Neutral competition explains the clonal composition of neural organoids

Cerebral organoids model the development of the human brain and are an indispensable tool for studying neurodevelopment. Whole-organoid lineage tracing has revealed the number of progeny arising from each initial stem cell to be highly diverse, with lineage sizes ranging from one to more than 20,000 cells. This exceeds what can be explained by existing stochastic models of corticogenesis, indicating the existence of an additional source of stochasticity. We propose an explanation in terms of the SAN model in which this additional source of stochasticity is the survival time of a lineage within a long-lived population of symmetrically dividing cells under neutral competition. We demonstrate that this model explains the experimentally observed variability of lineage sizes and we derive a formula that captures the quantitative relationship between survival time and lineage size. Finally, we show that our model implies the existence of a regulatory mechanism to keeps the size of the symmetrically dividing cell population constant. Overall design: Barcode-based Lineagetracing to measure the lineage size distribution in brain organoids in three replicates