When a null mutation of a gene causes a complete developmental arrest, the gene is typically considered essential for life. Yet, in most cases null mutations have more subtle effects on the phenotype. Here we used the phenotypic severity of mutations as a tool to examine system-level dynamics of gene expression. We classify genes required for the normal development of the mouse molar into different categories that range from essential to subtle modification of the phenotype. Collectively, we call these the developmental keystone genes. Transcriptome profiling using microarray and RNAseq analyses of patterning stage mouse molars show highly elevated expression levels for genes essential for the progression of tooth development, a result reminiscent of essential genes in single cell organisms. Elevated expression levels of progression genes were also detected in developing rat molars, suggesting evolutionary conservation of this system-level dynamics. Single-cell RNAseq analyses of developing mouse molars reveal that even though the size of the expression domain, measured in number of cells, is the main driver of organ-level expression, progression genes show high cell-level transcript abundances. Progression genes are also upregulated within their pathways, which themselves are highly expressed. In contrast, a high proportion of the genes required for normal tooth patterning are secreted ligands that are expressed in fewer cells than their receptors and intracellular components. Overall, even though expression patterns of individual genes can be highly different, conserved system-level principles of gene expression can be detected using phenotypically defined gene categories.

中文翻译：

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哺乳动物牙齿发育所需的关键基因的系统级分析

当基因的无效突变导致发育完全停止时，通常认为该基因是生命必不可少的。然而，在大多数情况下，无效突变对表型具有更微妙的影响。在这里，我们使用突变的表型严重性作为检查基因表达的系统级动态的工具。我们将小鼠磨牙正常发育所需的基因分为不同的类别，从表型的必要修饰到微妙修饰。我们将这些统称为发育关键基因。使用微阵列和模式化阶段小鼠磨牙的RNAseq分析进行转录组分析，显示出牙齿发育进程必不可少的基因的表达水平高度升高，这使人想起单细胞生物中的必需基因。在发育中的大鼠臼齿中也检测到进展基因的表达水平升高，表明该系统水平动力学的进化保守性。对发育中的小鼠臼齿的单细胞RNAseq分析显示，即使以细胞数量衡量的表达域大小是器官水平表达的主要驱动力，但进展基因仍显示出高细胞水平的转录本丰度。进阶基因在其途径中也被上调，其自身被高度表达。相反，正常牙齿构图所需的大部分基因是分泌的配体，在其细胞中表达的配体比其受体和细胞内组分少。总体而言，即使单个基因的表达方式可能有很大差异，