A reference human induced pluripotent stem cell line for large-scale collaborative studies

Caroline B. Pantazis, Andrian Yang, Erika Lara, Justin A. McDonough, Cornelis Blauwendraat, Lirong Peng, Hideyuki Oguro, Jitendra Kanaujiya, Jizhong Zou, David Sebesta, Gretchen Pratt, Erin Cross, Jeffrey Blockwick, Philip Buxton, Lauren Kinner-Bibeau, Constance Medura, Christopher Tompkins, Stephen Hughes, Marianita Santiana, Faraz FaghriMike A. Nalls, Daniel Vitale, Shannon Ballard, Yue A. Qi, Daniel M. Ramos, Kailyn M. Anderson, Julia Stadler, Priyanka Narayan, Jason Papademetriou, Luke Reilly, Matthew P. Nelson, Sanya Aggarwal, Leah U. Rosen, Peter Kirwan, Venkat Pisupati, Steven L. Coon, Sonja W. Scholz, Theresa Priebe, Miriam Öttl, Jian Dong, Marieke Meijer, Lara J.M. Janssen, Vanessa S. Lourenco, Rik van der Kant, Dennis Crusius, Dominik Paquet, Ana Caroline Raulin, Guojun Bu, Aaron Held, Brian J. Wainger, Rebecca M.C. Gabriele, Jackie M. Casey, Selina Wray, Dad Abu-Bonsrah, Clare L. Parish, Melinda S. Beccari, Don W. Cleveland, Emmy Li, Indigo V.L. Rose, Martin Kampmann, Carles Calatayud Aristoy, Patrik Verstreken, Laurin Heinrich, Max Y. Chen, Birgitt Schüle, Dan Dou, Erika L.F. Holzbaur, Maria Clara Zanellati, Richa Basundra, Mohanish Deshmukh, Sarah Cohen, Richa Khanna, Malavika Raman, Zachary S. Nevin, Madeline Matia, Jonas Van Lent, Vincent Timmerman, Bruce R. Conklin, Katherine Johnson Chase, Ke Zhang, Salome Funes, Daryl A. Bosco, Lena Erlebach, Marc Welzer, Deborah Kronenberg-Versteeg, Guochang Lyu, Ernest Arenas, Elena Coccia, Lily Sarrafha, Tim Ahfeldt, John C. Marioni, William C. Skarnes, Mark R. Cookson, Michael E. Ward, Florian T. Merkle*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including differentiation to commonly used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field.

Original languageEnglish
Pages (from-to)1685-1702.e22
Number of pages41
JournalCell Stem Cell
Volume29
Issue number12
DOIs
Publication statusPublished - 1 Dec 2022

Bibliographical note

Funding Information:
M.M. is supported by the ZonMw-Veni program (09150161810052) from the Dutch Research Council ( NWO ). R.v.d.K is supported by a CZI NDCN Pilot Grant (2020-222244(5022)). D.P. is supported by grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). M.S.B. is supported by a T32AG066596-01 training grant from the NIH. D.W.C. is funded by R01-NS27036. A.H. is supported by NRSA postdoctoral fellowship from the NIH (F32NS114319). B.J.W. is a New York Stem Cell Foundation - Robertson Investigator (NYSCF-I-R44). S.W. and R.G. are supported by Alzheimer’s Research UK (ARUK-SRF2016B-2), the UCL Neurogenetic Therapies Program, generously funded by The Sigrid Rausing Trust and the National Institute for Health Research University College London Hospitals Biomedical Research Centre . E.L. is funded by the National Defense Science and Engineering Graduate Fellowship from the DoD . I.V.L.R. is funded by the California Institute for Regenerative Medicine Scholars Research Training Program (EDUC4-12812) and the Ruth L. Kirschstein National Research Service Award (T32 NS115706) from the NIH. M.K. is funded by a Chan Zuckerberg Initiative Ben Barres Early Career Acceleration award. P.V. is supported by Mission Lucidity, an ERC consolidator grant, and Research Foundation Flanders ( FWO ). C.C. is funded by the Marie Skłodowska-Curie Actions - Seal of Excellence FWO and postdoctoral fellowship. B.S. and P.V. are supported by the CZI NDCN and Amici Lovanienses . L.H. is funded by the DFG (471227244). D.D. was supported by T32-AG-000255 from the NIH. E.L.F.H. is funded by NINDS R01 NS060698. M.D. and S.C. are supported by a CZI NDCN Collaborative Pairs Award. M.R. is supported by a grant from the NIH (R01GM127557) and the Tufts Springboard Award ( Tufts University ). J.V.L. is supported by a DOC-PRO4 PhD fellowship from the University of Antwerp and an FWO-Flanders travel grant to perform the research at Gladstone Institute. K.J.C. and K.Z. are supported by grants from NIH- NINDS / NIA (R01NS117461), DoD (W81XWH-21-1-0082), Target ALS , and the Frick Foundation for ALS Research . Funding from the Dan and Diane Riccio Fund for Neuroscience, the Angel Fund for ALS research, and the Radala Foundation was provided to D.A.B. for this work. L.E. is supported by the Studienstiftung des deutschen Volkes and the International Max Planck Research School ( IMPRS ) for The Mechanisms of Mental Function and Dysfunction (MMFD). D.K-V. is supported by grants from the CZI (2020-221779(5022) & 2021-235147) and Alzheimer Forschung Initiative e.V. (20019p). G.L. and E.A. are supported by EU H2020-MSCA-ITN-2018 (813851), CZI NDCN (2018-191929), EU H2020-FETOPEN (HS-SEQ, 899687), Wallenberg Scholar (KAW2018.0232), ERC Advanced (PreciseCellPD, 884608), SSF (SB16-0065), VR (2020-01426), Hjarnfonden (FO2019-0068), Cancerfonden (CAN2016/572), and Karolinska Institutet (StratRegen 2018). L.S. is supported by the Training Program in Stem Cell Biology fellowship from the New York State Department of Health (NYSTEM-C32561GG).

