Neutral competition within a long-lived population of symmetrically dividing cells shapes the clonal composition of cerebral organoids
Cerebral organoids model the development of the human brain and have become an indispensable tool for studying neural development and neuro-developmental diseases. Comprehensive whole-organoid lineage tracing has revealed the fates of the lineages arising from each initial stem cells to be highly diverse, with lineage sizes ranging from one to more than 20,000 cells. This variability exceeds what can be explained by existing stochastic models of corticogenesis, which indicates that an additional source of stochasticity must exist. We propose the quantitative SAN model in which this additional source of stochasticity is neutral competition within a long-lived population of symmetrically dividing cells. In this model, the eventual size of a lineage is determined by its survival time within this population of symmetrically dividing cells, which due to neutral competition varies widely between individual lineages. We demonstrate the SAN model to explain the experimentally observed variability of lineage sizes and use it to 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 mechanism which keeps the size of the population of symmetrically diving cells approximately constants, and that it enables this mechanism to be probed experimentally.