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

HipSci Consortium; 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; Richard Durbin; Franca Fraternali; Oliver Stegle; Ewan Birney; Nicholas M Luscombe; Davide Danovi; Fiona M Watt

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

HipSci Consortium, 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, Richard Durbin, Franca Fraternali, Oliver Stegle, Ewan Birney, Nicholas M Luscombe, Davide DanoviFiona M Watt

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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.

Original language	English
Pages (from-to)	2078-2087.e3
Journal	Cell Reports
Volume	26
Issue number	8
Early online date	19 Feb 2019
DOIs	https://doi.org/10.1016/j.celrep.2019.01.094
Publication status	Published - 19 Feb 2019

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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ArticleIdentifying Extrinsic versus Intrinsic_VIGILANTE_Accepted24January2019_GOLD VoR (CC BY)Final published version, 3.85 MBLicence: CC BY

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HipSci Consortium, Vigilante, A., Laddach, A., Moens, N., Meleckyte, R., Leha, A., Ghahramani, A., Culley, O. J., Kathuria, A., Hurling, C., Vickers, A., Wiseman, E., Tewary, M., Zandstra, P. W., Durbin, R., Fraternali, F., Stegle, O., Birney, E., Luscombe, N. M., ... Watt, F. M. (2019). Identifying Extrinsic versus Intrinsic Drivers of Variation in Cell Behavior in Human iPSC Lines from Healthy Donors. Cell Reports, 26(8), 2078-2087.e3. https://doi.org/10.1016/j.celrep.2019.01.094

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

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",

author = "{HipSci Consortium} and Alessandra Vigilante and Anna Laddach and Nathalie Moens and Ruta Meleckyte and Andreas Leha and Arsham Ghahramani and Culley, {Oliver J} and Annie Kathuria and Chloe Hurling and Alice Vickers and Erika Wiseman and Mukul Tewary and Zandstra, {Peter W} and Richard Durbin and Franca Fraternali and Oliver Stegle and Ewan Birney and Luscombe, {Nicholas M} and Davide Danovi and Watt, {Fiona M}",

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doi = "10.1016/j.celrep.2019.01.094",

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HipSci Consortium, Vigilante, A , Laddach, A , Moens, N , Meleckyte, R, Leha, A, Ghahramani, A , Culley, OJ , Kathuria, A , Hurling, C , Vickers, A, Wiseman, E, Tewary, M, Zandstra, PW, Durbin, R, Fraternali, F, Stegle, O, Birney, E, Luscombe, NM, Danovi, D & Watt, FM 2019, 'Identifying Extrinsic versus Intrinsic Drivers of Variation in Cell Behavior in Human iPSC Lines from Healthy Donors', Cell Reports, vol. 26, no. 8, pp. 2078-2087.e3. https://doi.org/10.1016/j.celrep.2019.01.094

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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

PY - 2019/2/19

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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

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KW - genetic variation

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KW - stem cell niche

KW - stem cells

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DO - 10.1016/j.celrep.2019.01.094

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SN - 2211-1247

VL - 26

SP - 2078-2087.e3

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -

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

Abstract

Keywords

UN SDGs

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