Funding Information:
This research was supported in part by the Intramural Research Program of the NIH , National Institute on Aging (NIA), Department of Health and Human Services (ZO1 AG000535), as well as the National Institute of Neurological Disorders and Stroke (NINDS) . A.Y. is supported by an EMBL-EBI /Cambridge Computational Biomedical Postdoctoral Fellowship (EBPOD). V.P. is supported by a UK Regenerative Medicine Platform grant from the Medical Research Council (MR/R015724/1). F.T.M. is a New York Stem Cell Foundation - Robertson Investigator (NYSCF-R-156) and is supported by the Wellcome Trust and Royal Society (211221/Z/18/Z) and a Ben Barres Early Career Acceleration Award from the Chan Zuckerberg Initiative’s Neurodegeneration Challenge Network ( CZI NDCN 191942) that supported the costs of directed differentiation and single-cell sequencing. J.C.M. acknowledges core funding from the European Molecular Biology Laboratory and from Cancer Research UK (C9545/A29580). We thank Greg Strachnan and the MRC Metabolic Diseases Unit Imaging Core Facility for assistance with imaging and Katarzyna Kania and the staff at the Genomics Core Facility of the Cancer Research UK Cambridge Institute for assistance with single-cell library preparation and sequencing. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA ( https://hpc.nih.gov/ ). This research has been conducted using the UK Biobank Resource under Application Number 33601. We gratefully acknowledge the contribution of the Scientific Services at the Jackson Laboratory for work described in this publication, including the Cellular Engineering service, the Genome Technologies service for expert assistance with whole genome sequencing and DNA and RNA preparation, the Flow Cytometry service for expertise in the p53 assay, the Cytogenetics laboratory for G-band karyotyping and analysis of several iPSC sub-lines, and Scientific Instrument Services.

Funding Information:
This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA), Department of Health and Human Services (ZO1 AG000535), as well as the National Institute of Neurological Disorders and Stroke (NINDS). A.Y. is supported by an EMBL-EBI/Cambridge Computational Biomedical Postdoctoral Fellowship (EBPOD). V.P. is supported by a UK Regenerative Medicine Platform grant from the Medical Research Council (MR/R015724/1). F.T.M. is a New York Stem Cell Foundation - Robertson Investigator (NYSCF-R-156) and is supported by the Wellcome Trust and Royal Society (211221/Z/18/Z) and a Ben Barres Early Career Acceleration Award from the Chan Zuckerberg Initiative's Neurodegeneration Challenge Network (CZI NDCN 191942) that supported the costs of directed differentiation and single-cell sequencing. J.C.M. acknowledges core funding from the European Molecular Biology Laboratory and from Cancer Research UK (C9545/A29580). We thank Greg Strachnan and the MRC Metabolic Diseases Unit Imaging Core Facility for assistance with imaging and Katarzyna Kania and the staff at the Genomics Core Facility of the Cancer Research UK Cambridge Institute for assistance with single-cell library preparation and sequencing. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (https://hpc.nih.gov/). This research has been conducted using the UK Biobank Resource under Application Number 33601. We gratefully acknowledge the contribution of the Scientific Services at the Jackson Laboratory for work described in this publication, including the Cellular Engineering service, the Genome Technologies service for expert assistance with whole genome sequencing and DNA and RNA preparation, the Flow Cytometry service for expertise in the p53 assay, the Cytogenetics laboratory for G-band karyotyping and analysis of several iPSC sub-lines, and Scientific Instrument Services. M.M. is supported by the ZonMw-Veni program (09150161810052) from the Dutch Research Council (NWO). R.v.d.K is supported by a CZI NDCN Pilot Grant (2020-222244(5022)). D.P. is supported by grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). M.S.B. is supported by a T32AG066596-01 training grant from the NIH. D.W.C. is funded by R01-NS27036. A.H. is supported by NRSA postdoctoral fellowship from the NIH (F32NS114319). B.J.W. is a New York Stem Cell Foundation - Robertson Investigator (NYSCF-I-R44). S.W. and R.G. are supported by Alzheimer's Research UK (ARUK-SRF2016B-2), the UCL Neurogenetic Therapies Program, generously funded by The Sigrid Rausing Trust and the National Institute for Health Research University College London Hospitals Biomedical Research Centre. E.L. is funded by the National Defense Science and Engineering Graduate Fellowship from the DoD. I.V.L.R. is funded by the California Institute for Regenerative Medicine Scholars Research Training Program (EDUC4-12812) and the Ruth L. Kirschstein National Research Service Award (T32 NS115706) from the NIH. M.K. is funded by a Chan Zuckerberg Initiative Ben Barres Early Career Acceleration award. P.V. is supported by Mission Lucidity, an ERC consolidator grant, and Research Foundation Flanders (FWO). C.C. is funded by the Marie Skłodowska-Curie Actions - Seal of Excellence FWO and postdoctoral fellowship. B.S. and P.V. are supported by the CZI NDCN and Amici Lovanienses. L.H. is funded by the DFG (471227244). D.D. was supported by T32-AG-000255 from the NIH. E.L.F.H. is funded by NINDS R01 NS060698. M.D. and S.C. are supported by a CZI NDCN Collaborative Pairs Award. M.R. is supported by a grant from the NIH (R01GM127557) and the Tufts Springboard Award (Tufts University). J.V.L. is supported by a DOC-PRO4 PhD fellowship from the University of Antwerp and an FWO-Flanders travel grant to perform the research at Gladstone Institute. K.J.C. and K.Z. are supported by grants from NIH-NINDS/NIA (R01NS117461), DoD (W81XWH-21-1-0082), Target ALS, and the Frick Foundation for ALS Research. Funding from the Dan and Diane Riccio Fund for Neuroscience, the Angel Fund for ALS research, and the Radala Foundation was provided to D.A.B. for this work. L.E. is supported by the Studienstiftung des deutschen Volkes and the International Max Planck Research School (IMPRS) for The Mechanisms of Mental Function and Dysfunction (MMFD). D.K-V. is supported by grants from the CZI (2020-221779(5022) & 2021-235147) and Alzheimer Forschung Initiative e.V. (20019p). G.L. and E.A. are supported by EU H2020-MSCA-ITN-2018 (813851), CZI NDCN (2018-191929), EU H2020-FETOPEN (HS-SEQ, 899687), Wallenberg Scholar (KAW2018.0232), ERC Advanced (PreciseCellPD, 884608), SSF (SB16-0065), VR (2020-01426), Hjarnfonden (FO2019-0068), Cancerfonden (CAN2016/572), and Karolinska Institutet (StratRegen 2018). L.S. is supported by the Training Program in Stem Cell Biology fellowship from the New York State Department of Health (NYSTEM-C32561GG). All co-first authors (C.B.P. A.Y. E.L. J.A.M. C.B. and L.P.) contributed equally to this manuscript and all authors agree that they can both indicate their equal contribution and re-order the list of co-first authors in their own publication records. Conceptualization, C.B.P. A.Y. E.L. J.A.M. C.B. L.P. M.A.N. S.L.C. S.W.S. R.v.d.K. D.P. G.B. B.J.W. S.W. C.L.P. D.W.C. M.K. P.V. B.S. E.L.F.H. S.C. B.R.C. K.Z. D.A.B. D.K.-V. E.A. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M.; methodology, C.B.P. A.Y. E.L. J.A.M. C.B. L.P. M.A.N. S.L.C. S.W.S. R.v.d.K. D.P. G.B. B.J.W. S.W. C.L.P. D.W.C. M.K. P.V. B.S. E.L.F.H. S.C. B.R.C. K.Z. D.A.B. D.K.-V. E.A. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M; validation, A.Y. E.L. J.A.M. C.B. L.P. H.O. J.K. T.P. M.O. J.D. M.M. L.J.M.J. V.S.L. R.v.d.K. D.C. D.P. A.-C.R. G.B. A.H. B.J.W. R.M.C.G. J.M.C. S.W. D.A.-B. C.L.P. M.S.B. D.W.C. E.L. I.V.L.R. M.K. C.C.A. P.V. L.H. M.Y.C. B.S. D.D. E.L.F.H. M.C.Z. R.B. M.D. S.C. R.K. M.R. Z.S.N. M.M. J.V.L. B.R.C. K.J.C. K.E. S.F. D.A.B. L.E. M.W. D.K.-V. G.L. E.A. E.C. L.S. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M.; formal analysis, C.B.P. A.Y. E.L. J.A.M. C.B. L.P. D.S. G.P. E.C. J.B. P.B. L.K.-B. C.M. C.T. S.H. W.C.S. M.R.C. M.E.W. F.T.M.; investigation, A.Y. E.L. J.A.M. C.B. L.P. H.O. J.K. J.Z. D.S. G.P. E.C. J.B. P.B. L.K.-B. C.M. C.T. S.H. M.S. F.F. M.A.N. D.V. S.B. Y.A.Q. D.M.R. K.A.M. J.P. L.R. M.P.N. S.A. L.U.R. P.K. V.P. S.L.C. S.W.S. T.P. M.Ö. J.D. M.M. L.J.M.J. V.S.L. R.v.d.K. D.C. D.P. A-C.R. G.B. A.H. B.J.W. R.M.C.G. J.M.C. S.W. D.A.-B. C.L.P. M.S.B. D.W.C. E.L. I.V.L.R. M.K. C.C.A. P.V. L.H. M.Y.C. B.S. D.D. E.L.F.H. M.C.Z. R.B. M.D. S.C. R.K. M.R. Z.S.N. M.M. J.V.L. B.R.C. K.J.C. K.E. S.F. D.A.B. L.E. M.W. D.K.-V. G.L. E.A. E.C. L.S. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M.; resources, all co-authors; data curation, C.B.P. A.Y. C.B. L.P. F.F. M.A.N. D.V. S.B.; writing – original draft, C.B.P. A.Y. E.L. J.A.M. C.B. L.P. W.C.S. M.R.C. M.E.W. F.T.M; writing – reviewing & editing, all co-authors; supervision, J.Z. D.S. G.P. F.F. M.A.N. S.L.C. S.W.S. R.v.d.K. D.P. G.B. B.J.W. S.W. C.L.P. D.W.C. M.K. P.V. B.S. E.L.F.H. S.C. V.T. B.R.C. K.Z. D.A.B. D.K.-V. E.A. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M.; visualization, C.B.P. A.Y. E.L. J.A.M. C.B. L.P. H.O. J.K. J.Z. D.S. G.P. E.C. J.B. P.B. L.K.-B. C.M. C.T. S.H. M.S. K.M.A. T.P. M.O. J.D. M.M. L.J.M.J. V.S.L. R.v.d.K. D.C. D.P. A.-C.R. G.B. A.H. B.J.W. R.M.C.G. J.M.C. S.W. D.A.-B. C.L.P. M.S.B. D.W.C. E.L. I.V.L.R. M.K. C.C.A. P.V. L.H. M.Y.C. B.S. D.D. E.L.F.H. M.C.Z. R.B. M.D. S.C. R.K. M.R. Z.S.N. M.M. J.V.L. B.R.C. K.J.C. K.E. S.F. D.A.B. L.E. M.W. D.K.-V. G.L. E.A. E.C. L.S. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M.; project administration, C.B.P. A.Y. E.L. J.A.M. C.B. L.P. H.O. J.Z. D.S. G.P. M.S. F.F. M.A.N. P.N. J.P. S.L.C. R.v.d.K. D.P. G.B. B.J.W. S.W. C.L.P. D.W.C. M.K. P.V. B.S. E.L.F.H. S.C. B.R.C. K.Z. D.A.B. D.K.-V. E.A. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M.; funding acquisition, M.A.N. S.L.C. S.W.S. R.v.d.K. D.P. G.B. B.J.W. S.W. C.L.P. D.W.C. M.K. P.V. B.S. E.L.F.H. S.C. V.T. B.R.C. K.Z. D.A.B. D.K.-V. E.A. T.A. J.C.M. M.R.C. M.E.W. F.T.M. S.W.S. is on the scientific advisory council of the Lewy Body Dementia Association and the MSA Coalition. S.W.S. is an editorial board member for the Journal of Parkinson Disease and JAMA Neurology. S.W.S. received research support from Cerevel Therapeutics. M.K. serves on the scientific advisory boards of Engine Biosciences, Casma Therapeutics, Cajal Neuroscience, and Alector and is a consultant to Modulo Bio and Recursion Therapeutics. Participation by researchers from Data Tecnica International, LLC in this project was part of a competitive contract awarded to Data Tecnica International, LLC by the National Institutes of Health to support open science research. M.A.N. also currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc. E.A. is founder, shareholder, and scientific advisor of Cholestenix, Ltd. We support inclusive, diverse, and equitable conduct of research.

