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.
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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.)
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 figures and tables
Extended Data Figure 1 Standard IMPC allele variants included in this study.
a, Conditional-ready, knockout-first allele (tm1a) design (top) with LacZ reporter, and the Cre-converted (tm1b, bottom) version lacking the neo cassette and critical exon. The promoter driven variant is illustrated. b, Schematic of the small number of alleles included where the distal loxP had been lost during targeting (tm1e, top) and the converted (tme.1) variant with the neo cassette removed. c, Velocigene ‘definitive null’ design (top, tm1) where the LacZ cassette replaces the coding sequence of the target gene, and Cre-excised variant (bottom, tm1.1). Details of all alleles used are listed in Supplementary Table 2 and 5. Additional details and schematics of all allele variants are available at http://www.mousephenotype.org/about-ikmc/targeting-strategies.
Extended Data Figure 2 Distribution of lethal, subviable and viable lines for each IMPC Centre.
Spine (a) and mosaic (b) plots of progress examining primary viability of IMPC lines for each IMPC Centre, segmented by ‘Lethal’, ‘Subviable’ or ‘Viable’ outcome. The mosaic plot shows the significant overrepresentation of viable lines from UCD and lethal lines from ICS, NING, and TCP. c, d, Spine and mosaic plots of primary viability outcome by chromosome, showing no significant deviation from the expected distribution. e, Comparison of the percentage of viable, subviable, and lethal lines between genes for which no targeted knockout alleles have been reported (novel) and genes for which one or more knockout alleles has been reported. BCM, Baylor College of Medicine; GMC, German Mouse Clinic; H, MRC Harwell; ICS, Institut Clinique del la Souris (PHENOMIN); J, The Jackson Laboratory; NING, Model Animal Research Center, Nanjing University; RBRC, RIKEN BioResource Center; TCP, Toronto Centre for Phenogenomics; UCD, University of California, Davis; WTSI, Wellcome Trust Sanger Institute.
Extended Data Figure 3 Multiple GOSlim categories show enrichment for lethal and subviable genes versus viable genes from the IMPC dataset.
The analysis was performed for GO Process (a), GO Function (b) and GO Component (c) categories. On the x axis is the proportion of genes in each class that are annotated for the GO Slim group for each category. d–f, Novel lethal IMPC genes, previously reported IMPC genes and all MGI genes were subject to the same analysis, showing the large effect analysis and characterization of lethal genes has on GO analysis.
Extended Data Figure 4 Schematic of the IMPC embryonic lethal phenotyping pipeline.
Lines were defined as lethal if zero homozygous animals were identified after ≥ 28 animals had been genotyped. The KOMP2/IMPC centres began with a mid-gestation (E12.5) screen, while the DMDD program initiated screening at the organogenesis phase (E14.5). If no homozygotes were identified (after ≥ 28 embryos screened), centres examined and characterized embryos at the pattern formation stage (E9.5). Homozygous embryos at this stage were scored for gross anatomical defects and imaged using OPT. If live homozygotes were identified at E12.5, centres proceeded with the screen at E15.5 or E18.5. This decision was based on the presence of any observable phenotype at E12.5 and was at the discretion of the centre. Embryos collected at E15.5 were imaged via iodine-contrast microCT. Once sufficient numbers were collected, image registration and quantitative volumetric analysis was performed. Each time point should be considered independently, as some included strains have not been completely analysed and progression through each time point is at the discretion of the centre. For each term, two mutants with the same phenotype were required to score a hit.
Extended Data Figure 5 Cardiac defects in Strn3, Atg3, and Slc39a8 mutant embryos.
a, b, Severe fetal oedema and sporadic haemorrhaging in E15.5 homozygous mutant embryos versus controls (n = 7 mutants analysed) c, d, Subtle but consistent cardiac septal defects (arrowhead) observed in transverse micro-CT volume sections in Strn3−/− embryos (d) versus control (c) (n = 5 mutants analysed). e, f, Atg3+/− (e) and Atg3−/− (f) E14.5 embryos imaged by micro-CT after contrast staining showed evidence of heart morphological defects including ventricular septal defects (white arrows in f). Atg3−/− mice also showed abnormal atrio–ventricular valves (n = 4 mutants analysed). g–j, Transverse (g, h) and coronal (i, j) sections through micro-CT volumes of mutant and control Slc39a8 E14.5 embryos revealed heart morphological defects including ventricular septal defects (white arrows in h). Slc39a8−/− mice also showed the absence of sternum, a small chest cavity and a small liver (j) (n = 4 mutants analysed).
