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Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage

Nature Biotechnology volume 29, pages 11321144 (2011) | Download Citation


The International Stem Cell Initiative analyzed 125 human embryonic stem (ES) cell lines and 11 induced pluripotent stem (iPS) cell lines, from 38 laboratories worldwide, for genetic changes occurring during culture. Most lines were analyzed at an early and late passage. Single-nucleotide polymorphism (SNP) analysis revealed that they included representatives of most major ethnic groups. Most lines remained karyotypically normal, but there was a progressive tendency to acquire changes on prolonged culture, commonly affecting chromosomes 1, 12, 17 and 20. DNA methylation patterns changed haphazardly with no link to time in culture. Structural variants, determined from the SNP arrays, also appeared sporadically. No common variants related to culture were observed on chromosomes 1, 12 and 17, but a minimal amplicon in chromosome 20q11.21, including three genes expressed in human ES cells, ID1, BCL2L1 and HM13, occurred in >20% of the lines. Of these genes, BCL2L1 is a strong candidate for driving culture adaptation of ES cells.

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The International Stem Cell Initiative is funded by The International Stem Cell Forum. The authors would like to acknowledge the following: Medical Research Council, UK (P.W.A., H.M.); Mohammad Pakzad & Adeleh Taei, Royan Institute (H.B., G.H.S.); California Institute for Regenerative Medicine (CIRM) (E.C., P.W.L.); Institute of Medical Biology, A*STAR, Singapore (J.M.C.); Ministry of Education, Youth and Sports of the Czech Republic (P.D., A.H.); Stem Cell Research Center of the 21st Century Frontier Research Program, Ministry of Education, Science & Technology, Republic of Korea (SC-1140) (D.R.L., S.K.O.); Ministry of Science and Technology of China (863 program 2006AA02A102) (L.G.); Swedish Research Council, Cellartis (O.H.); Department of Biotechnology, Government of India, UK-India Education and Research Initiative and the Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India (M.I.); Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, Leading Project of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) of the Japan Society for the Promotion of Science (JSPS), Grants in-Aid for Scientific Research of JSPS and MEXT (T.I., S.Y., K.T.); Swiss National Science Foundation (grant no. 4046-114410) (M.J.); Shanghai Science and Technology Developmental Foundation (06DJ14001), Chinese Ministry of Science and Technology (2007CB948004) (Y.J.); funding from the North West Science Fund, UK (S.K.); One North East Regional Developmental Agency, Medical Research Council, UK, Newcastle University (M.L.); research funding from the Australian Stem Cell Centre (A.L.L.); The Netherlands Proteomics Consortium grant T4-3 (C.M.); Stem Cell Network, Canada (A.N.); National BioResource Project, MEXT, Japan (N.N.); Singapore Stem Cell Consortium (SSCC) & the Agency for Science Technology and Research (A*STAR) (S.K.W.O., P.R.) and the Genome Institute of Singapore Core Genotyping Lab (P.R.); Academy of Finland, Sigrid Juselius Foundation (T.O.); Conselho Nacional de Desenvolvimento Científico e Tecnológico/Departamento de Ciência e Tecnologia do Ministério da Saúde (CNPq/MS/DECIT), and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (L.V.P.); supported by the kind donation of Judy and Sidney Swartz (B.R.); financial support from the Faculty of Medicine, University of New South Wales (UNSW) and the National Health and Medical Research Council (NHMRC) Program Grant no. 568969 (Perminder Sachdev), South Eastern Sydney and Illawarra Area Health Service (SEIAHS) for making hES cell line Endeavour-2 available for this study, and H. Chung and J. Kim for their help in preparing the samples (K.S.); Academy of Finland (grant 218050), the Competitive Research Funding of the Tampere University Hospital (grant 9F217) (H. Skottman).

Author information

Author notes

    • Tetsuya Ishii
    •  & Nick Strelchenko

    Present addresses: Japan Science and Technology Agency, Tokyo, Japan (T. Ishii) and Department of Obstetrics and Gynecology, New York University Langone Medical Center, New York, New York, USA (N. Strelchenko).

    • Yuri Verlinsky



  1. Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield, UK.

    • Katherine Amps
    • , Peter W Andrews
    • , Angela Ford
    • , Paul J Gokhale
    •  & Harry Moore
  2. North East England Stem Cell Institute at Life, International Centre for Life, Newcastle upon Tyne, UK.

    • George Anyfantis
    • , Lyle Armstrong
    •  & Majlinda Lako
  3. Institute of Medical Biology, A-STAR, Immunos, Singapore.

