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

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Vigilante, Alessandra 
Laddach, Anna 
Moens, Nathalie 
Meleckyte, Ruta 
Leha, Andreas 

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.

SNV, cell adhesion, dimensionality reduction, fibronectin, genetic variation, high content imaging, iPSC, stem cell niche, stem cells, Animals, Biological Variation, Population, Cell Differentiation, Cell Line, Cell Proliferation, Humans, Induced Pluripotent Stem Cells, Mice, Phenotype, Polymorphism, Single Nucleotide, Transcriptome
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Cell Rep
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Elsevier BV
Wellcome Trust (098503/B/12/Z)
Medical Research Council (MC_PC_12026)