Natural variation in gene expression and viral susceptibility revealed by neural progenitor cell villages
Michael F. Wells, James Nemesh, Sulagna Ghosh, Jana M. Mitchell, Max R. Salick, Curtis J. Mello, Daniel Meyer, Olli Pietiläinen, Federica Piccioni, Ellen J. Guss, Kavya Raghunathan, Matthew Tegtmeyer, Derek Hawes, Anna Neumann, Kathleen A. Worringer, Daniel Ho, Sravya Kommineni, Karrie Chan, Brant K. Peterson, Joseph J. Raymond, John T. Gold, Marco T. Siekmann, Emanuela Zuccaro, Ralda Nehme, Ajamete Kaykas, Kevin Eggan, Steven A. McCarroll
Abstract
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 village" experimental platform we used to analyze genetic, molecular, and phenotypic heterogeneity 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 variation, 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 regulators 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.