Article | Published:

High-throughput discovery of novel developmental phenotypes

Nature volume 537, pages 508514 (22 September 2016) | Download Citation

  • A Corrigendum to this article was published on 08 November 2017

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.

References

  1. 1.

    et al. Phenotypic annotation of the mouse X chromosome. Genome Res . 20, 1154–1164 (2010)

  2. 2.

    Capitalizing on large-scale mouse mutagenesis screens. Nat. Rev. Genet. 1, 109–115 (2000)

  3. 3.

    , & A phenotype-based screen for embryonic lethal mutations in the mouse. Proc. Natl Acad. Sci. USA 95, 7485–7490 (1998)

  4. 4.

    & The art and design of genetic screens: mouse. Nat. Rev. Genet. 6, 557–567 (2005)

  5. 5.

    Preclinical research: Make mouse studies work. Nature 507, 423–425 (2014)

  6. 6.

    , & Believe it or not: how much can we rely on published data on potential drug targets? Nat. Rev. Drug Discov. 10, 712 (2011)

  7. 7.

    et al. Mouse large-scale phenotyping initiatives: overview of the European mouse disease clinic (EUMODIC) and of the Wellcome Trust Sanger Institute mouse genetics project. Mamm. Genome 23, 600–610 (2012)

  8. 8.

    et al. The mammalian gene function resource: the international knockout mouse consortium. Mamm. Genome 23, 580–586 (2012)

  9. 9.

    et al. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics. Nat. Genet. 47, 969–978 (2015)

  10. 10.

    et al. A conditional knockout resource for the genome-wide study of mouse gene function. Nature 474, 337–342 (2011)

  11. 11.

    et al. High-throughput engineering of the mouse genome coupled with high-resolution expression analysis. Nat. Biotechnol. 21, 652–659 (2003)

  12. 12.

    et al. Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes. Cell 154, 452–464 (2013)

  13. 13.

    et al. Bloomsbury report on mouse embryo phenotyping: recommendations from the IMPC workshop on embryonic lethal screening. Dis. Model. Mech . 6, 571–579 (2013)

  14. 14.

    et al.; The Gene Ontology Consortium. Gene ontology: tool for the unification of biology. Nat. Genet. 25, 25–29 (2000)

  15. 15.

    et al. Gene essentiality and synthetic lethality in haploid human cells. Science 350, 1092–1096 (2015)

  16. 16.

    et al. High-resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities. Cell 163, 1515–1526 (2015)

  17. 17.

    et al. Identification and characterization of essential genes in the human genome. Science 350, 1096–1101 (2015)

  18. 18.

    et al. Optical projection tomography as a tool for 3D microscopy and gene expression studies. Science 296, 541–545 (2002)

  19. 19.

    , , , & A novel 3D mouse embryo atlas based on micro-CT. Development 139, 3248–3256 (2012)

  20. 20.

    , , & Automated pipeline for anatomical phenotyping of mouse embryos using micro-CT. Development 141, 2533–2541 (2014)

  21. 21.

    et al. 4D atlas of the mouse embryo for precise morphological staging. Development 142, 3583–3591 (2015)

  22. 22.

    et al. Phenotyping structural abnormalities in mouse embryos using high-resolution episcopic microscopy. Dis. Model. Mech . 7, 1143–1152 (2014)

  23. 23.

    et al. Cbx4 regulates the proliferation of thymic epithelial cells and thymus function. Development 140, 780–788 (2013)

  24. 24.

    & Isolation and genetic characterization of cell-lineage mutants of the nematode Caenorhabditis elegans. Genetics 96, 435–454 (1980)

  25. 25.

    , & Predicting mutation outcome from early stochastic variation in genetic interaction partners. Nature 480, 250–253 (2011)

  26. 26.

    , , & Variability in gene expression underlies incomplete penetrance. Nature 463, 913–918 (2010)

  27. 27.

    , & Different phenotypes for mice deficient in either activins or activin receptor type II. Nature 374, 356–360 (1995)

  28. 28.

    et al. The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice. Dev. Biol. 213, 157–169 (1999)

  29. 29.