    • Stuart Avery
    • , Alan Colman
    • , Jeremy M Crook
    •  & Barbara B Knowles
  4. Royan Institute for Reproductive Biomedicine, Department of Genetics, Tehran, Islamic Republic of Iran.

    • Hossein Baharvand
    •  & Hamid Gourabi
  5. Stanford University, Stanford, California, USA.

    • Julie Baker
    •  & Eric Chiao
  6. Sheffield Diagnostic Genetic Services, Sheffield Children's NHS Trust, Sheffield, UK.

    • Duncan Baker
    • , Anne Dalton
    •  & Edna Maltby
  7. Wolfson Centre for Stem Cells, Tissue Engineering & Modelling (STEM), Centre for Biomolecular Sciences, University of Nottingham, UK.

    • Maria B Munoz
    • , Chris Denning
    •  & Lorraine Young
  8. USC Stem Cell Core Facility, The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Stephen Beil
    •  & Victoria Fox
  9. Stem Cell Unit, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, Israel.

    • Nissim Benvenisty
    • , Tamar Golan-Lev
    • , Oded Kopper
    •  & Yoav Mayshar
  10. Racine IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

    • Dalit Ben-Yosef
    •  & Tzvia Frumkin
  11. Department of Cell Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

    • Dalit Ben-Yosef
  12. Regenerative Medicine Institute, Cedars-Sinai Medical Institute, Los Angeles, California, USA.

    • Juan-Carlos Biancotti
    • , Neta Lavon
    •  & Kavita Narwani
  13. Department of Pathology and Immunology, Faculty of Medicine, Geneva University, Geneva, Switzerland.

    • Alexis Bosman
    •  & Marisa Jaconi
  14. USC Epigenome Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Romulo Martin Brena
    • , Peter W Laird
    • , Fei Pan
    • , Hui Shen
    •  & Daniel J Weisenberger
  15. Department of Reproductive Medicine, St. Marys's Hospital, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.

    • Daniel Brison
  16. Cellartis AB, Goteborg, Sweden.

    • Gunilla Caisander
    • , Johan Hyllner
    •  & Raimund Strehl
  17. Faculty of Life Sciences, University of Manchester, Manchester, UK.

    • María V Camarasa
    •  & Susan Kimber
  18. Genome Institute of Singapore, Singapore.

    • Jieming Chen
    • , Wishva Herath
    • , Astrid Kresentia Irwanto
    • , Linda S Lim
    • , Paul Robson
    •  & Jameelah Sheik Mohamed
  19. Hoffmann-LaRoche, Nutley, New Jersey, USA.

    • Eric Chiao
  20. Department of Obstetrics & Gynaecology, Seoul National University College of Medicine, Seoul, Republic of Korea.

    • Young Min Choi
    •  & Shin Yong Moon
  21. Bioprocessing Technology Institute, Singapore.

    • Andre B H Choo
    •  & Steve K W Oh
  22. Roslin Cells Ltd., Roslin Biocentre, Roslin, Midlothian, UK.

    • Daniel Collins
    • , Paul A De Sousa
    •  & Janet Downie
  23. Singapore Stem Cell Consortium, A-STAR, Singapore.

    • Alan Colman
    • , Jeremy M Crook
    • , Grace Selva Raj
    •  & Shirani Sivarajah
  24. Centre for Neural Engineering, The University of Melbourne, Parkville, Australia.

    • Jeremy M Crook
    •  & Shirani Sivarajah
  25. Optics and Nanoelectronics Research Group, NICTA Victorian Research Laboratory, The University of Melbourne, Parkville, Australia.

    • Jeremy M Crook
    •  & Shirani Sivarajah
  26. Department of Surgery, St. Vincent's Hospital, The University of Melbourne, Fitzroy, Australia.

    • Jeremy M Crook
  27. Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • George Q Daley
  28. Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • George Q Daley
  29. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.

    • George Q Daley
  30. Harvard Stem Cell Institute, Boston, Massachusetts, USA.

    • George Q Daley
  31. Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.

    • Paul A De Sousa
    •  & Steve Pells
  32. Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.

    • Petr Dvorak
  33. WiCell Research Institute, Madison, Wisconsin, USA.

    • Karen D Montgomery
    •  & Tenneille E Ludwig
  34. Department of Obstetrics and Gynecology, Hopital Cantonal Fribourgois, Freibourg, Switzerland.

    • Anis Feki
  35. National Laboratory for Embryonic Stem Cell Research (LaNCE), Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, Brazil.

    • Ana M Fraga
    •  & Lygia V Pereira
  36. Institute of Reproductive & Stem Cell Engineering, Central South University, Reproductive & Genetic Hospital CITIC-XIANGYA, Changsha, Hunan, People's Republic of China.