Publisher Copyright:
© 2022

Funding

M.M. is supported by the ZonMw-Veni program (09150161810052) from the Dutch Research Council ( NWO ). R.v.d.K is supported by a CZI NDCN Pilot Grant (2020-222244(5022)). D.P. is supported by grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). M.S.B. is supported by a T32AG066596-01 training grant from the NIH. D.W.C. is funded by R01-NS27036. A.H. is supported by NRSA postdoctoral fellowship from the NIH (F32NS114319). B.J.W. is a New York Stem Cell Foundation - Robertson Investigator (NYSCF-I-R44). S.W. and R.G. are supported by Alzheimer’s Research UK (ARUK-SRF2016B-2), the UCL Neurogenetic Therapies Program, generously funded by The Sigrid Rausing Trust and the National Institute for Health Research University College London Hospitals Biomedical Research Centre . E.L. is funded by the National Defense Science and Engineering Graduate Fellowship from the DoD . I.V.L.R. is funded by the California Institute for Regenerative Medicine Scholars Research Training Program (EDUC4-12812) and the Ruth L. Kirschstein National Research Service Award (T32 NS115706) from the NIH. M.K. is funded by a Chan Zuckerberg Initiative Ben Barres Early Career Acceleration award. P.V. is supported by Mission Lucidity, an ERC consolidator grant, and Research Foundation Flanders ( FWO ). C.C. is funded by the Marie Skłodowska-Curie Actions - Seal of Excellence FWO and postdoctoral fellowship. B.S. and P.V. are supported by the CZI NDCN and Amici Lovanienses . L.H. is funded by the DFG (471227244). D.D. was supported by T32-AG-000255 from the NIH. E.L.F.H. is funded by NINDS R01 NS060698. M.D. and S.C. are supported by a CZI NDCN Collaborative Pairs Award. M.R. is supported by a grant from the NIH (R01GM127557) and the Tufts Springboard Award ( Tufts University ). J.V.L. is supported by a DOC-PRO4 PhD fellowship from the University of Antwerp and an FWO-Flanders travel grant to perform the research at Gladstone Institute. K.J.C. and K.Z. are supported by grants from NIH- NINDS / NIA (R01NS117461), DoD (W81XWH-21-1-0082), Target ALS , and the Frick Foundation for ALS Research . Funding from the Dan and Diane Riccio Fund for Neuroscience, the Angel Fund for ALS research, and the Radala Foundation was provided to D.A.B. for this work. L.E. is supported by the Studienstiftung des deutschen Volkes and the International Max Planck Research School ( IMPRS ) for The Mechanisms of Mental Function and Dysfunction (MMFD). D.K-V. is supported by grants from the CZI (2020-221779(5022) & 2021-235147) and Alzheimer Forschung Initiative e.V. (20019p). G.L. and E.A. are supported by EU H2020-MSCA-ITN-2018 (813851), CZI NDCN (2018-191929), EU H2020-FETOPEN (HS-SEQ, 899687), Wallenberg Scholar (KAW2018.0232), ERC Advanced (PreciseCellPD, 884608), SSF (SB16-0065), VR (2020-01426), Hjarnfonden (FO2019-0068), Cancerfonden (CAN2016/572), and Karolinska Institutet (StratRegen 2018). L.S. is supported by the Training Program in Stem Cell Biology fellowship from the New York State Department of Health (NYSTEM-C32561GG). This research was supported in part by the Intramural Research Program of the NIH , National Institute on Aging (NIA), Department of Health and Human Services (ZO1 AG000535), as well as the National Institute of Neurological Disorders and Stroke (NINDS) . A.Y. is supported by an EMBL-EBI /Cambridge Computational Biomedical Postdoctoral Fellowship (EBPOD). V.P. is supported by a UK Regenerative Medicine Platform grant from the Medical Research Council (MR/R015724/1). F.T.M. is a New York Stem Cell Foundation - Robertson Investigator (NYSCF-R-156) and is supported by the Wellcome Trust and Royal Society (211221/Z/18/Z) and a Ben Barres Early Career Acceleration Award from the Chan Zuckerberg Initiative’s Neurodegeneration Challenge Network ( CZI NDCN 191942) that supported the costs of directed differentiation and single-cell sequencing. J.C.M. acknowledges core funding from the European Molecular Biology Laboratory and from Cancer Research UK (C9545/A29580). We thank Greg Strachnan and the MRC Metabolic Diseases Unit Imaging Core Facility for assistance with imaging and Katarzyna Kania and the staff at the Genomics Core Facility of the Cancer Research UK Cambridge Institute for assistance with single-cell library preparation and sequencing. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA ( https://hpc.nih.gov/ ). This research has been conducted using the UK Biobank Resource under Application Number 33601. We gratefully acknowledge the contribution of the Scientific Services at the Jackson Laboratory for work described in this publication, including the Cellular Engineering service, the Genome Technologies service for expert assistance with whole genome sequencing and DNA and RNA preparation, the Flow Cytometry service for expertise in the p53 assay, the Cytogenetics laboratory for G-band karyotyping and analysis of several iPSC sub-lines, and Scientific Instrument Services. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA), Department of Health and Human Services (ZO1 AG000535), as well as the National Institute of Neurological Disorders and Stroke (NINDS). A.Y. is supported by an EMBL-EBI/Cambridge Computational Biomedical Postdoctoral Fellowship (EBPOD). V.P. is supported by a UK Regenerative Medicine Platform grant from the Medical Research Council (MR/R015724/1). F.T.M. is a New York Stem Cell Foundation - Robertson Investigator (NYSCF-R-156) and is supported by the Wellcome Trust and Royal Society (211221/Z/18/Z) and a Ben Barres Early Career Acceleration Award from the Chan Zuckerberg Initiative's Neurodegeneration Challenge Network (CZI NDCN 191942) that supported the costs of directed differentiation and single-cell sequencing. J.C.M. acknowledges core funding from the European Molecular Biology Laboratory and from Cancer Research UK (C9545/A29580). We thank Greg Strachnan and the MRC Metabolic Diseases Unit Imaging Core Facility for assistance with imaging and Katarzyna Kania and the staff at the Genomics Core Facility of the Cancer Research UK Cambridge Institute for assistance with single-cell library preparation and sequencing. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (https://hpc.nih.gov/). This research has been conducted using the UK Biobank Resource under Application Number 33601. We gratefully acknowledge the contribution of the Scientific Services at the Jackson Laboratory for work described in this publication, including the Cellular Engineering service, the Genome Technologies service for expert assistance with whole genome sequencing and DNA and RNA preparation, the Flow Cytometry service for expertise in the p53 assay, the Cytogenetics laboratory for G-band karyotyping and analysis of several iPSC sub-lines, and Scientific Instrument Services. M.M. is supported by the ZonMw-Veni program (09150161810052) from the Dutch Research Council (NWO). R.v.d.K is supported by a CZI NDCN Pilot Grant (2020-222244(5022)). D.P. is supported by grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). M.S.B. is supported by a T32AG066596-01 training grant from the NIH. D.W.C. is funded by R01-NS27036. A.H. is supported by NRSA postdoctoral fellowship from the NIH (F32NS114319). B.J.W. is a New York Stem Cell Foundation - Robertson Investigator (NYSCF-I-R44). S.W. and R.G. are supported by Alzheimer's Research UK (ARUK-SRF2016B-2), the UCL Neurogenetic Therapies Program, generously funded by The Sigrid Rausing Trust and the National Institute for Health Research University College London Hospitals Biomedical Research Centre. E.L. is funded by the National Defense Science and Engineering Graduate Fellowship from the DoD. I.V.L.R. is funded by the California Institute for Regenerative Medicine Scholars Research Training Program (EDUC4-12812) and the Ruth L. Kirschstein National Research Service Award (T32 NS115706) from the NIH. M.K. is funded by a Chan Zuckerberg Initiative Ben Barres Early Career Acceleration award. P.V. is supported by Mission Lucidity, an ERC consolidator grant, and Research Foundation Flanders (FWO). C.C. is funded by the Marie Skłodowska-Curie Actions - Seal of Excellence FWO and