    , & From mouse to human: evolutionary genomics analysis of human orthologs of essential genes. PLoS Genet . 9, e1003484 (2013)

  30. 30.

    , , & Defining the role of essential genes in human disease. PLoS One 6, e27368 (2011)

  31. 31.

    et al. Human Gene Mutation Database (HGMD): 2003 update. Hum. Mutat. 21, 577–581 (2003)

  32. 32.

    et al. The human gene mutation database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum. Genet. 133, 1–9 (2014)

  33. 33.

    et al. The NHGRI GWAS catalog, a curated resource of SNP-trait associations. Nucleic Acids Res . 42, D1001–D1006 (2014)

  34. 34.

    & A syndrome of severe midface retraction, multiple skull anomalies, clubfeet, and cardiac and renal malformations in sibs. Am. J. Med. Genet. 1, 361–375 (1978)

  35. 35.

    et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat. Genet. 45, 18–24 (2013)

  36. 36.

    et al. Glycogenin-1 deficiency and inactivated priming of glycogen synthesis. N. Engl. J. Med. 362, 1203–1210 (2010)

  37. 37.

    et al. A new muscle glycogen storage disease associated with glycogenin-1 deficiency. Ann. Neurol. 76, 891–898 (2014)

  38. 38.

    et al. Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2. Nat. Genet. 39, 1071–1073 (2007)

  39. 39.

    et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016)

  40. 40.

    , , , & Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet . 9, e1003709 (2013)

  41. 41.

    et al. Identification of a large set of rare complete human knockouts. Nat. Genet. 47, 448–452 (2015)

  42. 42.

    et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335, 823–828 (2012)

  43. 43.

    Human knockout research: new horizons and opportunities. Trends Genet . 31, 108–115 (2015)

  44. 44.

    et al. Health and population effects of rare gene knockouts in adult humans with related parents. Science 352, 474–477 (2016)

  45. 45.

    et al. One-step generation of mice carrying reporter and conditional alleles by CRISPR/Cas-mediated genome engineering. Cell 154, 1370–1379 (2013)

  46. 46.

    et al. Too many roads not taken. Nature 470, 163–165 (2011)

  47. 47.

    , , , & Design and implementation of a custom built optical projection tomography system. PLoS One 8, e73491 (2013)

  48. 48.

    , & Structural stabilization of tissue for embryo phenotyping using micro-CT with iodine staining. PLoS One 8, e84321 (2013)

  49. 49.

    & Practical cone-beam tomography. J. Opt. Soc. Am. A 33, 3640–3646 (1984)

  50. 50.

    , , , & Anatomical phenotyping in the brain and skull of a mutant mouse by magnetic resonance imaging and computed tomography. Physiol. Genomics 24, 154–162 (2006)

  51. 51.

    et al. Mouse behavioral mutants have neuroimaging abnormalities. Hum. Brain Mapp. 28, 567–575 (2007)

  52. 52.

    , , & Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. J. Comput. Assist. Tomogr. 18, 192–205 (1994)

  53. 53.

    et al. A reproducible evaluation of ANTs similarity metric performance in brain image registration. Neuroimage 54, 2033–2044 (2011)

  54. 54.

    et al. Longitudinal neuroanatomical changes determined by deformation-based morphometry in a mouse model of Alzheimer’s disease. Neuroimage 42, 19–27 (2008)

  55. 55.

    , & Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage 15, 870–878 (2002)

  56. 56.

    , , , & The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease. Nucleic Acids Res . 43, D726–D736 (2015)

  57. 57.

    & Expanding the mammalian phenotype ontology to support automated exchange of high throughput mouse phenotyping data generated by large-scale mouse knockout screens. J. Biomed. Semantics 6, 11 (2015)

  58. 58.

    et al. Ensembl 2015. Nucleic Acids Res . 43, D662–D669 (2015)

  59. 59.

    , , , & Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res . 33, D514–D517 (2005)

Download references

Acknowledgements

The authors thank all IMPC members and partners for their contribution to the consortium effort, including this study, and acknowledge the contributions of J. Rossant, S. L. Adamson, and T. Bubela. This work was supported by NIH grants U42 OD011185 (S.A.M.), U54 HG006332 (R.E.B., K.S.), U54 HG006348-S1 and OD011174 (A.L.B.), HG006364-03S1 and U42 OD011175 (K.C.K.L.), U54 HG006370 (P.F., A.-M.M., H.E.P., S.D.M.B.) and additional support provided by the The Wellcome Trust, Medical Research Council Strategic Award (L.T., S.W., S.D.M.B.), Government of Canada through Genome Canada and Ontario Genomics (OGI-051)(C.M., S.D.M.B.), Wellcome Trust Strategic Award “Deciphering the Mechanisms of Developmental Disorders (DMDD)” (WT100160) (D.A., T.M.), National Centre for Scientific Research (CNRS), the French National Institute of Health and Medical Research (INSERM), the University of Strasbourg (UDS), the “Centre Européen de Recherche en Biologie et en Médecine”, the “Agence Nationale de la Recherche” under the frame programme “Investissements d’Avenir” labelled ANR-10-IDEX-0002-02, ANR-10-INBS- 07 PHENOMIN to (Y.H.), The German Federal Ministry of Education and Research by Infrafrontier grant 01KX1012 (S.M., V.G.D., H.F., M.H.d.A.)

Author information

Author notes

    • Mary E. Dickinson
    • , Ann M. Flenniken
    • , Xiao Ji
    • , Lydia Teboul
    •  & Michael D. Wong

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular Physiology and Biophysics, Houston, Texas 77030, USA

    • Mary E. Dickinson
    • , Chih-Wei Hsu
    • , Sowmya Kalaga
    • , Lance C. Keith
    • , Melissa L. McElwee
    •  & Leeyean Wong
  2. The Toronto Centre for Phenogenomics, Toronto, Ontario M5T 3H7, Canada

    • Ann M. Flenniken
    • , Michael D. Wong
    • , Hibret Adissu
    • , Susan Newbigging
    • , Lauryl M. J. Nutter
    • , Ruolin Guo
    • , Dawei Qu
    • , Shoshana Spring
    • , Lisa Yu
    • , Jacob Ellegood
    • , Lily Morikawa
    • , Xueyuan Shang
    • , Pat Feugas
    • , Amie Creighton
    • , Patricia Castellanos Penton
    • , Ozge Danisment
    • , R. Mark Henkelman
    •  & Colin McKerlie
  3. Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

    • Ann M. Flenniken
  4. Genomics and Computational Biology Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Xiao Ji
  5. Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK

    • Lydia Teboul
    • , Henrik Westerberg
    • , James M. Brown
    • , James Cleak
    • , Neil R. Horner
    • , Sara J. Johnson
    • , Thomas N. Lawson
    • , Zsombor Szoke-Kovacs
    • , Michelle E. Stewart
    • , Carol Copley
    • , Jackie Harrison
    • , Samantha Joynson
    • , Sara Wells
    • , Ann-Marie Mallon
    •  & Steve D. M. Brown
  6. Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario M5T 3H7, Canada

    • Michael D. Wong
    •  & R. Mark Henkelman
  7. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK

    • Jacqueline K. White
    • , Brendan Doe
    • , Antonella Galli
    • , Ramiro Ramirez-Solis
    • , Edward Ryder
    • , Nicola Griggs
    • , Catherine L. Tudor
    • , Angela L. Green
    • , Cecilia Icoresi Mazzeo
    • , Emma Siragher
    • , Charlotte Lillistone
    • , Elizabeth Tuck
    • , Diane Gleeson
    • , Debarati Sethi
    • , Tanya Bayzetinova
    • , Jonathan Burvill
    • , Bishoy Habib
    • , Lauren Weavers
    • , Ryea Maswood
    • , Evelina Miklejewska
    • , Michael Woods
    • , Evelyn Grau
    • , Stuart Newman
    • , Caroline Sinclair
    • , Ellen Brown
    • , Allan Bradley
    • , William C. Skarnes
    •  & David J. Adams
  8. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK

