1. Identifying Extrinsic versus Intrinsic Drivers of Variation in Cell Behavior in Human iPSC Lines from Healthy Donors
- Author
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Vigilante, Alessandra, Laddach, Anna, Moens, Nathalie, Meleckyte, Ruta, Leha, Andreas, Ghahramani, Arsham, Culley, Oliver J, Kathuria, Annie, Hurling, Chloe, Vickers, Alice, Wiseman, Erika, Tewary, Mukul, Zandstra, Peter W, HipSci Consortium, Durbin, Richard, Fraternali, Franca, Stegle, Oliver, Birney, Ewan, Luscombe, Nicholas M, Danovi, Davide, Watt, Fiona M, Durbin, Richard [0000-0002-9130-1006], and Apollo - University of Cambridge Repository
- Subjects
iPSC ,Induced Pluripotent Stem Cells ,Gene Expression ,cell adhesion ,Cell Differentiation ,Tumour Biology ,Polymorphism, Single Nucleotide ,Cell Line ,Mice ,Phenotype ,Biological Variation, Population ,fibronectin ,stem cells ,SNV ,genetic variation ,high content imaging ,Animals ,Humans ,stem cell niche ,Transcriptome ,Genetics & Genomics ,Computational & Systems Biology ,dimensionality reduction ,Cell Proliferation - 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.
- Published
- 2019
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