It is widely known that a functional placenta is vital for normal embryonic development, but how much it may contribute to embryonic lethality has never before been systematically studied. Our research, published in Nature, demonstrates for the first time a remarkable co-association between embryonic lethality and placental defects, and further shows how common placental abnormalities are when embryos develop abnormally. A DMDD blog post, Placental defects are highly prevalent in embryonic lethals, provides a summary of the main findings.
Our latest data release includes placental phenotype data for more than 100 mutant lines, with more than 2000 associated placenta morphology and yolk sac images. A systematic analysis was conducted of specific layers of the placenta by immunostaining:
LEFT: Isolectin BSI-B4, MIDDLE: Tpbpa, RIGHT: Yolk sac
The analysis identified dozens of gene mutations that cause placental development to fail, most of them previously unknown to affect the placenta. These findings further advance our understanding of the genetic requirements for normal placentation.
The data release also includes HREM image data for an additional 5 lines, and HREM phenotyping data for 4 lines. Five additional early lethal lines have also been identified.
Throughout the DMDD project we continue to add data for existing lines, and in this release we have added P14 viability for mutant lines, Theiler stage (where assessed), and the voxel size of each HREM image stack.
DMDD held a successful HREM/Phenotyping workshop in Vienna, run by Wolfgang Weninger (of the Medical University of Vienna) and Tim Mohun (the Crick). The workshop introduced the DMDD project, how HREM works, how the scoring is done, and how phenotypes present themselves in HREM data, and included lectures, demonstrations and hands on sessions. Based on the success of this event, a further workshop is being considered for next year.
DMDD had an exhibition stand at the American Society of Human Genetics meeting in Orlando, which ran from 17-21 October. Angela Green and Antonella Galli, from the Wellcome Trust Sanger Institute presented at the stand, reporting that it attracted much attention.
Dorota Szumska, University of Oxford, gave a presentation at the Cardiovascular Development Meeting at the University of Padua, Italy. The meeting ran from 28-30 September, and was organised by theWorking Group on Development, Anatomy & Pathology.
Dorota's talk, titled Deciphering the Mechanisms of Developmental Disorders (DMDD): a powerful new resource for studying congenital heart disease (CHD) discussed findings from the DMDD project that show the range and remarkable frequency of cardiac defects that have been identified.
Wolfgang Weninger, of the Medical University of Vienna will give a presentation at the Annual German Anatomy Society meeting. His talk, titled Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice will discuss the DMDD finding that no matter how profound the malformation, each phenotype shows highly variable penetrance within a mutant line, which presents challenging implications for efforts to identify human disease correlates.
The associated publication, Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice, was published in Wellcome Open Research.
A new set of DMDD embryo and placenta data has been released today, taking our total dataset to 9.5 million images of around 1300 embryos. Phenotypes are available for embryos from 73 different knockout lines, for example this Hmgxb3 knockout which had exencephaly. Embryos from this line had a range of other phenotypes including edema, abnormalities of the optic cup, and defects of the venous system including an abnormal ductus venosus valve and blood in the lymph vessels. We have also phenotyped the placentas from 124 lines and added data on the sex of each embryo.
Visitors to our website can now compare HREM embryo images with the closest-matching, annotated histological section from the Kaufman Atlas of Mouse Development. This follows a major project by the eMouseAtlas team at the University of Edinburgh to digitise the Kaufman Atlas at high resolution. The annotated Kaufman sections can be viewed alongside DMDD embryo images to help users who are unfamiliar with the detailed morphological features of a mouse embryo as it develops.
DMDD will have an exhibition stand at the Society for Developmental Biology 76th Annual Meeting in Minneapolis, from 13 - 16 July. Visit stand 11 to speak to Dorota Szumska, one of our phenotyping experts, and explore our database of embryonic lethal knockout mouse lines. You can also pick up promotional flyers, and a free DMDD mug (while stocks last!)
Tim Mohun visited the Tommy’s National Centre for Miscarriage Research at the University of Birmingham to give a seminar about DMDD data and its potential to shed light on the genetic causes of miscarriage.
