Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice [version 1; referees: 1 approved, 2 approved with reservations]
Background: Identifying genes that are essential for mouse embryonic 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...
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doaj-fb3eb4cbdfa84c55a7e4e090899e7ce52020-11-24T23:02:40ZengWellcomeWellcome Open Research2398-502X2016-11-01110.12688/wellcomeopenres.9899.110670Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice [version 1; referees: 1 approved, 2 approved with reservations]Robert Wilson0Stefan H. Geyer1Lukas Reissig2Julia Rose3Dorota Szumska4Emily Hardman5Fabrice Prin6Christina McGuire7Ramiro Ramirez-Solis8Jacqui White9Antonella Galli10Catherine Tudor11Elizabeth Tuck12Cecilia Mazzeo13James C. Smith14Elizabeth Robertson15David J. Adams16Timothy Mohun17Wolfgang J. Weninger18The Francis Crick Institute, London, UKDivision of Anatomy, Center for Anatomy & Cell Biology, Medical University of Vienna, Wien, AustriaDivision of Anatomy, Center for Anatomy & Cell Biology, Medical University of Vienna, Wien, AustriaDivision of Anatomy, Center for Anatomy & Cell Biology, Medical University of Vienna, Wien, AustriaWellcome Trust Centre for Human Genetics, Oxford, UKThe Francis Crick Institute, London, UKThe Francis Crick Institute, London, UKThe Francis Crick Institute, London, UKWellcome Trust Sanger Institute, Cambridge, UKWellcome Trust Sanger Institute, Cambridge, UKWellcome Trust Sanger Institute, Cambridge, UKWellcome Trust Sanger Institute, Cambridge, UKWellcome Trust Sanger Institute, Cambridge, UKWellcome Trust Sanger Institute, Cambridge, UKThe Francis Crick Institute, London, UKSir William Dunn School of Pathology, University of Oxford, Oxford, UKWellcome Trust Sanger Institute, Cambridge, UKThe Francis Crick Institute, London, UKDivision of Anatomy, Center for Anatomy & Cell Biology, Medical University of Vienna, Wien, AustriaBackground: Identifying genes that are essential for mouse embryonic 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. Methods: Here we present results gathered to date in the Deciphering the Mechanisms of Developmental Disorders (DMDD) programme, cataloguing the morphological defects identified from comprehensive imaging of 220 homozygous mutant embryos from 42 lethal and subviable lines, analysed at E14.5. Results: Virtually all embryos show multiple abnormal phenotypes and 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. Conclusions: Overall, the most striking finding is that no matter how profound the malformation, each phenotype shows highly variable penetrance within a mutant line. These findings have challenging implications for efforts to identify human disease correlates.https://wellcomeopenresearch.org/articles/1-1/v1Animal GeneticsGenomics |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Robert Wilson Stefan H. Geyer Lukas Reissig Julia Rose Dorota Szumska Emily Hardman Fabrice Prin Christina McGuire Ramiro Ramirez-Solis Jacqui White Antonella Galli Catherine Tudor Elizabeth Tuck Cecilia Mazzeo James C. Smith Elizabeth Robertson David J. Adams Timothy Mohun Wolfgang J. Weninger |
spellingShingle |
Robert Wilson Stefan H. Geyer Lukas Reissig Julia Rose Dorota Szumska Emily Hardman Fabrice Prin Christina McGuire Ramiro Ramirez-Solis Jacqui White Antonella Galli Catherine Tudor Elizabeth Tuck Cecilia Mazzeo James C. Smith Elizabeth Robertson David J. Adams Timothy Mohun Wolfgang J. Weninger Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice [version 1; referees: 1 approved, 2 approved with reservations] Wellcome Open Research Animal Genetics Genomics |
author_facet |
Robert Wilson Stefan H. Geyer Lukas Reissig Julia Rose Dorota Szumska Emily Hardman Fabrice Prin Christina McGuire Ramiro Ramirez-Solis Jacqui White Antonella Galli Catherine Tudor Elizabeth Tuck Cecilia Mazzeo James C. Smith Elizabeth Robertson David J. Adams Timothy Mohun Wolfgang J. Weninger |
author_sort |
Robert Wilson |
title |
Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice [version 1; referees: 1 approved, 2 approved with reservations] |
title_short |
Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice [version 1; referees: 1 approved, 2 approved with reservations] |
title_full |
Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice [version 1; referees: 1 approved, 2 approved with reservations] |
title_fullStr |
Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice [version 1; referees: 1 approved, 2 approved with reservations] |
title_full_unstemmed |
Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice [version 1; referees: 1 approved, 2 approved with reservations] |
title_sort |
highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice [version 1; referees: 1 approved, 2 approved with reservations] |
publisher |
Wellcome |
series |
Wellcome Open Research |
issn |
2398-502X |
publishDate |
2016-11-01 |
description |
Background: Identifying genes that are essential for mouse embryonic 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. Methods: Here we present results gathered to date in the Deciphering the Mechanisms of Developmental Disorders (DMDD) programme, cataloguing the morphological defects identified from comprehensive imaging of 220 homozygous mutant embryos from 42 lethal and subviable lines, analysed at E14.5. Results: Virtually all embryos show multiple abnormal phenotypes and 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. Conclusions: Overall, the most striking finding is that no matter how profound the malformation, each phenotype shows highly variable penetrance within a mutant line. These findings have challenging implications for efforts to identify human disease correlates. |
topic |
Animal Genetics Genomics |
url |
https://wellcomeopenresearch.org/articles/1-1/v1 |
work_keys_str_mv |
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