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Common genetic variation drives molecular heterogeneity in human iPSCs

Author

Listed:
  • Helena Kilpinen

    (European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
    University College London)

  • Angela Goncalves

    (Wellcome Trust Sanger Institute, Wellcome Genome Campus)

  • Andreas Leha

    (Wellcome Trust Sanger Institute, Wellcome Genome Campus
    University Medical Center Göttingen)

  • 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
    St Vincent’s Institute of Medical Research)

  • 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
    University of Cambridge, Cambridge Biomedical Campus
    NHS Blood and Transplant, Cambridge Biomedical Campus)

  • Ludovic Vallier

    (Wellcome Trust Sanger Institute, Wellcome Genome Campus
    Wellcome Trust and MRC Cambridge Stem Cell Institute and Biomedical Research Centre, Anne McLaren Laboratory, University of Cambridge)

  • 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)

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.

Suggested Citation

  • 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 Faulcon, 2017. "Common genetic variation drives molecular heterogeneity in human iPSCs," Nature, Nature, vol. 546(7658), pages 370-375, June.
    • Handle: RePEc:nat:nature:v:546:y:2017:i:7658:d:10.1038_nature22403
    DOI: 10.1038/nature22403
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    Citations

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    Cited by:

    1. Sulagna Ghosh & Ralda Nehme & Lindy E. Barrett, 2022. "Greater genetic diversity is needed in human pluripotent stem cell models," Nature Communications, Nature, vol. 13(1), pages 1-7, December.
    2. Chang Lu & Jan Zaucha & Rihab Gam & Hai Fang & Smithers & Matt E. Oates & Miguel Bernabe-Rubio & James Williams & Natalie Zelenka & Arun Prasad Pandurangan & Himani Tandon & Hashem Shihab & Raju Kalai, 2023. "Hypothesis-free phenotype prediction within a genetics-first framework," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Yuan Guan & Annika Enejder & Meiyue Wang & Zhuoqing Fang & Lu Cui & Shih-Yu Chen & Jingxiao Wang & Yalun Tan & Manhong Wu & Xinyu Chen & Patrik K. Johansson & Issra Osman & Koshi Kunimoto & Pierre Rus, 2021. "A human multi-lineage hepatic organoid model for liver fibrosis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Qiliang Ding & Matthew M. Edwards & Ning Wang & Xiang Zhu & Alexa N. Bracci & Michelle L. Hulke & Ya Hu & Yao Tong & Joyce Hsiao & Christine J. Charvet & Sulagna Ghosh & Robert E. Handsaker & Kevin Eg, 2021. "The genetic architecture of DNA replication timing in human pluripotent stem cells," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    5. Benjamin J. Schmiedel & Job Rocha & Cristian Gonzalez-Colin & Sourya Bhattacharyya & Ariel Madrigal & Christian H. Ottensmeier & Ferhat Ay & Vivek Chandra & Pandurangan Vijayanand, 2021. "COVID-19 genetic risk variants are associated with expression of multiple genes in diverse immune cell types," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    6. Drew R. Neavin & Angela M. Steinmann & Nona Farbehi & Han Sheng Chiu & Maciej S. Daniszewski & Himanshi Arora & Yasmin Bermudez & Cátia Moutinho & Chia-Ling Chan & Monique Bax & Mubarika Tyebally & Vi, 2023. "A village in a dish model system for population-scale hiPSC studies," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    7. Matthew Tegtmeyer & Jatin Arora & Samira Asgari & Beth A. Cimini & Ajay Nadig & Emily Peirent & Dhara Liyanage & Gregory P. Way & Erin Weisbart & Aparna Nathan & Tiffany Amariuta & Kevin Eggan & Marzi, 2024. "High-dimensional phenotyping to define the genetic basis of cellular morphology," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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