In around 30% of knockout lines studied by DMDD the embryos have edema – swelling due to fluid trapped in the embryo’s tissues. Most of us have experienced edema at some point, after a bee sting, an infection or perhaps from hitting your thumb with a hammer. But in the embryos we study, edema is typically more generalised. It often surrounds the brain, abdomen or the entire body, like this Traf6 knockout that shows edema around the skull and back.
A new post on our blog explores what this type of edema signifies, and why it is so common in embryos from embryonic lethal knockout lines.
DMDD will be exhibiting at the International Society for Developmental Biologists 2017 meeting in Singapore from 18 - 22 June. At our stand, members of the collaboration will be on hand to show you our database of images and phenotypes for embryonic lethal knockout mice. You can also sign up to our mailing list and receive a free mug! Visit stand 11 to find out more.
Tim Mohun visited the Open Data Institute in London on 12 May to give a lunchtime talk 'Using open data to understand the causes of genetic birth defects'. His talk was live streamed to a world-wide audience and can be accessed on the ODI YouTube channel.
Around 1 in 4 pregnancies ends in miscarriage. It can happen for many reasons, including infection and hormonal imbalances, but in many cases a definite reason cannot be found. Around half of all miscarriages that occur before 12 weeks of pregnancy are thought to be caused by a gene mutation or chromosomal abnormality that prevents the embryo from developing as it should. One approach to understanding, and potentially preventing, pregnancy loss is to identify gene mutations that have an adverse effect on embryo development.
A recent blog post explores how DMDD embryo phenotype data could reveal new candidate genes for study in relation to miscarriage.
DMDD embryo phenotype data is now available in the Mouse Genome Informatics (MGI) database, complimenting the existing morphological phenotype data that is held there. We have contributed data for 63 knockout lines, and will provide phenotypes for additional lines as they become available.
A new blog post explores the importance of using an ontology in making phenotype data consistent and easily sharable: Tea, dinner or supper?
Analysis of DMDD phenotype data has shown that knocking out the same gene in mouse embryos that are virtually genetically identical can result in a wide range and severity of abnormal phenotypes. This suggests that the relationship between gene mutation and consequence is more complex than previously suspected.
The article Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice, published in Wellcome Open Research, presents an analysis of 220 embryos, each missing one of 42 genes known to be crucial for embryo survival. Using high-resolution images, detailed phenotypes were identified down to the scale of individual nerves or blood vessels. Of the 398 different phenotypes observed, only three were present in every embryo with the same missing gene. The image shows, for example, one embryo missing the gene Coro1c shows abnormal viscerocranium morphology (right), while another is unaffected (left).
Cecilia Icoresi Mazzeo of the Wellcome Trust Sanger Institute attended the Genomics of Rare Disease Meeting to present ‘Models of human disease from embryonic lethal lines’, an overview of DMDD phenotype data and disease associations.
Stefan Geyer, of the Medical University of Vienna visited Bethesda, MD to give a presentation at the 11th Structural Birth Defects Meeting. His talk, titled Deciphering the Mechanisms of Developmental Disorders covered the main phenotyping results from the DMDD programme, including the observation of variable phenotype penetrance and analysis to identify phenotype-disease associations.
DMDD will have a strong presence at the joint BSCB/BSDB/Genetics Society Spring Meeting, which is taking place at the University of Warwick from 2 - 5 April. In addition to an exhibition stand, where you can pick up your free DMDD mug, we’ll give an invited talk and present three posters. More details about our presence at this meeting, including poster titles, can be found on the DMDD blog.
Additional image and phenotype data has been released for embryos and placentas from embryonic lethal knockout mouse lines. The database now holds data on 70 mutant lines that have been phenotyped in detail using the Mammalian Phenotype ontology. For example, the image shows a Fut8 embryo that was found to have a spinal haemhorrage, amongst other phenotypes.