postdoctoral fellowship. B.S. and P.V. are supported by the CZI NDCN and Amici Lovanienses. L.H. is funded by the DFG (471227244). D.D. was supported by T32-AG-000255 from the NIH. E.L.F.H. is funded by NINDS R01 NS060698. M.D. and S.C. are supported by a CZI NDCN Collaborative Pairs Award. M.R. is supported by a grant from the NIH (R01GM127557) and the Tufts Springboard Award (Tufts University). J.V.L. is supported by a DOC-PRO4 PhD fellowship from the University of Antwerp and an FWO-Flanders travel grant to perform the research at Gladstone Institute. K.J.C. and K.Z. are supported by grants from NIH-NINDS/NIA (R01NS117461), DoD (W81XWH-21-1-0082), Target ALS, and the Frick Foundation for ALS Research. Funding from the Dan and Diane Riccio Fund for Neuroscience, the Angel Fund for ALS research, and the Radala Foundation was provided to D.A.B. for this work. L.E. is supported by the Studienstiftung des deutschen Volkes and the International Max Planck Research School (IMPRS) for The Mechanisms of Mental Function and Dysfunction (MMFD). D.K-V. is supported by grants from the CZI (2020-221779(5022) & 2021-235147) and Alzheimer Forschung Initiative e.V. (20019p). G.L. and E.A. are supported by EU H2020-MSCA-ITN-2018 (813851), CZI NDCN (2018-191929), EU H2020-FETOPEN (HS-SEQ, 899687), Wallenberg Scholar (KAW2018.0232), ERC Advanced (PreciseCellPD, 884608), SSF (SB16-0065), VR (2020-01426), Hjarnfonden (FO2019-0068), Cancerfonden (CAN2016/572), and Karolinska Institutet (StratRegen 2018). L.S. is supported by the Training Program in Stem Cell Biology fellowship from the New York State Department of Health (NYSTEM-C32561GG). All co-first authors (C.B.P. A.Y. E.L. J.A.M. C.B. and L.P.) contributed equally to this manuscript and all authors agree that they can both indicate their equal contribution and re-order the list of co-first authors in their own publication records. Conceptualization, C.B.P. A.Y. E.L. J.A.M. C.B. L.P. M.A.N. S.L.C. S.W.S. R.v.d.K. D.P. G.B. B.J.W. S.W. C.L.P. D.W.C. M.K. P.V. B.S. E.L.F.H. S.C. B.R.C. K.Z. D.A.B. D.K.-V. E.A. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M.; methodology, C.B.P. A.Y. E.L. J.A.M. C.B. L.P. M.A.N. S.L.C. S.W.S. R.v.d.K. D.P. G.B. B.J.W. S.W. C.L.P. D.W.C. M.K. P.V. B.S. E.L.F.H. S.C. B.R.C. K.Z. D.A.B. D.K.-V. E.A. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M; validation, A.Y. E.L. J.A.M. C.B. L.P. H.O. J.K. T.P. M.O. J.D. M.M. L.J.M.J. V.S.L. R.v.d.K. D.C. D.P. A.-C.R. G.B. A.H. B.J.W. R.M.C.G. J.M.C. S.W. D.A.-B. C.L.P. M.S.B. D.W.C. E.L. I.V.L.R. M.K. C.C.A. P.V. L.H. M.Y.C. B.S. D.D. E.L.F.H. M.C.Z. R.B. M.D. S.C. R.K. M.R. Z.S.N. M.M. J.V.L. B.R.C. K.J.C. K.E. S.F. D.A.B. L.E. M.W. D.K.-V. G.L. E.A. E.C. L.S. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M.; formal analysis, C.B.P. A.Y. E.L. J.A.M. C.B. L.P. D.S. G.P. E.C. J.B. P.B. L.K.-B. C.M. C.T. S.H. W.C.S. M.R.C. M.E.W. F.T.M.; investigation, A.Y. E.L. J.A.M. C.B. L.P. H.O. J.K. J.Z. D.S. G.P. E.C. J.B. P.B. L.K.-B. C.M. C.T. S.H. M.S. F.F. M.A.N. D.V. S.B. Y.A.Q. D.M.R. K.A.M. J.P. L.R. M.P.N. S.A. L.U.R. P.K. V.P. S.L.C. S.W.S. T.P. M.Ö. J.D. M.M. L.J.M.J. V.S.L. R.v.d.K. D.C. D.P. A-C.R. G.B. A.H. B.J.W. R.M.C.G. J.M.C. S.W. D.A.-B. C.L.P. M.S.B. D.W.C. E.L. I.V.L.R. M.K. C.C.A. P.V. L.H. M.Y.C. B.S. D.D. E.L.F.H. M.C.Z. R.B. M.D. S.C. R.K. M.R. Z.S.N. M.M. J.V.L. B.R.C. K.J.C. K.E. S.F. D.A.B. L.E. M.W. D.K.-V. G.L. E.A. E.C. L.S. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M.; resources, all co-authors; data curation, C.B.P. A.Y. C.B. L.P. F.F. M.A.N. D.V. S.B.; writing – original draft, C.B.P. A.Y. E.L. J.A.M. C.B. L.P. W.C.S. M.R.C. M.E.W. F.T.M; writing – reviewing & editing, all co-authors; supervision, J.Z. D.S. G.P. F.F. M.A.N. S.L.C. S.W.S. R.v.d.K. D.P. G.B. B.J.W. S.W. C.L.P. D.W.C. M.K. P.V. B.S. E.L.F.H. S.C. V.T. B.R.C. K.Z. D.A.B. D.K.-V. E.A. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M.; visualization, C.B.P. A.Y. E.L. J.A.M. C.B. L.P. H.O. J.K. J.Z. D.S. G.P. E.C. J.B. P.B. L.K.-B. C.M. C.T. S.H. M.S. K.M.A. T.P. M.O. J.D. M.M. L.J.M.J. V.S.L. R.v.d.K. D.C. D.P. A.