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

TY - JOUR

T1 - Identifying Extrinsic versus Intrinsic Drivers of Variation in Cell Behavior in Human iPSC Lines from Healthy Donors

AU - Vigilante, Alessandra

AU - Laddach, Anna

AU - Moens, Nathalie

AU - Meleckyte, Ruta

AU - Leha, Andreas

AU - Ghahramani, Arsham

AU - Culley, Oliver J

AU - Kathuria, Annie

AU - Hurling, Chloe

AU - Vickers, Alice

AU - Wiseman, Erika

AU - Tewary, Mukul

AU - Zandstra, Peter W

AU - Durbin, Richard

AU - Fraternali, Franca

AU - Stegle, Oliver

AU - Birney, Ewan

AU - Luscombe, Nicholas M

AU - Danovi, Davide

AU - Watt, Fiona M

AU - HipSci Consortium

N1 - Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2019/2/19

Y1 - 2019/2/19

N2 - 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.

AB - 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.

KW - SNV

KW - cell adhesion

KW - dimensionality reduction

KW - fibronectin

KW - genetic variation

KW - high content imaging

KW - iPSC

KW - stem cell niche

KW - stem cells

UR - https://www.scopus.com/pages/publications/85061444862

U2 - 10.1016/j.celrep.2019.01.094

DO - 10.1016/j.celrep.2019.01.094

M3 - Article

C2 - 30784590

SN - 2211-1247

VL - 26

SP - 2078-2087.e3

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -