Digital cousins: Simultaneous optimization of one model for BMP signaling in distant relatives reveals essential core.

Spatially distributed, nonuniform morphogen gradients play a crucial role in tissue organization during development across the animal kingdom. The Bone Morphogenetic Protein (BMP) pathway, a well-studied morphogen involved in dorsal-ventral (D-V) axis patterning, has been extensively studied in zebrafish, , and other organisms. Given that this pathway is highly conserved in both form and function, we sought to determine whether a core mathematical model that constrained topology and biophysical parameters could fully reproduce the observed dynamics of gradient formation in both and zebrafish through changes in expression only. We used multi-objective optimization to simultaneously fit a single core model to and zebrafish data and conditions. By exploring a single model with varied parameters, we identified both the homology and diversification of the BMP pathway. We find that variation in a small subset of parameters-particularly diffusion-related rates-can reconcile the experimentally measured BMP gradients in both species under wild-type conditions, whereas fitting both WT and mutant conditions requires additional species-specific regulatory extensions beyond the core model. This approach, involving simulation and multispecies optimization, provides a systematic method to explore the minimal parametric variations needed to account for interspecies differences in a developmental pathway. Rather than making predictive claims, our finding offers a framework for improving the interpretability and translational relevance of cross-species models.