Extended Data Figure 6 High-resolution 3D imaging reveals phenotypes in Tmem100 and Eya4 mutant embryos.
Tmem100−/− embryos had abnormal heart development compared to Tmem100+/+ controls. E9.5 Tmem100−/− embryos had large pericardial effusion and cardiac dysmorphology and enlargement (arrow) when compared to E9.5 Tmem100+/+ (wild-type) embryos as seen by OPT imaging (a) and bright-field microscopy(c) resulting in lethality. (n = 8 Tmem100+/+ versus n = 8 Tmem100−/−, with all 8 showing the defect). b, LacZ expression in the E12.5 Tmem100+/− embryo indicated expression in the heart (arrows), blood vessels and craniofacial regions (blue). d–i, Micro-CT imaging revealed a small cochlear volume in E15.5 Eya4−/− embryos. E15.5 Eya4−/− embryos were registered to an average control dataset of the same age followed by automated analysis to show that mutant embryos had a statistically smaller cochlear volume compared to Eya4+/+ (wild-type) embryos. d, Transverse, coronal, and sagittal sections through the right cochlea are marked with a horizontal and vertical dashed line in the transverse section to indicate the location of the coronal and sagittal sections, respectively. The colours correspond to areas of larger (red) and smaller (blue) volumes in the knockout embryos. The colour bar minimum corresponds to a false discovery rate (FDR) threshold of 5%. Hypoplastic bilateral cochlear structures are highlighted in blue, (n = 8 Eya4+/+ (wild-type) versus n = 8 Eya4−/− (knockout), with all eight showing the defect). e, LacZ imaging in the E12.5 Eya4+/− revealed Eya4 gene expression (blue) in the cochlear region (arrow). f, g, H&E stained histological sections through the right cochlea of an Eya4+/+ embryo (f) compared to an Eya4−/−embryo (g) confirmed the hypoplastic phenotype. h, i, Higher magnification of the region (indicated by the white boxes) showed abnormal perilymphatic (periotic) mesenchyme in mutant embryos. In the mutant embryo (i) the perilymphatic mesenchyme did not show rarefaction and had reduced vacuolation compared to control (h) (arrows), suggesting that the cochlear hypoplasia was due to delayed perilymph development.
Extended Data Figure 7 Whole brain MRI reveals many volume changes in the P7 Tox3−/− mice.
a, P7 Tox3−/− knockout mouse brains were registered to an average control dataset of P7 Tox3+/+ (wild-type) brains. The colours correspond to areas of larger (red) and smaller (blue) relative volumes in the knockout embryos. The colour bar minimum corresponds to a false discovery rate (FDR) threshold of 5%. Knockout mice exhibited altered volumes in multiple brain structures including an enlarged pons, amygdala and thalamus/hypothalamus and a decreased pontine nucleus when compared to the wild-type brains (arrows). Most striking was the decrease in the size of the cerebellum of the knockout mice (arrows). (n = 8 Tox3+/+ versus n = 10 Tox3−/−, with all 10 showing the defects). Histological analysis of Tox3−/− mice revealed abnormal development of the cerebellum. b, c, The cerebellum of P7 Tox3−/− mice is hypoplastic and dysplastic characterized by markedly reduced fissure formation, poor delineation of folia and disorganized cortical structure and layering (c) when compared to the P7 Tox3+/+ mice (b) (arrows). In some segments, there was complete absence of folial pattern. d, e, Higher magnification revealed that the normally transient external granular layer was absent in the Tox3−/− mice and the subjacent molecular layer was hypotrophic and irregular in thickness and in multiple foci very thin or absent; in these foci the Purkinje cells extended to the pial surface (arrows). The Purkinje cell layer was also jumbled with no evidence of cell polarity (e).
