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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.

Author information

1
Centre for Stem Cells and Regenerative Medicine, King's College London, Floor 28, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, UK.
2
Randall Division, King's College London, New Hunts House, Great Maze Pond, London SE1 9RT, UK.
3
Centre for Stem Cells and Regenerative Medicine, King's College London, Floor 28, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
4
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
5
Centre for Stem Cells and Regenerative Medicine, King's College London, Floor 28, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
6
Centre for Stem Cells and Regenerative Medicine, King's College London, Floor 28, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK; School of Biomedical Engineering, The University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada; Michael Smith Laboratories, The University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada.
7
School of Biomedical Engineering, The University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada; Michael Smith Laboratories, The University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada.
8
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
9
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
10
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, UK.
11
Centre for Stem Cells and Regenerative Medicine, King's College London, Floor 28, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK. Electronic address: davide.danovi@kcl.ac.uk.
12
Centre for Stem Cells and Regenerative Medicine, King's College London, Floor 28, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK. Electronic address: fiona.watt@kcl.ac.uk.

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.

KEYWORDS:

SNV; cell adhesion; dimensionality reduction; fibronectin; genetic variation; high content imaging; iPSC; stem cell niche; stem cells

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