The earliest developmental origins of dysmorphologies are poorly understood in many congenital diseases. They often remain elusive because the first signs of genetic misregulation may initiate as subtle changes in gene expression, which are hard to detect and can be obscured later in development by secondary effects. Here, we develop a method to trace back the origins of phenotypic abnormalities by accurately quantifying the 3D spatial distribution of gene expression domains in developing organs. By applying Geometric Morphometrics to 3D gene expression data obtained by Optical Projection Tomography, we determined that our approach is sensitive enough to find regulatory abnormalities that have never been detected previously. We identified subtle but significant differences in the gene expression of a downstream target of a Fgfr2 mutation associated with Apert syndrome, demonstrating that these mouse models can further our understanding of limb defects in the human condition. Our method can be applied to different organ systems and models to investigate the etiology of malformations.
16The earliest developmental origins of dysmorphologies are poorly understood in many congenital 17 diseases. They often remain elusive because the first signs of genetic misregulation may initiate as 18 subtle changes in gene expression, which can be obscured later in development due to secondary 19 phenotypic effects. We here develop a method to trace back the origins of phenotypic abnormalities by 20 accurately quantifying the 3D spatial distribution of gene expression domains in developing organs. By 21 applying geometric morphometrics to 3D gene expression data obtained by Optical Projection 22 Tomography, our approach is sensitive enough to find regulatory abnormalities never previously 23 detected. We identified subtle but significant differences in gene expression of a downstream target of 24 the Fgfr2 mutation associated with Apert syndrome. Challenging previous reports, we demonstrate that 25Apert syndrome mouse models can further our understanding of limb defects in the human condition. 26Our method can be applied to other organ systems and models to investigate the etiology of 27 malformations. 28
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