Identifying Extrinsic versus Intrinsic Drivers of Variation in Cell Behavior in Human iPSC Lines from Healthy Donors

Abstract

Summary: Large cohorts of human induced pluripotent stem cells (iPSCs) from healthy donors are a potentially powerful tool for investigating the relationship between genetic variants and cellular behavior. Here, we integrate high content imaging of cell shape, proliferation, and other phenotypes with gene expression and DNA sequence datasets from over 100 human iPSC lines. By applying a dimensionality reduction approach, Probabilistic Estimation of Expression Residuals (PEER), we extracted factors that captured the effects of intrinsic (genetic concordance between different cell lines from the same donor) and extrinsic (cell responses to different fibronectin concentrations) conditions. We identify genes that correlate in expression with intrinsic and extrinsic PEER factors and associate outlier cell behavior with genes containing rare deleterious non-synonymous SNVs. Our study, thus, establishes a strategy for examining the genetic basis of inter-individual variability in cell behavior. : Cell behavior reflects both the intrinsic state of the cell and extrinsic signals it receives from its microenvironment. By integrating genomic, gene expression, and cell biology datasets from a large number of human iPSCs from healthy donors, Vigilante et al. show how genetic variation contributes to phenotypic variation. Keywords: iPSC, SNV, genetic variation, high content imaging, stem cells, dimensionality reduction, fibronectin, stem cell niche, cell adhesion