We've also added some new functionality to our website, including the ability to search for phenotypes by anatomy terms and the release of additional data about gene knockouts that are lethal very early in embryonic development. Highlights of the release, including examples of interesting phenotypes, can be found on the DMDD blog.
As part of the activities to raise global awareness of rare diseases, DMDD took part in Rare Disease Day by writing an article for the British Heart Foundation (BHF) blog.
Heart defects are diagnosed in at least 1 in 180 births. That’s around 12 newborn babies each day in the UK, with even more diagnoses later in life. Environmental influences such as excessive alcohol consumption can cause heart defects. But many are also the result of faulty genes that can be passed on from one generation to the next. Identifying the genes involved is key to understanding how to identify when a baby might be at risk and could also help us develop new ways to treat or prevent these heart defects. But with more than 20,000 genes in the human genome there are a mind-boggling number of possibilities.
DMDD analysis of knockout mouse embryos has identified a huge number of genes related to heart defects and other developmental abnormalities, and is now a potential goldmine of information on the genetic basis of heart conditions and rare disease.
Read the full article What happens when we ‘turn off’ a gene? on the BHF blog.
The Babraham Institute’s Myriam Hemberger visited the Gurdon Institute to give a seminar titled ‘Highlights from the DMDD consortium - novel insights into gene function during embryogenesis’.
An article published in Journal of Anatomy shows that measuring the amount of inter-digital webbing in mouse embryos between 14 and 15 days gestation is the best way to find out their exact stage of development.
This is a key result for researchers trying to understand the effect of gene mutations on mouse embryo development. If we want to discover a causal link between a mutation and a phenotype, we need to be sure that what we observe isn’t just a standard feature of embryo development. The morphology of an embryo can change very rapidly as it grows, so features that look abnormal at one stage of development could be completely normal at another stage. This means it’s vitally important to know an embryo’s precise developmental stage before attempting to identify phenotypes. Using this new technique, it’s now possible to stage a mouse embryo very precisely simply by looking at its fingers.
DMDD data released on Expression Atlas reveals the effect of single gene knockouts on the expression of all other genes in the mouse genome. The gene expression profiles of 11 knockout lines have been derived from whole embryos harvested at E9.5 and the results can be compared with wild-type controls using an interactive online tool. Users can investigate which genes are differentially expressed as a result of a gene knockout, with the potential to uncover genes with similar roles or compensatory effects when a related gene is knocked out. An overview of the expression profile data currently available can be found on the DMDD blog.
Tim Mohun visited the Newline Birth Defects Research Centre at the UCL Institute of Child Health to give a seminar on DMDD’s embryonic lethal knockout mouse data and lessons learnt about the genetic basis of developmental disorders.
"We call this the post-genomics era but in fact we are still very much living in a time where we don’t know how the genome works and how individual genes function."The latest in our series of interviews is with David Adams - joint DMDD grant holder and Senior Group Leader at the Wellcome Trust Sanger Institute. He talks about animal models for human disease, CRISPR and his personal interest in T-cells.
DMDD team members ran an exhibition stand to showcase the programme's image and phenotype data at a meeting of researchers funded by the Wellcome Trust, held at the Wellcome Genome Campus near Cambridge. It was a great opportunity to highlight our resource to potential data users from a wide range of research disciplines.
In a series of interviews we’re hearing from members of the DMDD programme. Who are they? What inspires them? And what do they hope that DMDD will achieve? This month’s interview is with Myriam Hemburger, who leads the team’s analysis of placentas from embryonic lethal knockout mouse lines.
A feature about the DMDD and IMPC consortia was published in the latest edition of Rare Revolution magazine, as part of their 'Clinical Spotlight' strand. It describes the important role that systematic phenotyping of mouse embryos plays in understanding the basis of rare genetic diseases. Subscribe to Rare Revolution magazine for free to read the article online.
New image and phenotype data is now available for embryos and placentas from embryonic lethal knockout mouse lines. Phenotypes detected in embryos include cleft palate and abnormal optic cup morphology. Placenta phenotypes include an aberrant fibrotic lesion and reduced density of blood vessels. A detailed overview of the new embryonic lethal data is available on the DMDD blog.
