Cell Rep. 2019 Feb 19;26(8):2078-2087.e3. doi: 10.1016/j.celrep.2019.01.094.

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

Vigilante A¹, Laddach A², Moens N³, Meleckyte R³, Leha A⁴, Ghahramani A⁵, Culley OJ³, Kathuria A³, Hurling C³, Vickers A³, Wiseman E³, Tewary M⁶, Zandstra PW⁷; HipSci Consortium, Durbin R⁸, Fraternali F², Stegle O⁹, Birney E⁹, Luscombe NM¹⁰, Danovi D¹¹, Watt FM¹².

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.