학술논문
Natural variation in gene expression and viral susceptibility revealed by neural progenitor cell villages.
Document Type
article
Author
Nemesh, James; Ghosh, Sulagna; Mitchell, Jana; Salick, Max; Mello, Curtis; Meyer, Daniel; Pietilainen, Olli; Piccioni, Federica; Guss, Ellen; Raghunathan, Kavya; Tegtmeyer, Matthew; Hawes, Derek; Neumann, Anna; Worringer, Kathleen; Ho, Daniel; Kommineni, Sravya; Chan, Karrie; Peterson, Brant; Raymond, Joseph; Gold, John; Siekmann, Marco; Zuccaro, Emanuela; Nehme, Ralda; Kaykas, Ajamete; Eggan, Kevin; McCarroll, Steven; Wells, Michael
Source
Cell Stem Cell. 30(3)
Subject
Language
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.