Abstract
The Deciphering the Mechanisms of Developmental Disorders programme has analysed the morphological and molecular phenotypes of embryonic and perinatal lethal mouse mutant lines in order to investigate the causes of embryonic lethality. Here we show that individual whole-embryo RNA-seq of 73 mouse mutant lines (>1000 transcriptomes) identifies transcriptional events underlying embryonic lethality and associates previously uncharacterised genes with specific pathways and tissues. For example, our data suggest that Hmgxb3 is involved in DNA-damage repair and cell-cycle regulation. Further, we separate embryonic delay signatures from mutant line-specific transcriptional changes by developing a baseline mRNA expression catalogue of wild-type mice during early embryogenesis (4–36 somites). Analysis of transcription outside coding sequence identifies deregulation of repetitive elements in Morc2a mutants and a gene involved in gene-specific splicing. Collectively, this work provides a large scale resource to further our understanding of early embryonic developmental disorders.
Highlights
The Deciphering the Mechanisms of Developmental Disorders programme has analysed the morphological and molecular phenotypes of embryonic and perinatal lethal mouse mutant lines in order to investigate the causes of embryonic lethality
We have created a baseline of wild-type transcriptomes over the period of somite formation as a stage reference. Using this baseline we have developed a method to enrich for the direct effects of the mutation on gene expression and identify a separate signature caused by developmental delay
We identified the molecular phenotypes of 53 homozygous mutant lines as well as of 20 lines where only heterozygous embryos could be retrieved at E9.5
Summary
The Deciphering the Mechanisms of Developmental Disorders programme has analysed the morphological and molecular phenotypes of embryonic and perinatal lethal mouse mutant lines in order to investigate the causes of embryonic lethality. We show that individual whole-embryo RNA-seq of 73 mouse mutant lines (>1000 transcriptomes) identifies transcriptional events underlying embryonic lethality and associates previously uncharacterised genes with specific pathways and tissues. Adult knock-out mice undergo a range of systematic phenotypic assessments to define genotype−phenotype associations These data provide vital information to further our understanding of human disease and developmental disorders[8]. It is estimated that around a third of all knock-out mutations in mice result in embryonic or perinatal (EP) lethality[9] and in these lines the adult phenotype can only be assessed in heterozygous individuals. The Deciphering the Mechanisms of Developmental Disorders (DMDD) programme was a 5-year project to systematically characterise EP lethal IMPC lines (defined as the absence of homozygous mutants after screening a minimum of 28 pups at P14). In addition to the embryos, placental tissues and yolk sacs were analysed which showed a high percentage of placental phenotypes among the embryonic-lethal mutant lines[17]
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