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 J. 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 L. 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 J. 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 L. Beales, Ewan Birney, Davide Danovi, Angus I. Lamond, Willem H. Ouwehand, Ludovic Vallier, Fiona M. Watt (Lead / Corresponding author), Richard Durbin (Lead / Corresponding author), Oliver Stegle (Lead / Corresponding author), Daniel J. Gaffney (Lead / Corresponding author)

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

363 Citations (Scopus)

225 Downloads (Pure)

Abstract

Induced pluripotent stem cell (iPSC) technology has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterisation of many existing iPSC lines limits their potential use for research and therapy. Here, we describe the systematic generation, genotyping and phenotyping of 711 iPSC lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative (HipSci: http://www.hipsci.org). Our study outlines the major sources of genetic and phenotypic variation in iPSCs 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 iPSC phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of rare, genomic copy number mutations that are repeatedly observed in iPSC reprogramming and 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

Keywords

Induced pluripotent stem cells
Gene expression
Gene regulation
Genetic variation

UN SDGs

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

Access to Document

10.1038/nature22403

Author Accepted ManuscriptAccepted author manuscript, 359 KB

1 Finished

Multidimensional Proteomic Analysis of Metabolic Stress & Cellular Phenotypes (Strategic Grant)
Cantrell, D. (Investigator) & Lamond, A. (Investigator)
1/01/15 → 31/12/19
Project: Research

363 Citations
1 Comment/debate

Corrigendum: Common genetic variation drives molecular heterogeneity in human iPSCs (Nature (2017) 546 (370-375) DOI: 10.1038/nature22403)
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. J., McCarthy, S. A., Meleckyte, R., Memari, Y., Moens, N. & Soares, F. & 23 others, Mann, A., Streeter, I., Agu, C. A., Alderton, A., Nelson, R., Harper, S., Patel, M., White, A., Patel, S. R., Clarke, L., Halai, R., Kirton, C. M., Kolb-Kokocinski, A., Beales, P. L., Birney, E., Danovi, D., Lamond, A., Ouwehand, W. H., Vallier, L., Watt, F. M. (Lead / Corresponding author), Durbin, R. (Lead / Corresponding author), Stegle, O. (Lead / Corresponding author) & Gaffney, D. J. (Lead / Corresponding author), 29 Jun 2017, In: Nature. 546, 7660, p. 686 1 p.
Research output: Contribution to journal › Comment/debate › peer-review

Open Access
12 Citations (Scopus)

Cite this

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. J., 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 = "Induced pluripotent stem cell (iPSC) technology has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterisation of many existing iPSC lines limits their potential use for research and therapy. Here, we describe the systematic generation, genotyping and phenotyping of 711 iPSC lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative (HipSci: http://www.hipsci.org). Our study outlines the major sources of genetic and phenotypic variation in iPSCs 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 iPSC phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of rare, genomic copy number mutations that are repeatedly observed in iPSC reprogramming and present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.",

keywords = "Induced pluripotent stem cells, Gene expression, Gene regulation, Genetic variation",

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 McCarthy, {Davis J.} 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 Beales, {Philip L.} 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.}",

note = "This work was funded with a strategic award from the Wellcome Trust and Medical Research Council (WT098503)",

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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, DJ, 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, PL, 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

TY - JOUR

T1 - Common genetic variation drives molecular heterogeneity in human iPSCs

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 J.

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 L.

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.

N1 - This work was funded with a strategic award from the Wellcome Trust and Medical Research Council (WT098503)

PY - 2017/6/15

Y1 - 2017/6/15

N2 - Induced pluripotent stem cell (iPSC) technology has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterisation of many existing iPSC lines limits their potential use for research and therapy. Here, we describe the systematic generation, genotyping and phenotyping of 711 iPSC lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative (HipSci: http://www.hipsci.org). Our study outlines the major sources of genetic and phenotypic variation in iPSCs 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 iPSC phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of rare, genomic copy number mutations that are repeatedly observed in iPSC reprogramming and present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.

AB - Induced pluripotent stem cell (iPSC) technology has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterisation of many existing iPSC lines limits their potential use for research and therapy. Here, we describe the systematic generation, genotyping and phenotyping of 711 iPSC lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative (HipSci: http://www.hipsci.org). Our study outlines the major sources of genetic and phenotypic variation in iPSCs 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 iPSC phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of rare, genomic copy number mutations that are repeatedly observed in iPSC reprogramming and present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.

KW - Induced pluripotent stem cells

KW - Gene expression

KW - Gene regulation

KW - Genetic variation

U2 - 10.1038/nature22403

DO - 10.1038/nature22403

M3 - Article

C2 - 28489815

SN - 0028-0836

VL - 546

SP - 370

EP - 375

JO - Nature

JF - Nature

IS - 7658

ER -

Common genetic variation drives molecular heterogeneity in human iPSCs

Abstract

Keywords

UN SDGs

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Projects

Multidimensional Proteomic Analysis of Metabolic Stress & Cellular Phenotypes (Strategic Grant)

Research output

Corrigendum: Common genetic variation drives molecular heterogeneity in human iPSCs (Nature (2017) 546 (370-375) DOI: 10.1038/nature22403)

Cite this