New image and phenotype data for embryos and placentas from embryonic lethal knockout mouse lines has been made available on the DMDD website today. The knockout data includes the ciliary gene Rpgrip1l as well as Atg16l1, a gene encoding a protein that forms part of a larger complex needed for autophagy. In total we have added HREM image data for 10 new lines, embryo phenotypes for 11 lines and placenta image and phenotype data for 6 lines.

The new data was released at the same time as enhancements to our website, which have been described in a separate blog post. Keep reading to see some highlights from the phenotype data.


The comprehensive and detailed nature of DMDD embryo phenotyping means that we are able to identify a wide range of abnormalities. In the data released today, a total of 423 phenotypes were scored across 78 embryos. These included gross morphological defects such as exencephaly and edema, but also abormalities on a much smaller scale such as an unusually small dorsal root ganglion, absent hypoglossal nerve and narrowing of the semicircular ear canal.

In the image below, a Trim45 embryo at E14.5, was found to have abnormal optic cup morphology and aphakia (a missing lens).

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HREM imaging of a Trim45 knockout embryo reveals abnormal optic cup morphology and aphakia on the left side.

3D modelling of the exterior of an Rpgrip1l knockout embryo at E14.5 revealed a cleft upper lip, as well as polydactyly.

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A 3D HREM model of an Rpgrip1l embryo shows a cleft upper lip.

All phenotypes are searchable on the DMDD website, highlighted on relevant images, and the full-resolution image data is available to explore online.


DMDD also carries out systematic phenotyping of the placentas from knockout lines. The image below shows a Cfap53 knockout placenta at E14.5, which was found to have an aberrant fibrotic lesion. The density of fetal blood vessels was also considerably reduced, the overall effect being to reduce the nutrient flow from mother to embryo.

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Placental histology for the line Cfap53 shows a fibrotic lesion (large arrow) and several regions of reduced blood vessel density (small arrows).



Work is underway to measure the gene expression profiles for embryos from embryonic lethal knockout lines, a study that complements the morphological phenotype data we are gathering. One of our ultimate goals is to allow data users to explore correlations between gene, morphological phenotype and gene expression profile. The first part of this dataset was released recently – a temporal baseline gene expression profile for wild type embryos.

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Example expression profiles of Nacad and Pdzk1 with increasing somite number. The data shows that, at this depth of sequencing, Nacad is switched on during somitogenesis and Pdzk1 is switched off.


The expression data is now accessible via a dedicated wild type gene expression profiling page on the DMDD website, which also gives background information about the analysis. Mutant expression data will follow in the new year.


Many of the genes studied by the DMDD programme are known to have links to human disease, including several new lines that have been made available in this release.

Rpgripl1: in humans, mutations in RPGRIPL1 are known to cause Joubert Syndrome (type 7) and Meckel Syndrome (type 5), a rare disorder affecting the cerebellum.

Cfap53: the human ortholog of this gene is known to be associated with visceral heterotaxy-6, in which organs have an abnormal placement and/or orientation.

Arhgef7: in humans the ortholog is associated with Borjeson-Forssman-Lehmann Syndrome.

Arid1b: in humans, mutations in ARID1B are associated with Coffin-Siris Syndrome.

Embryonic lethal lines with no known links to human disease may also be novel candidate genes for undiagnosed genetic disorders. Visit the DMDD website to explore the phenotype data.


HREM embryo image data has been added for Actn4, Arid1b, Cfap53, Crim1, Cyp11a1, Dmxl2, Fut8, Gas2l2, Mfsd7c, Rala.

Embryo phenotype data has been added for Atg16l1, Capza2, Coro1c, Crim1, Cyfip2Gas2l2, Gm5544Rala, Rpgrip1l, Syt1, Trim45.

Placenta image and phenotype data has been added for Arhgef7, Arid1b, Fam21, Fut8, Med23, Timmdc1.

If you have questions about the DMDD programme or our data, please email


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.

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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

The IMPC database of knockout mice can be found at


[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.

1 Faculty of Life Sciences, University of Manchester, UK