DMDD DATA TO REMAIN ACCESSIBLE TO ALL

 

 

As DMDD’s five-year Wellcome Trust grant draws to a close, the analysis of all 250 knockout mouse lines is almost complete. The remaining image and phenotype data will be added to our website over the coming weeks. We are excited to announce that we have secured additional funding from the Wellcome Trust, which we believe will allow us to maintain the website for a further two years. In the long term we are seeking to identify a suitable place to archive the data, so that it can remain accessible to all.


STAY UP TO DATE

Follow DMDD on Twitter to be notified which archive(s) the data is moved to, and also to find out about any future publications. We thank you for your support and hope you will continue to use the DMDD website in the future.

7 MOUSE PHENOTYPE RESOURCES

If you are interested in mouse phenotypes, you’ll have noticed that there are a wealth of resources available. Here’s our round-up of some of the best databases out there. Did we miss your favourite? Let us know by contacting us on Twitter @dmdduk.


Mouse Genome Informatics

 

 

 

 

 

 

Almost everyone will be familiar with this one, but no list of mouse resources would be complete without the MGI database. It covers gene characterisation, nomenclature, phenotypes, gene expression and tumour biology amongst many other datasets.

Use this resource: for a broad picture of mouse genetics. www.informatics.jax.org


Facebase

 

 

 

 

Around half of all birth defects involve the face, but in many cases the reason they occur remains unknown. The Facebase resource aims to tackle this problem with their database of head, skull and craniofacial data. The first five-year phase concentrated on the middle of the human face and the genetics of disorders such as cleft lip and palate. The second phase (which is currently underway) will expand Facebase to include other regions of the face, as well as developing new online search and analysis tools for the data.

Use this resource: if you’re specifically interested in craniofacial phenotypes. www.facebase.org


Monarch

 

 

 

 

The Monarch resource allows cross-species comparison of phenotype data without the user having detailed knowledge of each species’ genetics, development, anatomy, or the terminology used to describe it. The database contains phenotype data for many species including human, mouse, zebrafish and flies, which has been gathered from other dedicated phenotyping projects. The tools developed by Monarch allow users to explore phenotypic similarity between species and are intended to facilitate the identification of animal models of human disease.

Use this resource: to compare mouse phenotype data with phenotypes from many other species. www.monarchinitiative.org


Deciphering the Mechanisms of Developmental Disorders

DMDD LOGO

 

The DMDD database contains high-resolution images and detailed whole-embryo phenotype data for embryonic lethal knockout mouse lines. The High Resolution Episcopic Microscopy technique used for imaging allows phenotypes to be identified down to the level of abnormal positioning or morphology of individual nerves and blood vessels. Parallel screens identify placental phenotypes and carry out whole-embryo gene expression profiling, with all data freely available online. Around 80 lines have been phenotyped to date, with new data added regularly.

Use this resource: for whole-embryo images and phenotype datasets – primary screen data at an unprecedented level of detail. dmdd.org.uk


International Mouse Phenotyping Consortium

 

 

 

 

The IMPC has the ambitious goal of phenotyping knockout mice for 20,000 known and predicted mouse genes. For adult mice, the project provides primary screen data for all the major organ systems, and for many embryonic lethal lines there is also embryo data available. With nearly 6000 lines already analysed, there’s an enormous amount of data to explore.

Use this resource: to access phenotype data for a huge number of knockout mouse lines. www.mousephenotype.org


Origins of Bone and Cartilage Disease

 

 

 

OBCD is a collaboration working to identify the genetic causes of bone and cartilage disease – an important goal when you consider that around half of adults are affected by a bone or cartilage disorder. OBCD aims to phenotype mice from 1750 different knockout lines, and they have made a heatmap of their data freely available online. With nearly 500 lines phenotyped so far, there’s already a huge amount of data and much more to come.

Use this resource: if you’re specifically interested in phenotypes related to the bones and joints. www.boneandcartilage.com


eMouseAtlas

 

 

 

 

Last but not least, if you’re interested in mouse phenotypes you will probably also need information about normal mouse development. The eMouseAtlas resource provides 3D computer models of the developing mouse, covering everything from gross anatomy to detailed structure. It’s a useful point of comparison for phenotypes that have been observed in mutant mouse strains. As a nice project they have also re-digitised the original histological sections from Kaufman’s definitive book ‘The Atlas of Mouse Development‘, making the images available online in high resolution for the first time, together with their original annotations.

