Identifying extrinsic versus intrinsic drivers of variation in cell behavior in human iPSC lines from healthy donors
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
HipSci Consortium
Richard Durbin
Franca Fraternali
Oliver Stegle
Ewan Birney
Nicholas M Luscombe
Davide Danovi
Fiona M Watt
10779/crick.11409966.v1
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.
2019-12-19 18:06:09
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