Large-Scale Survey of Cell-Differentiation Programs in a Generative Model Reveals Regeneration as an Epiphenomenon of Development

BackgroundMulticellular organisms are characterized by a wide diversity of forms and complexity despite a restricted set of key molecules and mechanisms at the base of organismal development. Development combines three basic processes -- asymmetric cell division, signaling and gene regulation -- in a multitude of ways to create this overwhelming diversity of multicellular life-forms. Here, we use a generative model to test the limits to which such processes can be combined to generate multiple differentiation paths during development, and attempt to chart the diversity of multicellular organisms generated. ResultsWe sample millions of biologically feasible developmental schemes, allowing us to comment on the statistical properties of cell-differentiation trajectories they produce. We characterize model-generated organisms using the graph topology of their cell-type lineage maps. Remarkably, tree-type lineage differentiation maps are the rarest in our data. Additionally, a majority of the organisms generated by our model appear to be endowed with the ability to regenerate using pluripotent cells. ConclusionsOur results indicate that, in contrast to common views, cell-type lineage graphs are unlikely to be tree-like. Instead, they are more likely to be directed acyclic graphs, with multiple lineages converging on the same terminal cell-type. Furthermore, the high incidence of pluripotent cells in model-generated organisms stands in line with the long-standing hypothesis that whole body regeneration is an epiphenomenon of development. We discuss experimentally testable predictions of our model, and some ways to adapt the generative framework to test additional hypotheses about general features of development.