Quantification of gene expression patterns to reveal the origins of abnormal morphogenesis

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 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 the Fgfr2 mutation that were associated with Apert syndrome, demonstrating that these mouse models can further our understanding of limb defects in the human condition. Our ...

诸多先天性疾病的发育性形态异常，其早期起源至今仍未得到充分阐明。此类起源往往难以追溯，原因在于基因调控异常的初始信号，可能仅表现为难以检测的基因表达细微变化，且在后续发育进程中还会被次级效应所掩盖。本研究开发了一种方法，通过精准量化发育器官中基因表达结构域（gene expression domains）的三维空间分布，来追溯表型异常的起源。本研究将几何形态测量学（geometric morphometrics）应用于通过光学投影层析成像（Optical Projection Tomography）获取的三维基因表达数据，证实该方法具有足够高的灵敏度，能够检出此前从未被发现的调控异常。我们在成纤维细胞生长因子受体2（Fgfr2）突变的下游靶基因的表达中，发现了细微但具有统计学显著性的差异，该差异与阿佩尔综合征（Apert syndrome）相关；这一结果证明，此类小鼠模型能够帮助我们进一步理解人类疾病中的肢体缺陷。本研究……