Deciphering the Mechanisms of Developmental Disorders (DMDD): a new programme for phenotyping embryonic lethal mice

Mohun, Timothy J.; Adams, David J.; Baldock, Richard; Bhattacharya, Shoumo; Copp, Andrew J.; Hemberger, Myriam; Houart, Corinne; Hurles, Matt; Robertson, Elizabeth J.; Smith, James C.; Weaver, Tom; Weninger, Wolfgang J.

doi:10.1242/dmm.011957

Cited by 77 publications

(106 citation statements)

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“…Since approximately one third of gene knockouts in the mouse prove to be embryonic or perinatal lethal 1–3 , further study of such lines offers a unique opportunity to better understand the genetic regulation of embryo development and identify genetic determinants of congenital abnormalities. The data accumulated during three years of the DMDD programme provide the first opportunity to study in detail the identity, range and prevalence of morphological abnormalities in such mutants and offer a window on the opportunities (and pitfalls) such systematic studies present.…”

Section: Discussionmentioning

confidence: 99%

“…All embryos were produced by the Wellcome Trust Sanger Institute (https://www.sanger.ac.uk/mouseportal/) as part of the DMDD project 3 . Gene knockout lines produced as part of a systematic programme coordinated by the International Mouse Phenotyping Consortium (http://www.mousephenotype.org) were designated lethal if no homozygous mutants were present amongst a minimum of 28 pups at P14 and sub-viable if their proportion fell below 13% of total offspring 2 .…”

Section: Methodsmentioning

confidence: 99%

“…The most ambitious example of this is the attempt coordinated by the International Mouse Phenotyping Consortium (IMPC) to generate a catalogue of gene function, using a systematic approach to phenotyping of individual gene knockouts (KO) that cover the entire mouse genome. In generating KO lines from about one quarter of the total mouse genome so far, these studies have revealed that around one third of all mammalian genes are essential for life 1–3 , their removal resulting in embryonic or perinatal lethality. The study of such mutant lines provides a unique opportunity to gain a comprehensive overview of the genetic components regulating normal embryo development and, by inference, the identity of genes whose mutation may cause congenital abnormalities or developmental disease.…”

Section: Introductionmentioning

confidence: 99%

“…Deciphering the Mechanisms of Developmental Disorders (DMDD) is a five year, UK-based programme funded by the Wellcome Trust with the goal of studying 240 embryonic lethal KO lines 3 . By applying systematic phenotyping methods for homozygous mutant embryos with parallel efforts to identify placental abnormalities and changes in early embryo transcriptome profiles, DMDD offers a foundation for identifying novel genes important for developmental or clinical studies.…”

Section: Introductionmentioning

confidence: 99%

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Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice

Wilson¹,

Geyer²,

Reissig³

et al. 2017

Wellcome Open Res

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Identifying genes that are essential for mouse embryonic Background: development and survival through term is a powerful and unbiased way to discover possible genetic determinants of human developmental disorders. Characterising the changes in mouse embryos that result from ablation of lethal genes is a necessary first step towards uncovering their role in normal embryonic development and establishing any correlates amongst human congenital abnormalities.Here we present results gathered to date in the Deciphering the Methods: Mechanisms of Developmental Disorders (DMDD) programme, cataloguing the morphological defects identified from comprehensive imaging of 220 homozygous mutant and 114 wild type embryos from 42 lethal and subviable lines, analysed at E14.5.Virtually all mutant embryos show multiple abnormal phenotypes and Results: amongst the 42 lines these affect most organ systems. Within each mutant line, the phenotypes of individual embryos form distinct but overlapping sets. Subcutaneous edema, malformations of the heart or great vessels, abnormalities in forebrain morphology and the musculature of the eyes are all prevalent phenotypes, as is loss or abnormal size of the hypoglossal nerve.Overall, the most striking finding is that no matter how profound Conclusions: the malformation, each phenotype shows highly variable penetrance within a mutant line. These findings have challenging implications for efforts to identify human disease correlates.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice

Wilson¹,

Geyer²,

Reissig³

et al. 2017

Wellcome Open Res

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“…This lead to the inception of the Wellcome Trust-funded research program Deciphering the Mechanisms of Developmental Disorders (DMDD; https://dmdd.org.uk; [Mohun et al, 2013; Adams et al, 2013; Wilson et al, 2016]) that aims to characterize these lethal mutants further. The DMDD focuses on phenotyping embryonic lethal mutants to shed light on the genetic regulation of tissue differentiation, organ formation and embryo morphogenesis [Adams et al, 2013].…”

Section: Online Tools For Generating and Analyzing The Genes-of-intermentioning

confidence: 99%

Leveraging Online Resources to Prioritize Candidate Genes for Functional Analyses: Using the Fetal Testis as a Test Case

McClelland

Yao²

2017

Sex Dev

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With each new microarray or RNA-seq experiment, massive quantities of transcriptomic information are generated with the purpose to produce a list of candidate genes for functional analyses. Yet an effective strategy remains elusive to prioritize the genes on these candidate lists. In this review, we outline a prioritizing strategy by taking a step back from the bench and leveraging the rich range of public databases. This in silico approach provides an economical, less biased, and more effective solution. We discuss the publicly available online resources that can be used to answer a range of questions about a gene. Is the gene of interest expressed in the system of interest (using expression databases)? Where else is this gene expressed (using added-value transcriptomic resources)? What pathways and processes is the gene involved in (using enriched gene pathway analysis and mouse knockout databases)? Is this gene correlated with human diseases (using human disease variant databases)? Using mouse fetal testis as an example, our strategies identified 298 genes annotated as expressed in the fetal testis. We cross-referenced these genes to existing microarray data and narrowed the list down to cell-type-specific candidates (35 for Sertoli cells, 11 for Leydig cells, and 25 for germ cells). Our strategies can be customized so that they allow researchers to effectively and confidently prioritize genes for functional analysis.

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Gene Discovery in Lethal Foetal Disorders

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2017

Encyclopedia of Life Sciences

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Prenatal ultrasonography identifies an increasing number of foetal malformation phenotypes of unknown cause. For a significant number of these often lethal phenotypes, the underlying causal mutations are not identified yet, but animal data predict that up to 30% of the protein‐coding genes of our genome are implicated in embryonic development. Little attention has been paid to gene identification in these disorders, which often may present with a specific but so far unrecognised phenotype during foetal life. Counselling in prenatal diagnosis clinics to inform prognosis and management decisions but also recurrence risk in these situations remains unsatisfactory. Next‐generation sequencing offers unprecedented opportunities and perspectives to unravel the Mendelian basis of foetal disorders. Key Concepts Malformations and genetic disorders are the leading cause of infant mortality in the developed countries accounting for more than one third of cases. Foetal structural anomalies, often serious or lethal and of unknown cause despite current diagnostic genetic testing available, are increasingly identified at earlier gestational ages due to advancing ultrasound techniques. Counselling to inform prognosis and management decisions but also recurrence risk in these situations remains unsatisfactory. By identification of rare variants through whole exome or genome sequencing, many mutations in additional genes have been discovered to cause postnatal disease phenotypes. Next‐generation sequencing technologies have rarely been used to discover genes in which mutations cause early embryonic and foetal maldevelopment. On the basis of analysis of knockout and spontaneous mouse models, loss‐of‐function variants in up to 30% of genes could result in embryonic lethality in humans. Studying genes implicated in embryonic and foetal development and their phenotypes reveals important biological information on early errors in human morphogenesis and will contribute to annotate the function of relevant protein‐coding genes in our genome. Reliable applications of NGS strategies in future prenatal diagnosis will depend on our knowledge on specific foetal genotype–phenotype correlations.

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Deciphering the Mechanisms of Developmental Disorders (DMDD): a new programme for phenotyping embryonic lethal mice

Cited by 77 publications

References 18 publications

Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice

Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice

Leveraging Online Resources to Prioritize Candidate Genes for Functional Analyses: Using the Fetal Testis as a Test Case

Gene Discovery in Lethal Foetal Disorders

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