Natural variation in gene expression and viral susceptibility revealed by neural progenitor cell villages

Human genome variation contributes to diversity in neurodevelopmental outcomes and vulnerabilities; recognizing the underlying molecular and cellular mechanisms will require scalable approaches. Here, we describe a cell villageexperimental platform we used to analyze genetic, molecular, and phenotypic het-erogeneity across neural progenitor cells from 44 human donors cultured in a shared in vitro environment using algorithms (Dropulation and Census-seq) to assign cells and phenotypes to individual donors. Through rapid induction of human stem cell-derived neural progenitor cells, measurements of natural genetic varia-tion, and CRISPR-Cas9 genetic perturbations, we identified a common variant that regulates antiviral IFITM3 expression and explains most inter-individual variation in susceptibility to the Zika virus. We also detected expression QTLs corresponding to GWAS loci for brain traits and discovered novel disease-relevant regula-tors of progenitor proliferation and differentiation such as CACHD1. This approach provides scalable ways to elucidate the effects of genes and genetic variation on cellular phenotypes.

Automated summary

Human genome variation plays a role in diversity in neurodevelopmental outcomes and vulnerabilities. In order to understand the underlying molecular and cellular mechanisms, scalable approaches are needed. In this study, a cell villageexperimental platform was used to analyze genetic, molecular, and phenotypic heterogeneity in neural progenitor cells. The results identified a common variant that regulates antiviral IFITM3 expression and explains most inter-individual variation in susceptibility to the Zika virus, as well as potential regulators of progenitor proliferation and differentiation.