A central task in developmental biology is to learn the sequence of fate decisions that leads to each mature cell type in a tissue or organism. Recently, clonal labeling of cells using DNA barcodes has emerged as a powerful approach for identifying cells that share a common ancestry of fate decisions. Here we explore the idea that stochasticity of cell fate choice during tissue development could be harnessed to read out lineage relationships after a single step of clonal barcoding. By considering a generalized multitype branching process, we determine the conditions under which the final distribution of barcodes over observed cell types encodes their bona fide lineage relationships. We then propose a method for inferring the order of fate decisions. Our theory predicts a set of symmetries of barcode covariance that serves as a consistency check for the validity of the method. We show that broken symmetries may be used to detect multiple paths of differentiation to the same cell types. We provide computational tools for general use. When applied to barcoding data in hematopoiesis, these tools reconstruct the classical hematopoietic hierarchy and detect couplings between monocytes and dendritic cells and between erythrocytes and basophils that suggest multiple pathways of differentiation for these lineages.

发展生物学的中心任务是学习决定组织或生物体中每种成熟细胞类型的命运决定的顺序。最近，使用DNA条形码对细胞进行克隆标记已成为一种强大的方法，可用于鉴定具有共同命运决定祖先的细胞。在这里，我们探索了一种想法，即在克隆条形码的单个步骤后，可以利用组织发展过程中细胞命运选择的随机性来读出谱系关系。通过考虑通用的多类型分支过程，我们确定了条码在观察到的细胞类型上的最终分布编码其真实血统关系的条件。然后，我们提出一种推断命运决定顺序的方法。我们的理论预测了一组条形码协方差的对称性，这些对称性可作为方法有效性的一致性检查。我们表明，破碎的对称性可用于检测分化为相同细胞类型的多种途径。我们提供通用的计算工具。当应用于造血过程中的条形码数据时，这些工具可重建经典的造血体系，并检测单核细胞与树突状细胞之间以及红细胞与嗜碱性粒细胞之间的偶联，为这些谱系提供了多种分化途径。