    • Terrence F. Meehan
    • , Jeremy Mason
    • , Ilinca Tudose
    • , Jonathan Warren
    • , Paul Flicek
    •  & Helen E. Parkinson
  9. Centre for Anatomy and Cell Biology, Medical University of Vienna, Vienna A-1090, Austria

    • Wolfgang J. Weninger
  10. The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

    • Hibret Adissu
    • , Susan Newbigging
    • , Lauryl M. J. Nutter
    • , Monica J. Justice
    •  & Colin McKerlie
  11. The Jackson Laboratory, Bar Harbor, Maine 04609, USA

    • Candice N. Baker
    • , L. Brianna Caddle
    • , James M. Denegre
    • , Mary E. Dolan
    • , Sarah M. Edie
    • , Kevin A. Peterson
    • , Matthew McKay
    • , Barbara Urban
    • , Caroline Lund
    • , Erin Froeter
    • , Taylor LaCasse
    • , Adrienne Mehalow
    • , Emily Gordon
    • , Leah Rae Donahue
    • , Robert Taft
    • , Peter Kutney
    • , Stephanie Dion
    • , Leslie Goodwin
    • , Susan Kales
    • , Rachel Urban
    • , Kristina Palmer
    • , Robert E. Braun
    • , Karen L. Svenson
    •  & Stephen A. Murray
  12. Mouse Biology Program, University of California, Davis, California 95618, USA

    • Lynette Bower
    • , Dave Clary
    • , Louise Lanoue
    • , Douglas J. Rowland
    • , Amanda G. Trainor
    •  & K. C. Kent Lloyd
  13. Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, Monterotondo Scalo I-00015, Italy

    • Francesco Chiani
    • , Alessia Gambadoro
    •  & Glauco P. Tocchini-Valentini
  14. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Mark J. Daly
    • , Monkol Lek
    • , Kaitlin E. Samocha
    •  & Daniel G. MacArthur
  15. Program in Medical and Population Genetics, Broad Institute MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • Mark J. Daly
    • , Monkol Lek
    • , Kaitlin E. Samocha
    •  & Daniel G. MacArthur
  16. Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics and German Mouse Clinic, Neuherberg 85764, Germany

    • Helmut Fuchs
    • , Valerie Gailus-Durner
    • , Susan Marschall
    •  & Martin Hrabe de Angelis
  17. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA

    • Juan Gallegos
    • , John R. Seavitt
    • , Monica J. Justice
    •  & Arthur L. Beaudet
  18. 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 Guo
    •  & Xiang Gao
  19. 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 Mark
    • , Mohammed Selloum
    • , Olivia Wendling
    • , Fabien Pertuy
    • , Deborah Bitz
    • , Bruno Weber
    • , Patrice Goetz-Reiner
    • , Hughes Jacobs
    • , Elise Le Marchand
    • , Amal El Amri
    • , Leila El Fertak
    • , Hamid Ennah
    • , Dalila Ali-Hadji
    • , Abdel Ayadi
    • , Marie Wattenhofer-Donze
    • , Sylvie Jacquot
    • , Philippe André
    • , Marie-Christine Birling
    • , Guillaume Pavlovic
    • , Tania Sorg
    •  & Yann Herault
  20. RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan

    • Masaru Tamura
    • , Shigeharu Wakana
    • , Atsushi Yoshiki
    • , Shinya Ayabe
    • , Mizuho Iwama
    •  & Ayumi Murakami
  21. Children’s Hospital Oakland Research Institute, Oakland, California 94609, USA

    • David B. West
  22. IMPC, San Anselmo, California 94960, USA

    • Mark Moore
  23. Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising 81675, Germany

    • Martin Hrabe de Angelis
  24. German Center for Diabetes Research (DZD), Neuherberg 85764, Germany

    • Martin Hrabe de Angelis
  25. The Francis Crick Institute Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW1 1AT, UK

    • Tim Mohun
  26. Departments of Genetics and Psychiatry, Perlman School of Medicine, University of Pennsylvania, Philadelphia Pennsylvania 19104, USA

