A large-scale study of DMDD data [1] has shown that inactivating the same gene in mouse embryos that are virtually genetically identical can result in a wide range and severity of physical abnormalities. This suggests that the relationship between gene mutation and embryo development is more complex than previously thought.

The article ‘Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice‘ was published in Wellcome Open Research.


The study considered 220 mouse embryos, each with one of 42 different genes inactivated. These genes are part of a set known as ‘embryonic lethal’, because they are so crucial to development that an embryo missing any one of them can’t survive to birth. Studying these genes can help us understand how embryos develop, why some miscarry and why some mutations can lead to abnormalities.

Each embryo was scanned in minute detail, meaning that even the smallest differences in features could be identified – right down to the level of whether the structures of individual nerves, muscles and small blood vessels were abnormal. It was also possibe to see whether having the same, single missing gene affected all embryos in exactly the same way.

Clinicians commonly find that people with the same genetic disease can show different symptoms or be affected with differing severity. In part this is likely to be due to the fact that we all differ in our precise genetic makeup. However, the results of this study in mice shows that even when individuals have virtually identical genomes, the same mutation can lead to a variety of different outcomes amongst affected embryos.


Click to view larger image.
A comparison of two embryos that are both missing the embryonic lethal gene Coro1c. The embryo on the right has abnormal viscerocranium (facial skeleton) morphology, while the embryo on the left does not.


A total of 398 different abnormalities (known as abnormal phenotypes) were observed across the 220 embryos. Surprisingly, almost none of the phenotypes were found in every embryo with the same missing gene. A phenotype that does not occur for every embryo missing a particular gene is said to have ‘incomplete penetrance’ and this phenomenon was seen regardless of how profound the abnormality was. Incompete penetrance was observed for phenotypes ranging from severe heart malformations to relatively minor defects such as the abnormal positioning of nerves.

Dr Tim Mohun, who led the study at DMDD said:

“This is a striking result, coming as it does from such a large study in which embryos have been analysed in unprecedented detail. It shows us that even with an apparently simple and well-defined mutation, the precise outcome can be both complex and variable. We have a lot to learn about the roles of these lethal genes in embryonic development to understand why this happens.”

The result was put in context by Dr Andrew Chisholm, Head of Cellular and Developmental Sciences at the Wellcome Trust, who added that “the fundamental processes driving how we develop have been conserved through evolution, which makes studying animal models enormously helpful in increasing our understanding of why some babies develop birth defects. This study throws new light on what we thought was a fairly straightforward relationship between what’s coded in our genes and how we develop. Researchers need to appreciate this added layer of complexity, as well as endeavouring to unpick the intricate processes of genetic control at play.”

All image and phenotype data gathered by the DMDD programme is freely available to the scientific community at Dr David Adams, Group Leader at the Wellcome Trust Sanger Institute who contributed to the work, said “this study highlights the power of genetic analyses in mice and provides an unprecedented resource of data to inform clinical genetic studies in humans.”

The research described in this blog post was funded by the Wellcome Trust with support from the Francis Crick Institute.


[1] Wilson R, Geyer SH, Reissig L et al. Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice, Wellcome Open Res 2016, 1:1 (doi: 10.12688/wellcomeopenres.9899.2)


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.