As well as adding data regularly to the website, we continuously review the content and usability, and have launched some significant enhancements today. We've made search more prominent on the homepage, and added lots of new content such as detailed protocols for each analysis, information about the generation of knockout alleles and a dedicated 'HREM Methods' section. Find out more about the website enhancements on the DMDD blog.
The team were at Newcastle University to run an exhibition stand at the 2016 Cardiac Development Meeting.
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.
The DMDD programme is co-ordinated from the Francis Crick Institute, and we were excited to take part in the Crick's official opening celebrations in the presence of The Queen and The Duke of Edinburgh.
High Resolution Episcopic Microscopy (HREM) is a technique that allows embryos to be imaged in unprecedented 3D detail. It's the main imaging method used by the DMDD programme, as the detailed images enable us to identify a wide range of developmental abnormalities that result from mouse gene knockouts. A new post on our blog explores the HREM technique and its benefits.
DMDD were at the Cambridge Rare Disease Summit on 25 October, giving demonstrations of our database. It was great to share our data with the rare disease community and to meet people doing such important research.
The Jackson Laboratory invites gene nomination submissions for phase II of the JAX KOMP production and phenotyping program. The goal is to generate 1000 new mouse lines using CRISPR/Cas9 and characterise them using the IMPC phenotyping pipeline.
Around a third of targeted gene knockouts in mice are embryonic lethal. But not all deaths occur during gestation - a significant number of gene knockouts result in death at or shortly after the time of birth. Mice from these knockout lines provide a valuable animal model of human neonatal death and they are the focus of a pilot phenotype screen by the DMDD Programme. Twenty knockout lines will be studied, with the first results expected at the end of 2016.
Knowing the 'normal' expression of genes during embryo development is key to understanding the differences that occur due to genetic mutations. As part of work to understand the underlying transcriptional processes in developing embryos from knockout mouse lines, DMDD has now released a gene expression profile for wild-type mouse embryos between E8.5 and E10.5. The new dataset reveals the typical expression profile of genes during this crucial period of embryonic development, including their abundance, and when they are turned on and off.
Around a third of mammalian genes are essential for life, and the recent Nature paper 'High-throughput discovery of novel developmental phenotypes' describes some achievements from the study of these genes in knockout mice. The results include an observation of incomplete phenotype penetrance, and the identification of novel candidate genes for undiagnosed human disease.
Systematic knockout mouse screens, like those of the IMPC and DMDD, are vital to understand gene function on a genome-wide scale. The DMDD blog provides a digested read: 'Three new results from knockout mouse screens'.
The Wellcome Trust Sanger Institute (WTSI) is now hiring for a Postdoctoral Fellow to join the DMDD programme. Based in the Vertebrate Genetics and Genomics group at the WTSI, the successful candidate will use RNA-seq and a range of high-throughput sequence analysis tools to identify genes and regulatory networks perturbed as a result of gene knockout. (Applications for this post have now closed.)
The 2016 Autumn meeting of the British Society for Developmental Biology takes place in Edinburgh from 28 - 30 August, and DMDD will be exhibiting there together with our colleagues from the e-Mouse Atlas Project. After a successful exhibit at the joint BSDB/BSCB Spring meeting back in April, we're excited to be attending 'The use of chimeras to study developmental mechanisms: from lineage tracing to disease models'. Visit the exhibition to find out about our embryonic lethal knockout mouse lines, and get a demo of our database.
Today is the final day for the DMDD team at Mill Hill Laboratory before moving to the new Francis Crick Institute building. From next week we'll be settling into our new home on Midland Road, near St. Pancras station, where we'll have a brand new lab.
This week sees the launch of the DMDD YouTube channel. We've added videos that explore our embryonic lethal mouse data in 3D, giving a new way to visualise phenotypes that we've observed in our knockout lines.