Extended Data Figure 8 Whole brain MRI reveals enlarged ventricles in the P7 Rsph9−/− mice.
a, P7 Rsph9−/− mouse brains showed enlarged left and right lateral ventricles (arrows) when virtually sectioned from rostral to caudal and compared to an average of P7 Rsph9+/+ mouse brains. (n = 8 Rsph9+/+ versus n = 10 Rsph9−/−, with all 10 showing the defects). Histological analysis of Rsph9−/− (knockout) mice confirmed abnormal brain development. b, c, Arrows indicate severe hydrocephalus of the left and right lateral ventricles of the Rsph9−/− P7 mice (c) compared to the Rsph9+/+ mice (b). The third ventricle was also enlarged but not seen in this section. d, e, Higher magnification of the cerebrum showed marked rarefaction, cavitation, and loss of periventricular cortical tissue (arrow) in the knockout mice (e) compared to wild type (d). f, g, Coronal section through the nasal region revealed that the sinuses of the knockout mice were filled with pus (asterisks) (g).
Extended Data Figure 9 Phenotype hit rates from the adult phenotyping pipeline for lethal, subviable and viable lines.
a, Comparison of hit rates between lethal and subviable line heterozygotes versus viable line homozygotes. b, Homozygous subviable cohorts showed a much higher hit rate than lethal line heterozygotes or viable line homozygotes.
Extended Data Figure 10 Multiple phenotypes in Gyg and Kdm8 null embryos.
LacZ expression in Gyg heterozygous and homozygous embryos at E12.5 showed specific, strong expression in the heart and surrounding major vessels (that is, the dorsal aorta, the carotid artery and umbilical artery) (a, b), consistent with smooth muscle cells at this stage. Homozygous embryos were collected at expected proportions at E12.5, E15.5 and E18.5 and could not be distinguished from wild-type and heterozygous embryos by outward appearance. However, inspection of cross-sections through the whole embryo micro-CT images of E18.5 and E15.5 embryos showed abnormalities in several areas of the developing embryo. Thickened myocardium was evident in the hearts of 2 out of 3 homozygotes examined at E15.5 as shown in Fig. 5. Coronal cross-sections also confirmed thickened myocardium in E18.5 mutant hearts (arrows; n = 5 mutants), compare wild type (c) to Gygtm1b/tm1b(d). From the E18.5 sections, it was also obvious that the thymus was enlarged in mutants (n = 5 mutants) compared with controls (*), but the thymus appeared normal in E15.5 mutant embryos (data not shown). E18.5 mutant embryos also exhibited abnormal gaps in the brain and spinal cord that we interpret as neural degeneration; compare wild-type littermates (e) to Gygtm1b/tm1b mutants (f) (n = 5 mutants). Abnormalities in the nervous system, similar to abnormalities in the heart, were obvious at E15.5. Representative images are shown from sagittal cross-sections through a wild-type (g) and a homozygous Gyg mutant E15.5 embryo (h) (n = 3). E15.5 Gygtm1b/tm1b mutant embryos have a flattened forebrain with reduced lateral ventricles, as well as excess space within the cephalic and cervical flexures. i–t, Tm1a and tm1b alleles can lead to phenotypes of differing strength in Kdm8 mutants. Abnormal phenotype of Kmd8tm1a/tm1a mice at E18.5: i, k, m, o, q, wild-type fetuses; j, l, n, p, r, mutant fetuses. i, j, gross morphological appearance of E18.5 fetuses. k–n, Photomicrographs of the palate and heart taken during necropsy. g–j, Histological sections at similar levels of the trachea and the nasal cavities, (n = 4 mutants analysed at E18.5). Morphology of wild-type (s) and mutants (t) Kmd8 embryos at E9.5 captured by OPT showing developmental delay at that stage, including small size and lack of turning. Arrows, unfused palatal shelves; arrowheads, arch of the aorta. n = 7 mutants analysed at E9.5, scale bar = 1 mm.
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Dickinson, M., Flenniken, A., Ji, X. et al. High-throughput discovery of novel developmental phenotypes. Nature 537, 508–514 (2016). https://doi.org/10.1038/nature19356
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