Dynamic genetic regulation across cellular differentiation in heterogeneous differentiating cultures

Understanding the molecular effects of genetic variation across different cellular contexts is crucial for identifying the mechanisms underlying disease-associated loci. The dynamic interplay between genetic variants and their regulatory impact on gene expression across different human cell types, developmental stages, and environmental conditions remains underexplored. A major challenge is assaying the large space of dynamic cellular conditions in order to characterize context-specific regulatory phenotypes. To do this, our study harnessed the potential of heterogeneous differentiating cultures (HDCs), a multi-cell-type in vitro system in which cells asynchronously differentiate from iPSCs into a broad spectrum of cell types and cell states. We generated single-cell RNA-sequencing data from over 900,000 human cells generated from 53 individuals. Our study underscores the utility of HDCs in revealing the intricate genetic regulation at play in diverse and dynamic cellular contexts, setting the stage for accelerated discovery of disease mechanisms and therapeutic targets.