Around a third of mammalian genes are essential for life, and the recent Nature paper from the IMPC  ‘High-throughput discovery of novel developmental phenotypes‘ [1] describes some achievements from sytematic study of these genes in knockout mice.

Screens like those of the IMPC and DMDD are vital to understand gene function on a genome-wide scale and, based on the results recently published in Nature, here are some reasons why.


Lethal genes in the mouse are known to be enriched for human disease genes [2,3]. When additional data from the IMPC was included on the genes essential for survival of the embryo, this enrichment was increased even further. More than half of the human disease genes considered were essential for mouse embryo survival. The study also found a remarkable correlation between the core essential genes in humans and mice.

Systematic knockout mouse screens provide data that could not be derived from human patients. These new results further underline the importance of mouse models in the study of human disease, and their relevance in a clinical setting.


A suprising observation from knockout mouse screens is the incomplete penetrance of phenotypes for many lines.

One example of this is the sub-viability of lines. The IMPC has found that in around 11% of knockout lines some homozygous pups were observed, but fewer than the 1 in 4 pups predicted by Mendelian genetics. Some pups were able to survive with the homozygous gene knockout, but some weren’t.

Incomplete penetrance is a result also echoed in DMDD data. For example, in the seven Adamts3 knockout embryos studied, all display subcutaneous edema and absent lymph sac, while only two display a bifid ureter.

Click to view larger image.
Subcutaneous edema and bifid ureter (left side) observed in an Adamts3 mutant embryo. The red arrows highlight a single ureter on the right side, but two branches on the left side.

Data from systematic screens of knockout mice is showing, on an unprecedented scale, that even for a complete gene knockout, the observed phenotypes can vary from embryo to embryo. Given the standardised background and allele construction, this is a suprising result and could suggest an underlying stochastic process.


As part of its systematic screen, the IMPC has identified 22 essential mouse genes with human orthologs that are not known to be associated with any human disease. These are potential candidates for undiagnosed diseases and could shine new light on the causes of genetic disorders.

Efforts are continuing to study knockouts of every gene in the mouse genome. As these datasets grow in size, so too does the potential for them to help us understand gene expression and the genetic basis of human disease.

The DMDD database of embryonic-lethal mouse knockouts can be found at dmdd.org.uk.

The IMPC database of knockout mice can be found at www.mousephenotype.org.


[1] The IMPC Collaboration (2016)
High-throughput discovery of novel developmental phenotypes
Nature  doi:10.1038/nature19356

[2] B. Georgi1, B. F. Voight1, M. Bućan1 (2013)
From mouse to human: evolutionary genomics analysis of human orthologs of essential genes
PLoS Genet 9(5): e1003484. doi: 10.1371/journal.pgen.1003484

1 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, USA

[3] J. E. Dickerson 1, A. Zhu1, D. L. Robertson1 K. E. Hentges1 (2011)
Defining the role of essential genes in human disease
PLoS ONE, 6(11), e27368. http://doi.org/10.1371/journal.pone.0027368

1 Faculty of Life Sciences, University of Manchester, UK


New DMDD data is now available on our website. This week we’ve added HREM embryo image stacks for 12 new lines, embryo phenotype data for 12 lines and placental phenotype data for a further 10 lines.

For full details on what we’ve released see the bottom of this post, or look at our updates page.  But here are a few highlights we found while reviewing the data.



Our embryo phenotyping team were particularly interested in the lines Smg9 and Col4a3bp.

Smg9 showed malformations affecting several organ systems. The most prominent were malformations in the nervous system (including exencephaly) and in the cardiovacular system. This data release includes phenotype annotations for 6 embryos in the Smg9 line, meaning that penetrance data can be explored for the related phenotypes.

An embryo with a mutation of the gene Smg9 displays exencephaly.
An embryo with a mutation of the gene Smg9 displays exencephaly.

Line Col4a3bp showed malformations of the cardiovascular system and the axial skeleton.



Our placenta team highlighted Brd2, a transcriptional regulator belonging to the therapeutically important BET (bromodomains and extra terminal domain) family of proteins with epigenetic functions.

As well as exhibiting severe growth retardation, placentas from this line showed a massively reduced vascular density that will result in insufficient nutrient supply to the embryo.

Brd2 placentas display reduced vascular density.
A comparison of wild-type and mutant placentas for the line Brd2 shows reduced vascular density in the mutant placentas.


The Brd2 line is also interesting from the point of view of mouse production. When the DMDD programme began back in 2013, all our knockout mouse lines were made using embryonic stem cells. Our partners at the Wellcome Trust Sanger Institute have recently begun using the CRISPR-Cas9 technique for creating knockout mice, and Brd2 is the first of these lines to make its way to the DMDD analysis pipeline.



Many of the genes studied by DMDD have human orthologues, mutations in which are related to known conditions. DMDD data is a way to examine, in great detail, the resulting phenotypes when these genes are knocked out in a mouse model.

New lines that may be relevant to clinicians (although not an exhaustive list) are:

Col4a3bp: in humans, diseases associated with COL4A3BP include mental retardation, autosomal dominant 34 and goodpasture syndrome.

Ssr2: the human ortholog of this gene is associated with calcaneonavicular coalition.

Trappc9: in humans, diseases associated with TRAPPC9 include intellectual disability, obesity, brain malformations, facial dysmorphism and Birk-Barel mental retardation dysmorphism syndrome.



HREM image data: Brd2, Camsap3, Col4a3bp, Cpt2, Eif3h, H13, Mir96, Npat, Nsun2, Pdzk1, Smg9, Trim45.

Embryo phenotype data: Adamts3, Camsap3, Col4a3bp, Dbn1, Duoxa2, Exoc3l2, Ogdh, Slc5a7, Smg9, Ssr2, Traf2, Trappc9.

Placental phenotype data: Brd2, Cnot4, Cog6, Col4a3bp, Cpt2, Cyp11a1, Pdzk1, Pgap2, Smg9, Wrap53.

Data is searchable by both gene and phenotype, and all image data can be viewed online at full resolution. To request the data offline, or for any enquiries please get in touch: contact@dmdd.org.uk.