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

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HipSci Consortium, Alessandra Vigilante, Anna Laddach, Nathalie Moens, Ruta Meleckyte, Andreas Leha, Arsham Ghahramani, Oliver J Culley, Annie Kathuria, Chloe Hurling, Alice Vickers, Erika Wiseman, Mukul Tewary, Peter W Zandstra, Richard Durbin, Franca Fraternali, Oliver Stegle, Ewan Birney, Nicholas M Luscombe, Davide Danovi & 1 more Fiona M Watt

Original languageEnglish
Pages (from-to)2078-2087.e3
JournalCell Reports
Volume26
Issue number8
Early online date19 Feb 2019
DOIs
Accepted/In press24 Jan 2019
E-pub ahead of print19 Feb 2019
Published19 Feb 2019

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Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

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Abstract

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.

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