High-throughput discovery of novel developmental phenotypes.
Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.
Department of Molecular Physiology and Biophysics, Houston, Texas 77030, USA.
Mary E
ME
Dickinson
The Toronto Centre for Phenogenomics, Toronto, Ontario M5T 3H7, Canada.|Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
Ann M
AM
Flenniken
Genomics and Computational Biology Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Xiao
X
Ji
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
Lydia
L
Teboul
The Toronto Centre for Phenogenomics, Toronto, Ontario M5T 3H7, Canada.|Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario M5T 3H7, Canada.
Michael D
MD
Wong
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Jacqueline K
JK
White
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Terrence F
TF
Meehan
Centre for Anatomy and Cell Biology, Medical University of Vienna, Vienna A-1090, Austria.
Wolfgang J
WJ
Weninger
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
Henrik
H
Westerberg
The Toronto Centre for Phenogenomics, Toronto, Ontario M5T 3H7, Canada.|The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Hibret
H
Adissu
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Candice N
CN
Baker
Mouse Biology Program, University of California, Davis, California 95618, USA.
Lynette
L
Bower
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
James M
JM
Brown
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
L Brianna
LB
Caddle
Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, Monterotondo Scalo I-00015, Italy.
Francesco
F
Chiani
Mouse Biology Program, University of California, Davis, California 95618, USA.
Dave
D
Clary
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
James
J
Cleak
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Program in Medical and Population Genetics, Broad Institute MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Mark J
MJ
Daly
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
James M
JM
Denegre
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Brendan
B
Doe
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Mary E
ME
Dolan
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Sarah M
SM
Edie
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics and German Mouse Clinic, Neuherberg 85764, Germany.
Helmut
H
Fuchs
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics and German Mouse Clinic, Neuherberg 85764, Germany.
Valerie
V
Gailus-Durner
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Antonella
A
Galli
Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, Monterotondo Scalo I-00015, Italy.
Alessia
A
Gambadoro
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Juan
J
Gallegos
SKL of Pharmaceutical Biotechnology and Model Animal Research Center, Collaborative Innovation Center for Genetics and Development, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China.
Shiying
S
Guo
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
Neil R
NR
Horner
Department of Molecular Physiology and Biophysics, Houston, Texas 77030, USA.
Chih-Wei
CW
Hsu
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
Sara J
SJ
Johnson
Department of Molecular Physiology and Biophysics, Houston, Texas 77030, USA.
Sowmya
S
Kalaga
Department of Molecular Physiology and Biophysics, Houston, Texas 77030, USA.
Lance C
LC
Keith
Mouse Biology Program, University of California, Davis, California 95618, USA.
Louise
L
Lanoue
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
Thomas N
TN
Lawson
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Program in Medical and Population Genetics, Broad Institute MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Monkol
M
Lek
Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), et Institut de Génétique Biologie Moléculaire et Cellulaire (IGBMC) CNRS, INSERM, University of Strasbourg, Illkirch-Graffenstaden 67404, France.
Manuel
M
Mark
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics and German Mouse Clinic, Neuherberg 85764, Germany.
Susan
S
Marschall
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Jeremy
J
Mason
Department of Molecular Physiology and Biophysics, Houston, Texas 77030, USA.
Melissa L
ML
McElwee
The Toronto Centre for Phenogenomics, Toronto, Ontario M5T 3H7, Canada.|The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Susan
S
Newbigging
The Toronto Centre for Phenogenomics, Toronto, Ontario M5T 3H7, Canada.|The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Lauryl M J
LM
Nutter
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Kevin A
KA
Peterson
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Ramiro
R
Ramirez-Solis
Mouse Biology Program, University of California, Davis, California 95618, USA.
Douglas J
DJ
Rowland
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Edward
E
Ryder
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Program in Medical and Population Genetics, Broad Institute MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Kaitlin E
KE
Samocha
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
John R
JR
Seavitt
Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), et Institut de Génétique Biologie Moléculaire et Cellulaire (IGBMC) CNRS, INSERM, University of Strasbourg, Illkirch-Graffenstaden 67404, France.
Mohammed
M
Selloum
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
Zsombor
Z
Szoke-Kovacs
RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan.
Masaru
M
Tamura
Mouse Biology Program, University of California, Davis, California 95618, USA.
Amanda G
AG
Trainor
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Ilinca
I
Tudose
RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan.
Shigeharu
S
Wakana
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Jonathan
J
Warren
Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), et Institut de Génétique Biologie Moléculaire et Cellulaire (IGBMC) CNRS, INSERM, University of Strasbourg, Illkirch-Graffenstaden 67404, France.
Olivia
O
Wendling
Children's Hospital Oakland Research Institute, Oakland, California 94609, USA.
David B
DB
West
Department of Molecular Physiology and Biophysics, Houston, Texas 77030, USA.
Leeyean
L
Wong
RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan.
Atsushi
A
Yoshiki
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Program in Medical and Population Genetics, Broad Institute MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Daniel G
DG
MacArthur
Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, Monterotondo Scalo I-00015, Italy.
Glauco P
GP
Tocchini-Valentini
SKL of Pharmaceutical Biotechnology and Model Animal Research Center, Collaborative Innovation Center for Genetics and Development, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China.
Xiang
X
Gao
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Paul
P
Flicek
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Allan
A
Bradley
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
William C
WC
Skarnes
The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Monica J
MJ
Justice
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Helen E
HE
Parkinson
IMPC, San Anselmo, California 94960, USA.
Mark
M
Moore
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
Sara
S
Wells
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Robert E
RE
Braun
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Karen L
KL
Svenson
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics and German Mouse Clinic, Neuherberg 85764, Germany.|Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising 81675, Germany.|German Center for Diabetes Research (DZD), Neuherberg 85764, Germany.
Martin Hrabe
MH
de Angelis
Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), et Institut de Génétique Biologie Moléculaire et Cellulaire (IGBMC) CNRS, INSERM, University of Strasbourg, Illkirch-Graffenstaden 67404, France.
Yann
Y
Herault
The Francis Crick Institute Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW1 1AT, UK.
Tim
T
Mohun
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
Ann-Marie
AM
Mallon
The Toronto Centre for Phenogenomics, Toronto, Ontario M5T 3H7, Canada.|Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario M5T 3H7, Canada.
R Mark
RM
Henkelman
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
Steve D M
SD
Brown
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
David J
DJ
Adams
Mouse Biology Program, University of California, Davis, California 95618, USA.
K C Kent
KC
Lloyd
The Toronto Centre for Phenogenomics, Toronto, Ontario M5T 3H7, Canada.|The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Colin
C
McKerlie
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Arthur L
AL
Beaudet
Departments of Genetics and Psychiatry, Perlman School of Medicine, University of Pennsylvania, Philadelphia Pennsylvania 19104, USA.
Maja
M
Bućan
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Stephen A
SA
Murray
D000818:Animals; D017124:Conserved Sequence / Q000235:genetics; D004194:Disease; D004622:Embryo, Mammalian / Q000196:embryology* / Q000378:metabolism*; D020043:Genes, Essential / Q000235:genetics*; D005804:Genes, Lethal / Q000235:genetics*; D055106:Genome-Wide Association Study; D057166:High-Throughput Screening Assays; D006801:Humans; D021621:Imaging, Three-Dimensional; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D019683:Penetrance; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017385:Sequence Homology