10779/crick.11409966.v1 Alessandra Vigilante Alessandra Vigilante Anna Laddach Anna Laddach Nathalie Moens Nathalie Moens Ruta Meleckyte Ruta Meleckyte Andreas Leha Andreas Leha Arsham Ghahramani Arsham Ghahramani Oliver J Culley Oliver J Culley Annie Kathuria Annie Kathuria Chloe Hurling Chloe Hurling Alice Vickers Alice Vickers Erika Wiseman Erika Wiseman Mukul Tewary Mukul Tewary Peter W Zandstra Peter W Zandstra HipSci Consortium HipSci Consortium Richard Durbin Richard Durbin Franca Fraternali Franca Fraternali Oliver Stegle Oliver Stegle Ewan Birney Ewan Birney Nicholas M Luscombe Nicholas M Luscombe Davide Danovi Davide Danovi Fiona M Watt Fiona M Watt Identifying extrinsic versus intrinsic drivers of variation in cell behavior in human iPSC lines from healthy donors The Francis Crick Institute 2019 SNV cell adhesion dimensionality reduction fibronectin genetic variation high content imaging iPSC stem cell niche stem cells HipSci Consortium Luscombe FC001110 0601 Biochemistry and Cell Biology 2019-12-19 18:06:09 Journal contribution https://crick.figshare.com/articles/journal_contribution/Identifying_extrinsic_versus_intrinsic_drivers_of_variation_in_cell_behavior_in_human_iPSC_lines_from_healthy_donors/11409966 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.