-C.R. G.B. A.H. B.J.W. R.M.C.G. J.M.C. S.W. D.A.-B. C.L.P. M.S.B. D.W.C. E.L. I.V.L.R. M.K. C.C.A. P.V. L.H. M.Y.C. B.S. D.D. E.L.F.H. M.C.Z. R.B. M.D. S.C. R.K. M.R. Z.S.N. M.M. J.V.L. B.R.C. K.J.C. K.E. S.F. D.A.B. L.E. M.W. D.K.-V. G.L. E.A. E.C. L.S. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M.; project administration, C.B.P. A.Y. E.L. J.A.M. C.B. L.P. H.O. J.Z. D.S. G.P. M.S. F.F. M.A.N. P.N. J.P. S.L.C. R.v.d.K. D.P. G.B. B.J.W. S.W. C.L.P. D.W.C. M.K. P.V. B.S. E.L.F.H. S.C. B.R.C. K.Z. D.A.B. D.K.-V. E.A. T.A. J.C.M. W.C.S. M.R.C. M.E.W. F.T.M.; funding acquisition, M.A.N. S.L.C. S.W.S. R.v.d.K. D.P. G.B. B.J.W. S.W. C.L.P. D.W.C. M.K. P.V. B.S. E.L.F.H. S.C. V.T. B.R.C. K.Z. D.A.B. D.K.-V. E.A. T.A. J.C.M. M.R.C. M.E.W. F.T.M. S.W.S. is on the scientific advisory council of the Lewy Body Dementia Association and the MSA Coalition. S.W.S. is an editorial board member for the Journal of Parkinson Disease and JAMA Neurology. S.W.S. received research support from Cerevel Therapeutics. M.K. serves on the scientific advisory boards of Engine Biosciences, Casma Therapeutics, Cajal Neuroscience, and Alector and is a consultant to Modulo Bio and Recursion Therapeutics. Participation by researchers from Data Tecnica International, LLC in this project was part of a competitive contract awarded to Data Tecnica International, LLC by the National Institutes of Health to support open science research. M.A.N. also currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc. E.A. is founder, shareholder, and scientific advisor of Cholestenix, Ltd. We support inclusive, diverse, and equitable conduct of research.

FundersFunder number
Angel Fund
CZI NDCN
California Institute for Regenerative Medicine Scholars Research Training ProgramEDUC4-12812
Dan and Diane Riccio Fund for Neuroscience
EU H2020-FETOPEN899687, 884608, KAW2018.0232
EU H2020-MSCA-ITN-2018813851, 2018-191929
Frick Foundation
Greg Strachnan
Marie Skłodowska-Curie Actions - Seal of Excellence FWOT32-AG-000255, 471227244
Mission Lucidity
Neurodegeneration Challenge NetworkCZI NDCN 191942
Radala Foundation
Sigrid Rausing Trust
National Institutes of Health33601, R01-NS27036, 09150161810052
U.S. Department of Defense
U.S. Department of Health and Human ServicesZO1 AG000535
National Institute on Aging
National Institute of Diabetes and Digestive and Kidney DiseasesR01DK125747
National Institute of Neurological Disorders and StrokeF32NS114319, R01GM127557, R01 NS060698, W81XWH-21-1-0082, R01NS117461
New York Stem Cell FoundationNYSCF-R-156
New York State Department of HealthNYSTEM-C32561GG
Gladstone Institutes
Tufts University
Israel National Road Safety AuthorityT32 NS115706
Alzheimer Forschung Initiative
Wellcome Trust
European Bioinformatics Institute
European Molecular Biology Laboratory
National Defense Science and Engineering Graduate
Chan Zuckerberg Initiative2020-221779(5022) & 2021-235147
International Max Planck Research School for Environmental, Cellular and Molecular Microbiology
Multiple System Atrophy Coalition
Cerevel Therapeutics
Medical Research CouncilMR/R015724/1
Royal Society211221/Z/18/Z
Cancer Research UKC9545/A29580
University College London
European Research Council
Deutsche Forschungsgemeinschaft390857198
Stiftelsen för Strategisk ForskningSB16-0065
Alzheimer’s Research UKARUK-SRF2016B-2
Fonds Wetenschappelijk Onderzoek
Nederlandse Organisatie voor Wetenschappelijk Onderzoek2020-222244(5022)
Karolinska Institutet
Studienstiftung des Deutschen Volkes
VetenskapsrådetCAN2016/572, 2020-01426, FO2019-0068
Universiteit Antwerpen
UCLH Biomedical Research Centre
International Max Planck Research School for Advanced Methods in Process and Systems Engineering
Cancer Research UK Cambridge Institute, University of Cambridge
scientific advisor of Cholestenix, Ltd.
scientific advisory council of the Lewy Body Dementia Association

    Keywords

    • CRISPR
    • differentiation
    • iPSC
    • karyotype
    • p53
    • pluripotent
    • reference
    • single-cell
    • stem cell
    • whole-genome

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