Use this resource: for a detailed description of normal mouse embryo morphology at any stage of development. www.emouseatlas.org

 

Tweet us if we missed your favourite database @dmdduk.

Cover image by Rama (Own work) [CC BY-SA 2.0 fr], via Wikimedia Commons.

FIND DMDD PHENOTYPE DATA IN THE MGI DATABASE

DMDD embryo phenotype data is now available in the Mouse Genome Informatics (MGI) database, complimenting the existing morphological phenotype data that is held there. To date we have contributed detailed phenotypes for 63 knockout lines, and will continue to provide additional data as it becomes available.

Each allele overview page shows the high level phenotypes that have been identified.

Click to view larger image.
An overview of the Sh3pxd2a tm1b(EUCOMM)Wtsi allele and the related high-level phenotypes identified by both DMDD and the IMPC.

 

Each high-level phenotype can then be expanded to show all relevant annotated terms. The image below shows all phenotypes related to the respiratory system for Sh3pxd2a tm1b(EUCOMM)Wtsi knockout embryos.

 

Respiratory system phenotypes scored for Sh3pxd2a tm1b(EUCOMM)Wtsi embryos.

 

For any DMDD phenotype, the original annotated embryo image and the full embryo image stack can be found in the DMDD database.

DMDD WEBSITE ENHANCEMENTS

Following user testing of the DMDD website at the BSCB/BSDB meeting earlier this year, we’ve been working behind the scenes on some enhancements to our site. The changes went live today, and here’s a rundown of what’s new.


HOMEPAGE

Perhaps the first thing you might notice is our updated homepage. If you’re planning to search the database for genes or phenotypes, a featured ‘SEARCH’ form on the homepage will make this quicker and easier.

 

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The enhanced DMDD homepage has a dedicated ‘SEARCH’ form, as well as additional information about the project.

We’ve introduced a ‘mega menu’ at the top of the page, so you can see more information about the different sections of the website and quickly navigate to the right place. The height of the homepage has also been decreased, so it’s easier to see all the content on laptop devices.

 

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A ‘mega menu’ provides additional information about each page to help with navigation.

 

Also on the homepage: get bite-sized bits of information about the DMDD programme from the new ‘ticker’ text, sign up to our email newsletter or refresh the page to see a variety of featured images from our dataset.


NEW CONTENT

DMDD recently released a temporal gene expression profile for wild type embryos – the first step towards providing molecular phenotypes for our embryonic lethal lines. We have now added a dedicated wild type gene expression profiling page, which provides some background information and a link to the dataset itself in Expression Atlas.

A new section titled ‘OUR RESEARCH’ includes content about the DMDD consortium, our analysis techniques and a list of our publications. Protocols for placental histology, transcriptional profiling and immunohistochemistry are now available, allowing users to repeat any results of interest, while the contribution by each of our consortium member institutions is detailed on the DMDD pipeline page.

We have added additional information about the mutant lines and how they were generated, updating the About the mutants page to include allele diagrams and information about how to request lines for future research.

Finally, a dedicated section about High Resolution Episcopic Microscopy (HREM) now provides detailed instructions for the HREM imaging technique. Over time this hub of information will grow to include videos and additional information on sample dissection for HREM imaging.

A new 'HREM methods' section is a hub on information about the HREM imaging technique.
A new ‘HREM methods’ section is a hub on information about the HREM imaging technique.

COMMUNICATIONS

Our website now has a dedicated news page highlighting data releases, additional content on the DMDD blog and other news related to the project. It’s also a place to find out where you can meet us at forthcoming events, and how to connect with us via social media.

We are also keen for you to tell others about our data. You can easily download flyers or other promotional materials about the DMDD programme from our Communications materials page.


STYLE

Finally, we’ve made some changes to the style of the site to increase its usability. The most immediately visible change is the switch from a serif font, which has small projecting features called ‘serifs’ at the end of strokes, to a sans serif font, which has no ‘serifs’ and better letter spacing to make the text more readable.

