Making sense of fragmentation and merging in lineage tracing experiments

Lineage tracing experiments give dynamic information on the functional behaviour of dividing cells. These experiments therefore have become an important tool for studying stem and progenitor cell fate behavior in vivo. When cell proliferation is high or the frequency of induced clones cannot be precisely controlled, the merging and fragmentation of clones renders the retrospective interpretation of clonal fate data highly ambiguous, potentially leading to unguarded interpretations about lineage relationships and fate behaviour. Here, we discuss and generalize statistical strategies to detect, resolve and make use of clonal fragmentation and merging. We first explain how to detect the rates of clonal fragmentation and merging using simple statistical estimates. We then discuss ways to restore the clonal provenance of labelled cells algorithmically and statistically and elaborate on how the process of clonal fragmentation can indirectly inform about cell fate. We generalize and extend results from the context of their original publication.