Genetic mosaicism can manifest as spatially variable phenotypes that vary from site to site within an organism. Here, we use imaging-based phenomics to quantitate phenotypes at many sites within the axial skeleton of CRISPR-edited G0 zebrafish. Through characterization of loss-of-function cell clusters in the developing skeleton, we identify a distinctive size distribution shown to arise from clonal fragmentation and merger events. We quantitate the phenotypic mosaicism produced by somatic mutations of two genes, plod2 and bmp1a, implicated in human osteogenesis imperfecta. Comparison of somatic, CRISPR-generated G0 mutants to homozygous germline mutants reveals phenotypic convergence, suggesting that CRISPR screens of G0 animals can faithfully recapitulate the biology of inbred disease models. We describe statistical frameworks for phenomic analysis of spatial phenotypic variation present in somatic G0 mutants. In sum, this study defines an approach for decoding spatially variable phenotypes generated during CRISPR-based screens.

遗传镶嵌可以表现为在生物体内不同位置的空间可变表型。在这里，我们使用基于成像的表型来对CRISPR编辑的G0斑马鱼的轴向骨架内许多部位的表型进行定量。通过表征发育中的骨骼中功能丧失的细胞簇，我们确定了一个独特的大小分布，该大小分布表明是由克隆片段化和合并事件引起的。我们量化由两个基因，plod2和bmp1a的体细胞突变产生的表型镶嵌，牵涉到人类成骨不全症。体细胞，CRISPR产生的G0突变体与纯合生殖系突变体的比较揭示了表型趋同，这表明G0动物的CRISPR筛选可以忠实地概括近交疾病模型的生物学特性。我们描述了体细胞G0突变体中存在的空间表型变异的表型分析的统计框架。总而言之，这项研究定义了一种用于解码在基于CRISPR的筛选过程中产生的空间可变表型的方法。