Clonal analysis for understanding fate biases in developing embryos

Multipotent progenitors that appear phenotypically similar often differ in the range of cell types they generate, which is typically described as fate bias. Traditional bulk lineage-tracing approaches, such as Cre/Lox systems, established qualitative progenitor–progeny relationships but offered limited insight into mechanisms governing tissue composition. Recent advances in lineage tracing combined with single-cell transcriptomics enable comprehensive characterization of clonal diversity at the whole-embryo scale, promising to provide mechanistic insights into developmental robustness. This review summarizes the current state of the art experimental and computational approaches in the field, with emphasis on emerging spatial and perturbation-based strategies in clonal biology. • Cell fate decisions follow a prime/bias/lock-in mechanism across contexts. • scRNA-seq manifolds approximate Waddington’s landscape but have key gaps. • RNA velocity and lineage tracing provide correlates, not causes, of bias. • clone2vec offers an alternative framework of clonal distribution description. • Spatial transcriptomics with perturbation screening can reveal causal biases.