID : 0000-0003-4675-8995
Christopher Lelliott
- Fonction : Auteur
- PersonId : 804743
- ORCID : 0000-0001-8087-4530
Sara Wells
- Fonction : Auteur
- PersonId : 764221
- ORCID : 0000-0002-0572-0600
Heather Cater
- Fonction : Auteur
- PersonId : 792660
- ORCID : 0000-0002-8696-6070
Wolfgang Wurst
- Fonction : Auteur
- PersonId : 758949
- ORCID : 0000-0003-4422-7410
Radislav Sedlacek
- Fonction : Auteur
- PersonId : 798452
- ORCID : 0000-0002-3352-392X
- IdRef : 241510597
David Adams
- Fonction : Auteur
- PersonId : 758522
- ORCID : 0000-0002-8722-4108
John Seavitt
- Fonction : Auteur
- PersonId : 797882
- ORCID : 0000-0003-3209-3187
Robert Braun
- Fonction : Auteur
- PersonId : 797885
- ORCID : 0000-0003-3856-9465
Colin Mckerlie
- Fonction : Auteur
- PersonId : 797879
- ORCID : 0000-0002-2232-0967
Yann Herault
- Fonction : Auteur
- PersonId : 741744
- IdHAL : yann-herault
- ORCID : 0000-0001-7049-6900
- IdRef : 077172639
Martin Hrabě de Angelis
- Fonction : Auteur
- PersonId : 758367
- ORCID : 0000-0002-7898-2353
- IdRef : 115604332
K. Lloyd
- Fonction : Auteur
- PersonId : 797887
- ORCID : 0000-0002-5318-4144
Steve Brown
- Fonction : Auteur
- PersonId : 797886
- ORCID : 0000-0002-0617-4824
Résumé
The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a 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 biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.
Domaines
Sciences du Vivant [q-bio]Origine | Publication financée par une institution |
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