Today sees the launch of Wellcome Open Research, a new publication platform for Wellcome Trust funded researchers. A set of articles released to coincide with the launch includes ‘Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice‘, a publication by the DMDD Programme. It explores the results of systematic efforts by the consortium to image and phenotype embryos from embryonic-lethal knockout mouse lines.


Papers submitted to WOR are published immediately as preprints, following a series of objective checks. They are then subject to a process of open peer review. WOR requires all supporting data to be made available, enabling other researchers to analyse and replicate published studies. By using services developed by the publisher F1000Research, research outputs can be made available faster and in ways that support reproducibility and transparency.

DMDD’s Tim Mohun on the reasons the team chose to publish in WOR:

“For us, the timing of the launch was perfect. We had reached a bit of a milestone in the DMDD project, having analysed enough different embryonic lethal genes that we could begin to consider the dataset as a whole and draw some initial conclusions. We wanted to share our findings with the research community as quickly as possible because we think the conclusions are interesting, important and, in part, puzzling.

Lots of research never sees the light of day. We only ever see the choice results and final conclusions in conventional scientific publications, but rarely all the accumulated data on which those studies rest. For screening studies like ours which are necessarily limited in depth but wide in scope, publications like Wellcome Open Research give the opportunity to make our data available for other scientists to use, hopefully helping to advance their work and avoiding duplication of effort”.

The DMDD paper ‘Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice‘ is currently undergoing peer review and this process can be followed online.

Read a longer interview with Tim Mohun and Jim Smith on the WOR blog.


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