Common genetic variation drives molecular heterogeneity in human iPSCs

Helena Kilpinen; Angela Goncalves; Andreas Leha; Vackar Afzal; Kaur Alasoo; Sofie Ashford; Sendu Bala; Dalila Bensaddek; Francesco Paolo Casale; Oliver J Culley; Petr Danecek; Adam Faulconbridge; Peter W Harrison; Annie Kathuria; Davis McCarthy; Shane A McCarthy; Ruta Meleckyte; Yasin Memari; Nathalie Moens; Filipa Soares; Alice Mann; Ian Streeter; Chukwuma A Agu; Alex Alderton; Rachel Nelson; Sarah Harper; Minal Patel; Alistair White; Sharad R Patel; Laura Clarke; Reena Halai; Christopher M Kirton; Anja Kolb-Kokocinski; Philip Beales; Ewan Birney; Davide Danovi; Angus I Lamond; Willem H Ouwehand; Ludovic Vallier; Fiona M Watt; Richard Durbin; Oliver Stegle; Daniel J Gaffney

doi:10.1038/nature22403

Common genetic variation drives molecular heterogeneity in human iPSCs

Helena Kilpinen, Angela Goncalves, Andreas Leha, Vackar Afzal, Kaur Alasoo, Sofie Ashford, Sendu Bala, Dalila Bensaddek, Francesco Paolo Casale, Oliver J Culley, Petr Danecek, Adam Faulconbridge, Peter W Harrison, Annie Kathuria, Davis McCarthy, Shane A McCarthy, Ruta Meleckyte, Yasin Memari, Nathalie Moens, Filipa SoaresAlice Mann, Ian Streeter, Chukwuma A Agu, Alex Alderton, Rachel Nelson, Sarah Harper, Minal Patel, Alistair White, Sharad R Patel, Laura Clarke, Reena Halai, Christopher M Kirton, Anja Kolb-Kokocinski, Philip Beales, Ewan Birney, Davide Danovi, Angus I Lamond, Willem H Ouwehand, Ludovic Vallier, Fiona M Watt, Richard Durbin, Oliver Stegle^*, Daniel J Gaffney

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.

Original language	English
Pages (from-to)	370-375
Number of pages	6
Journal	NATURE
Volume	546
Issue number	7658
Early online date	10 May 2017
DOIs	https://doi.org/10.1038/nature22403
Publication status	Published - 15 Jun 2017

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Common genetic variation drives_KILPINEN_Accepted27April2017Publishedonline10May2017_GREEN AAMAccepted author manuscript, 5.99 MB

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Kilpinen, H., Goncalves, A., Leha, A., Afzal, V., Alasoo, K., Ashford, S., Bala, S., Bensaddek, D., Casale, F. P., Culley, O. J., Danecek, P., Faulconbridge, A., Harrison, P. W., Kathuria, A., McCarthy, D., McCarthy, S. A., Meleckyte, R., Memari, Y., Moens, N., ... Gaffney, D. J. (2017). Common genetic variation drives molecular heterogeneity in human iPSCs. NATURE, 546(7658), 370-375. https://doi.org/10.1038/nature22403

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title = "Common genetic variation drives molecular heterogeneity in human iPSCs",

abstract = "Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.",

author = "Helena Kilpinen and Angela Goncalves and Andreas Leha and Vackar Afzal and Kaur Alasoo and Sofie Ashford and Sendu Bala and Dalila Bensaddek and Casale, {Francesco Paolo} and Culley, {Oliver J} and Petr Danecek and Adam Faulconbridge and Harrison, {Peter W} and Annie Kathuria and Davis McCarthy and McCarthy, {Shane A} and Ruta Meleckyte and Yasin Memari and Nathalie Moens and Filipa Soares and Alice Mann and Ian Streeter and Agu, {Chukwuma A} and Alex Alderton and Rachel Nelson and Sarah Harper and Minal Patel and Alistair White and Patel, {Sharad R} and Laura Clarke and Reena Halai and Kirton, {Christopher M} and Anja Kolb-Kokocinski and Philip Beales and Ewan Birney and Davide Danovi and Lamond, {Angus I} and Ouwehand, {Willem H} and Ludovic Vallier and Watt, {Fiona M} and Richard Durbin and Oliver Stegle and Gaffney, {Daniel J}",

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doi = "10.1038/nature22403",

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Kilpinen, H, Goncalves, A, Leha, A, Afzal, V, Alasoo, K, Ashford, S, Bala, S, Bensaddek, D, Casale, FP, Culley, OJ, Danecek, P, Faulconbridge, A, Harrison, PW, Kathuria, A, McCarthy, D, McCarthy, SA, Meleckyte, R, Memari, Y, Moens, N, Soares, F, Mann, A, Streeter, I, Agu, CA, Alderton, A, Nelson, R, Harper, S, Patel, M, White, A, Patel, SR, Clarke, L, Halai, R, Kirton, CM, Kolb-Kokocinski, A, Beales, P, Birney, E, Danovi, D, Lamond, AI, Ouwehand, WH, Vallier, L, Watt, FM, Durbin, R, Stegle, O & Gaffney, DJ 2017, 'Common genetic variation drives molecular heterogeneity in human iPSCs', NATURE, vol. 546, no. 7658, pp. 370-375. https://doi.org/10.1038/nature22403

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AU - Kilpinen, Helena

AU - Goncalves, Angela

AU - Leha, Andreas

AU - Afzal, Vackar

AU - Alasoo, Kaur

AU - Ashford, Sofie

AU - Bala, Sendu

AU - Bensaddek, Dalila

AU - Casale, Francesco Paolo

AU - Culley, Oliver J

AU - Danecek, Petr

AU - Faulconbridge, Adam

AU - Harrison, Peter W

AU - Kathuria, Annie

AU - McCarthy, Davis

AU - McCarthy, Shane A

AU - Meleckyte, Ruta

AU - Memari, Yasin

AU - Moens, Nathalie

AU - Soares, Filipa

AU - Mann, Alice

AU - Streeter, Ian

AU - Agu, Chukwuma A

AU - Alderton, Alex

AU - Nelson, Rachel

AU - Harper, Sarah

AU - Patel, Minal

AU - White, Alistair

AU - Patel, Sharad R

AU - Clarke, Laura

AU - Halai, Reena

AU - Kirton, Christopher M

AU - Kolb-Kokocinski, Anja

AU - Beales, Philip

AU - Birney, Ewan

AU - Danovi, Davide

AU - Lamond, Angus I

AU - Ouwehand, Willem H

AU - Vallier, Ludovic

AU - Watt, Fiona M

AU - Durbin, Richard

AU - Stegle, Oliver

AU - Gaffney, Daniel J

PY - 2017/6/15

Y1 - 2017/6/15

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U2 - 10.1038/nature22403

DO - 10.1038/nature22403

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SN - 0028-0836

VL - 546

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EP - 375

JO - NATURE

JF - NATURE

IS - 7658

ER -

Common genetic variation drives molecular heterogeneity in human iPSCs

Abstract

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