We’ve also changed the layout of each embryo page to make it immediately apparent what data is available for each embryo, without requiring multiple clicks.


YOUR FEEDBACK

Part of our user testing showed that users didn’t notice the feedback button on the right edge of pages, so we’ve moved this to the top right, where users look for it.

We’re excited to launch the enhanced version of our website and would like to know what you think. If you have any suggestions just click the ‘Feedback’ link at the top right of any page on our website, or post a comment below, to let us know your ideas. Make sure to leave your details if you’d like a response or are happy for us to contact you to find out more.

NEW FUNDING AWARDED FOR ePHENOTYPE

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 expected that the tool will be available by mid-2017.


AUTOMATED PHENOTYPING AND HEAT MAPS

Automated phenotyping of mouse embryos is now a well-established technique with Micro CT data (Wong et al, 2014) and recently a proof of principle using higher-resolution HREM data from the DMDD programme was also published (Henkelman et al, 2016). The technique works by combining wild-type embryos to create an average ‘atlas’ embryo. Morphological abnormalities in the mutant can then be determined via a statistical comparison between the mutant and the atlas.

The output of these screens is typically a heat map, showing the volumetric changes between the mutant and the reference embryo.

Click to see full-size image.
The coloured regions show statistically significant differences between males and females in the region of the gonads. (Henkelman et al, 2016) Image reproduced with the permission of Elsevier.

But is there more that we can learn from this heatmap data?


ePHENOTYPE

The team at IGMM believe that there is much more information to be mined from phenotype heat maps. By developing ePhenotype, they plan to unlock some of these hidden secrets.

Based on the eMouseAtlas tool, ePhenotype will allow web-based visualisation of the deformation field used to match a mutant embryo to an atlas model. A web interface will allow researchers to visualise the data in the context of a 3D model, and to select 3D regions of interest to investigate further.

Click to view full-size image.
Currently, eMouseAtlas provides virtual 3D reference models of different stages of mouse development (a). 2D lateral projections of these models can be highlighted and queried to identify embryos with matching phenotype expression patterns (b). The results are ranked (c) and can be inspected more closely (d). The ePhenotype search capabilities will allow users to query in 3D.

ePhenotype will show, in a more visual way than ever before, how mutants differ from their wild-type counterparts.

For those working on molecular phenotypes, the tool will also have the capability to map gene expression data onto a reference embryo, unlocking further insights from sequencing data.


LINKING GENOTYPE AND PHENOTYPE

Until now it has been difficult to correlate gene expression patterns with phenotype data, meaning that molecular and anatomical phenotypes have been considered quite separately.

Users of ePhenotype will be able make these links by visualising compound phenotypes from multiple embryo datasets. This will include the facility to map both gene expression patterns and phenotype data onto one atlas embryo.

Click to view full-size image.
In this example, ePhenotype combines the gene expression data from Fzd6 (top left) and Fzd3 (top right) mutant mouse embryos. The role of these genes in neural tube closure is well-known. (Wang et al., 2006).

ePhenotype will open up new possibilities to explore the relationship between genotype and phenotype. It is hoped that the tool will lead to new understanding of how genotype-phenotype relationships impact on embryogenesis and developmental disorders.


REFERENCES

M. D. Wong1, Y. Maezawa2, J. P. Lerch1, R. M. Henkelman1 (2014)
Automated pipeline for anatomical phenotyping of mouse embryos using micro-CT
Development, DOI: 10.1242/dev.107722

1 Mouse Imaging Centre (MICe), Hospital for Sick Children, University of Toronto, Toronto, Canada
2 The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada

R. Mark Henkelman1, Miriam Friedel1, Jason P. Lerch1, Robert Wilson2, Tim Mohun2 (2016)
Comparing homologous microscopic sections from multiple embryos using HREM
Developmental Biology [Epub ahead of print], DOI: 10.1016/j.ydbio.2016.05.011

1 Mouse Imaging Centre (MICe), Hospital for Sick Children, University of Toronto, Toronto, Canada
2 The Francis Crick Institute Mill Hill Laboratory, London, UK

Y. Wang1, N. Guo, J. Nathans
The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells
J. Neuroscience, DOI:10.1523/JNEUROSCI.4698-05-2005

1 John Hopkins University School of Medicine, Baltimore, USA