We are just getting started, so more videos will be added soon including instructional videos on how to access and analyse our data online. Visit the DMDD YouTube channel to find out more.
New embryo phenotype data and HREM images have been added for many mutant lines, taking our total dataset to more than 4 million images of 550 embryos. We now also have placental histology images and phenotypes available for over 100 lines.
Embryo phenotypes identified in the new data include severe heart abnormalities, situs invertus of the stomach and bifid ureter, while placental phenotypes include reduced vascular density and delayed development. Many of the new lines have human orthologues known to be linked to rare diseases, and are of potential interest to clinicians. Find out more about the new embryonic lethal data on the DMDD blog.
DMDD joint grant holder Professor Elizabeth Robertson, University of Oxford, has been awarded the 2016 Royal Medal by the Royal Society. The Royal Medal is one of the Society's premier awards. Each year medals are awarded for the most important contributions "to the advancement of Natural Knowledge" in the physical and biological sciences.
Previous winners include Dorothy Hodgkin, Francis Crick and Paul Nurse. Liz has received this award for her innovative work within the field of mouse embryology and development, establishing the pathways involved in early body planning of the mammalian embryo. Congratulations to Liz on this great achievement.
The Zika virus has raised global awareness of birth defects more than at any time in the last 50 years. A recent Nature Editorial explores the opportunities this presents to increase support for various research programmes related to birth defects. But what does it mean for research into the genetic basis of developmental disorders and rare diseases?
Read more about the effect of Zika on systematic screens of mouse mutations on the DMDD blog.
The team at the Babraham Institute have reached the major milestone of imaging the placentas from 100 knockout mouse lines. In the first systematic study of its kind, placenta images from every DMDD line are being annotated with detailed phenotypes.
The results show that many more mutant strains than expected show a distinct placental phenotype, highlighting the importance of the placenta in normal embryo development. Much of the placenta data is already available for users to analyse. Data on the full 100 lines imaged so far will be available in the next few weeks.
DMDD consortium members Richard Baldock and Chris Armit have been awarded a grant by the BBSRC to develop ePhenotype, a new visualisation tool for mouse embryo data. The tool will allow users to map phenotype deformation fields onto a reference embryo, with the hope that new insights can be gained from existing embryonic lethal data.
This exciting new project will take place at the Institute for Genetics and Molecular Medicine (IGMM) in Edinburgh, and it is hoped that the tool will be available by mid-2017. Read more about ePhenotype on the DMDD blog.
The team showcased the DMDD database at the European Conference on Rare Diseases in Edinburgh, and at the Young Embryologist Network in London. We were able to meet with clinicians, patient groups and developmental biologists, raising awareness of embryonic lethal mouse data and its potential applications.
For the first time, a reference mouse embryo atlas has been created using HREM image data. For other embryo imaging methods such as micro-CT, a reference embryo atlas has previously been shown to be the basis of automated phenotyping.
This new work (a collaboration between the DMDD programme and the Mouse Imaging Centre in Toronto) is a proof of principle for automated phenotyping of HREM data, which will now be tested in more detail. Read more about the mouse embryo atlas on our blog.
Pump priming awards are available from the MRC to support the receipt and preliminary use of gene knockout mouse lines developed and phenotyped through the International Mouse Phenotyping Consortium. Applications are invited from UK-based research groups to receive knockout mice and undertake early biological investigations that build on existing research expertise. (Closing date is 8 July 2016.)
New embryonic lethal data has been added to the DMDD database, including HREM images, embryo phenotype data and placenta data. Highlights of the new data include Smg9 embryos that display exencephaly and Brd2 placentas that show a massively reduced vascular density.
Many of the new lines have human orthologues with known links to diseases, including Goodpasture Syndrome and Birk-Barel Mental Retardation Dysmorphism Syndrome.
Users can search the database by gene or phenotype to explore lines relevant to their own research. More information about the new data is detailed on our blog.
The data releases page provides full details of the line data included in each release.
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We'll be attending the events below. If you'd like us to present to you, or have any questions about our resource, please contact us.