Around one third of all targeted gene knockouts in the mouse result in embryonic or perinatal death. Deciphering the Mechanisms of Developmental Disorders (DMDD) is a systematic screen of such knockout lines, carrying out detailed imaging and morphological phenotyping of the resulting embryos and placentas. Transcriptional profiling is also used to examine the changes in gene expression that result from gene deletion. The programme aims to identify 240 lethal genes and study their impact on embryo development as a first step towards understanding why they are critical for embryo survival.
Data derived for each knockout line is freely available to the scientific community in a custom online resource. The DMDD database links gene identity with detailed morphological phenotypes, and will ultimately evolve to include transcriptional profiles in an attempt to correlate between morphological and molecular phenotypes. It also provides an extensive library of wild-type embryos for comparison. The database is a novel resource for developmental biologists and clinicians, which aims to spark new research by providing primary screen data for a large number of lines.
Insights gained from DMDD data will shed light on the origins of human developmental disorders. We aim to identify gene knockouts with consequences in the mouse that mimic aspects of human congenital abnormalities, as well as identifying novel associations between individual genes and the differentiation of embryo tissues and structures.
Our work complements that of existing clinical genetic programmes such as the Deciphering Developmental Disorders (DDD) and UK10K projects, and our phenotype data has the potential to boost the statistical power of gene-disease association studies. Working together with clinicians, we hope our data will help underpin new diagnostic and therapeutic approaches for debilitating, and sometimes lethal, disorders.
DMDD studies knockout mouse lines produced as part of the Knockout Mouse Programme (KOMP), an international effort to knock out every gene in the mouse genome. Analysis of these lines is co-ordinated by the International Mouse Phenotyping Consortium (IMPC). DMDD takes a subset of the embryonic lethal lines, analysing them in unprecedented detail.
DMDD uses a combination of comprehensive 3D imaging, tissue histology, immunocytochemistry and transcriptomics to identify abnormalities in embryo and placental structure for each embryonic lethal line. All data is made freely available via this website, enabling individual researchers to identify lines relevant to their own research.
The DMDD pipeline details and illustrates the various stages of workflow, from mutant selection through to data publication.
DMDD images and phenotypes embryonic lethal mouse gene knockouts
Our research reveals critical genes for normal embryo development
All data is freely available through our database
More than 4 million images at near-histological resolution
Standardised embryo and placenta phenotypes annotated by anatomical experts