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 () and Daniel J. Gaffney ()
Additional contact information
Helena Kilpinen: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Angela Goncalves: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Andreas Leha: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Vackar Afzal: Centre for Gene Regulation & Expression, School of Life Sciences, University of Dundee
Kaur Alasoo: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Sofie Ashford: University of Cambridge, Cambridge Biomedical Campus
Sendu Bala: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Dalila Bensaddek: Centre for Gene Regulation & Expression, School of Life Sciences, University of Dundee
Francesco Paolo Casale: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Oliver J. Culley: Centre for Stem Cells & Regenerative Medicine, King’s College London, Tower Wing, Guy’s Hospital
Petr Danecek: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Adam Faulconbridge: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Peter W. Harrison: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Annie Kathuria: Centre for Stem Cells & Regenerative Medicine, King’s College London, Tower Wing, Guy’s Hospital
Davis McCarthy: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Shane A. McCarthy: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Ruta Meleckyte: Centre for Stem Cells & Regenerative Medicine, King’s College London, Tower Wing, Guy’s Hospital
Yasin Memari: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Nathalie Moens: Centre for Stem Cells & Regenerative Medicine, King’s College London, Tower Wing, Guy’s Hospital
Filipa Soares: Wellcome Trust and MRC Cambridge Stem Cell Institute and Biomedical Research Centre, Anne McLaren Laboratory, University of Cambridge
Alice Mann: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Ian Streeter: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Chukwuma A. Agu: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Alex Alderton: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Rachel Nelson: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Sarah Harper: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Minal Patel: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Alistair White: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Sharad R. Patel: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Laura Clarke: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Reena Halai: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Christopher M. Kirton: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Anja Kolb-Kokocinski: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Philip Beales: UCL Great Ormond Street Institute of Child Health, University College London
Ewan Birney: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Davide Danovi: Centre for Stem Cells & Regenerative Medicine, King’s College London, Tower Wing, Guy’s Hospital
Angus I. Lamond: Centre for Gene Regulation & Expression, School of Life Sciences, University of Dundee
Willem H. Ouwehand: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Ludovic Vallier: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Fiona M. Watt: Centre for Stem Cells & Regenerative Medicine, King’s College London, Tower Wing, Guy’s Hospital
Richard Durbin: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Oliver Stegle: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Daniel J. Gaffney: Wellcome Trust Sanger Institute, Wellcome Genome Campus

Nature, 2017, vol. 546, issue 7658, 370-375

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22403

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