    • Maja Bućan
  27. Charles River Laboratories, Wilmington, Massachusetts 01887, USA

    • Iva Morse
    •  & Frank Benso
  28. HelmholtzZentrum Munich, Institute of Developmental Genetics, 85764, Munich-Neuherberg, Germany

    • Wolfgang Wurst
  29. Technical University of Munich, Chair of Developmental Genetics, 85764, Munich-Neuherberg, Germany

    • Wolfgang Wurst
  30. German Center for Neurodegenerative Diseases (DZNE) Site Munich,, 81377, Munich, Germany

    • Wolfgang Wurst
  31. Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany

    • Wolfgang Wurst

Consortia

  1. The International Mouse Phenotyping Consortium

    The Jackson Laboratory

    Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS)

    Charles River Laboratories

    MRC Harwell

    The Toronto Centre for Phenogenomics

    The Wellcome Trust Sanger Institute

    RIKEN BioResource Center

Authors

  1. Search for Mary E. Dickinson in:

  2. Search for Ann M. Flenniken in:

  3. Search for Xiao Ji in:

  4. Search for Lydia Teboul in:

  5. Search for Michael D. Wong in:

  6. Search for Jacqueline K. White in:

  7. Search for Terrence F. Meehan in:

  8. Search for Wolfgang J. Weninger in:

  9. Search for Henrik Westerberg in:

  10. Search for Hibret Adissu in:

  11. Search for Candice N. Baker in:

  12. Search for Lynette Bower in:

  13. Search for James M. Brown in:

  14. Search for L. Brianna Caddle in:

  15. Search for Francesco Chiani in:

  16. Search for Dave Clary in:

  17. Search for James Cleak in:

  18. Search for Mark J. Daly in:

  19. Search for James M. Denegre in:

  20. Search for Brendan Doe in:

  21. Search for Mary E. Dolan in:

  22. Search for Sarah M. Edie in:

  23. Search for Helmut Fuchs in:

  24. Search for Valerie Gailus-Durner in:

  25. Search for Antonella Galli in:

  26. Search for Alessia Gambadoro in:

  27. Search for Juan Gallegos in:

  28. Search for Shiying Guo in:

  29. Search for Neil R. Horner in:

  30. Search for Chih-Wei Hsu in:

  31. Search for Sara J. Johnson in:

  32. Search for Sowmya Kalaga in:

  33. Search for Lance C. Keith in:

  34. Search for Louise Lanoue in:

  35. Search for Thomas N. Lawson in:

  36. Search for Monkol Lek in:

  37. Search for Manuel Mark in:

  38. Search for Susan Marschall in:

  39. Search for Jeremy Mason in:

  40. Search for Melissa L. McElwee in:

  41. Search for Susan Newbigging in:

  42. Search for Lauryl M. J. Nutter in:

  43. Search for Kevin A. Peterson in:

  44. Search for Ramiro Ramirez-Solis in:

  45. Search for Douglas J. Rowland in:

  46. Search for Edward Ryder in:

  47. Search for Kaitlin E. Samocha in:

  48. Search for John R. Seavitt in:

  49. Search for Mohammed Selloum in:

  50. Search for Zsombor Szoke-Kovacs in:

  51. Search for Masaru Tamura in:

  52. Search for Amanda G. Trainor in:

  53. Search for Ilinca Tudose in:

  54. Search for Shigeharu Wakana in:

  55. Search for Jonathan Warren in:

  56. Search for Olivia Wendling in:

  57. Search for David B. West in:

  58. Search for Leeyean Wong in:

  59. Search for Atsushi Yoshiki in:

  60. Search for Wolfgang Wurst in:

  61. Search for Daniel G. MacArthur in:

  62. Search for Glauco P. Tocchini-Valentini in:

  63. Search for Xiang Gao in:

  64. Search for Paul Flicek in:

  65. Search for Allan Bradley in:

  66. Search for William C. Skarnes in:

  67. Search for Monica J. Justice in:

  68. Search for Helen E. Parkinson in:

  69. Search for Mark Moore in:

  70. Search for Sara Wells in:

  71. Search for Robert E. Braun in:

  72. Search for Karen L. Svenson in:

  73. Search for Martin Hrabe de Angelis in:

  74. Search for Yann Herault in:

  75. Search for Tim Mohun in:

  76. Search for Ann-Marie Mallon in:

  77. Search for R. Mark Henkelman in:

  78. Search for Steve D. M. Brown in:

  79. Search for David J. Adams in:

  80. Search for K. C. Kent Lloyd in:

  81. Search for Colin McKerlie in:

  82. Search for Arthur L. Beaudet in:

  83. Search for Maja Bućan in:

  84. Search for Stephen A. Murray in:

Contributions

M.E.D., A.M.F., X.J., L.T., M.D.W., J.K.W., T.F.M., W.J.W., H.W., D.J.A., M.B., and S.A.M. contributed to the data analysis and writing of the paper. A.Y., A.B., L.B., L.B.C., F.C., B.D., H.F., A. Galli, A.G., V. G.-D., S.G., S.M., S.A.M., L.M.J.N., E.R., J.R.S., M.S., W.C.S., R.R.S., L.T., S.W. and J.K.W. generated animal models and identified lethal genes. M.E.D, A.M.F., X.J., H.W., L.T., J.M.B., N.R.H., T.F.M., M.E.Dolan and S.A.M. contributed to gene list analysis. H.A., L.B, L.B.C., C.N.B., J.C., J.M.D., M.E.D, S.M.E., A.M.F. A. Galli, C.-W.H., S.J.J., S.K., L.C.K., L.L., M.M., M.L.M., T.M., S.A.M., S.N., L.M.J.N., K.A.P., D.R., E.R., Z. S.-K., M.T., L.T., A.T., O.W., W.J.W., J.K.W. and L.W. contributed to the secondary lethal screen and data analysis. J.M.B., D.C., J.G., N.R.H, T.N.L., J.M., I.T. and J.W. provided informatics support. M.D.W. and R.M.H. performed the automated 3D analysis. J.M.B, N.R.H, I.T., J.W. and H.W. developed and implemented the IMPC portal, X.J, M.J.D., S.A.M., M.L., K.E.S., D.G.M., D.J.A. and M.B. contributed to the essential gene and human disease analysis. M.E.D, A.M.F., X.J, L.T., M.D.W., J.K.W, T.F.M, W.J.W., H.W., S.W., R.R-S., J.M.D., D.G.M., D.B.W., W.W., G.P.T.-V., X.G., P.F., W.C.S., A.B, M.J.J., H.E.P., M.Moore, S.W., R.E.B., K.S., M.H.d.A, Y.H., T.M., A.-M.M., R.M.H., S.D.M.B., D.J.A., K.C.K.L., C.M., A.L.B., M.B. and S.A.M. contributed to the design, management, execution of the work and review of the manuscript.

Corresponding author

Correspondence to Stephen A. Murray.

All data are freely available from the IMPC database hosted at EMBL-EBI via a web portal (mousephenotype.org), ftp (ftp://ftp.ebi.ac.uk/pub/databases/impc) and automatic programmatic interfaces. An archived version of the database will be maintained after cessation of funding (exp. 2021) for an additional 5 years. Allele and phenotype summaries are additionally archived with Mouse Genome Informatics at the Jackson Laboratory via direct data submissions (J:136110, J:148605, J:157064, J:157065, J:188991, J:211773).

Reviewer Information Nature thanks N. Copeland, L. Niswander and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Data

    This file contains Supplementary Table 1.

  2. 2.

    Supplementary Data

    This file contains Supplementary Table 2.

  3. 3.

    Supplementary Data

    This file contains Supplementary Table 3.

  4. 4.

    Supplementary Data

    This file contains Supplementary Table 4.

  5. 5.

    Supplementary Data

    This file contains Supplementary Table 5.

  6. 6.

    Supplementary Data

    This file contains Supplementary Table 6.

  7. 7.

    Supplementary Data

    This file contains Supplementary Tables 7-11.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature19356

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.