    • Lin Ge
    • , Lu Guangxiu
    •  & Ouyang Qi
  37. The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah University Medical Center, Jerusalem, Israel.

    • Michal Gropp
    •  & Benjamin Reubinoff
  38. Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.

    • Ales Hampl
  39. Institute of Experimental Medicine ASCR, Prague, Czech Republic.

    • Ales Hampl
  40. MRC Centre of Epidemiology for Child Health, Institute of Child Health, University College London, London, UK.

    • Katie Harron
  41. UK Stem Cell Bank, Division of Cell Biology and Imaging, National Institute for Biological Standards and Control, South Mimms, Herts, UK.

    • Lyn Healy
    •  & Glyn N Stacey
  42. Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

    • Frida Holm
    •  & Outi Hovatta
  43. Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.

    • Maneesha S Inamdar
    •  & Parvathy Venu
  44. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.

    • Tetsuya Ishii
    • , Kazutoshi Takahashi
    •  & Shinya Yamanaka
  45. Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes of Biological Sciences, CAS/Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.

    • Ying Jin
  46. Stem Cell Department, NRC Kurchatov Institute, Moscow, Russia.

    • Sergey Kiselev
  47. Vavilov Institute of General Genetics, Moscow, Russia.

    • Sergey Kiselev
    •  & Maria A Lagarkova
  48. Reproductive Genetics Institute, Chicago, Illinois, USA.

    • Valeri Kukharenko
    • , Anver Kuliev
    • , Nick Strelchenko
    •  & Yuri Verlinsky
  49. CSIRO Material Science and Engineering, Clayton, Australia.

    • Andrew L Laslett
    •  & Qi Zhou
  50. Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.

    • Andrew L Laslett
  51. Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Gangnam-gu, Seoul, Republic of Korea.

    • Dong Ryul Lee
  52. CHA Stem Cell Institute, CHA University, Gangnam-gu, Seoul, Republic of Korea.

    • Jeoung Eun Lee
  53. Shanghai Stem Cell Institute, Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.

    • Chunliang Li
    • , Yu Ma
    •  & Bowen Sun
  54. Department of Embryology and Genetics, Vrije Universiteit Brussel, Brussels, Belgium.

    • Ileana Mateizel
    • , Karen Sermon
    •  & Claudia Spits
  55. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Maria Mileikovsky
    •  & Andras Nagy
  56. Wolfson Centre for Age-Related Diseases, King's College London, London, UK.

    • Stephen L Minger
    •  & Yue Wu
  57. GE Healthcare, Cardiff, UK.

    • Stephen L Minger
    •  & Yue Wu
  58. Laboratory of Embryonic Stem Cell Research, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.

    • Takamichi Miyazaki
    •  & Hirofumi Suemori
  59. Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands.

    • Christine Mummery
    •  & Dorien Ward-van Oostwaard
  60. Institute for Integrated Cell-Material Sciences, Kyoto University, Ushinomiya-cho, Yoshida, Sakyo-ku, Kyoto, Japan.

    • Norio Nakatsuji
    •  & Shinya Yamanaka
  61. Institute of Reproductive Medicine & Population, Medical Research Center, Seoul National University, Seoul, Republic of Korea.

    • Sun Kyung Oh
  62. Research Programs Unit, Molecular Neurology, Biomedicum Stem Cell Centre, University of Helsinki, Finland.

    • Cia Olson
    • , Timo Otonkoski
    •  & Timo Tuuri
  63. Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Finland.

    • Timo Otonkoski
  64. Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut, USA.

    • In-Hyun Park
  65. The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Martin F Pera
  66. Viacyte, Athens, Georgia, USA.

    • Alan Robins
    • , Thomas C Schulz
    •  & Eric Sherrer
  67. Program for Developmental Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Janet Rossant
  68. Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran.

    • Ghasem H Salekdeh
  69. Stem Cell Laboratory, Faculty of Medicine, University of New South Wales, Australia.

    • Kuldip Sidhu
  70. Institute for Regenerative Medicine, University of Tampere, Tampere, Finland.

    • Heli Skottman
    •  & Riitta Suuronen
  71. Yamanaka iPS Cell Special Project, Japan Science and Technology Agency, Kawaguchi, Japan.

    • Shinya Yamanaka
  72. Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.

    • Shinya Yamanaka


  1. The International Stem Cell Initiative



    Project coordination: P.W.A. Cytogenetic analyses: D.B., A.D., E.M., K.D.M. and T.G.-L. Molecular karyotyping by SNP BeadChip: P.R. DNA methylation arrays: R.M.B. and P.W.L. Administration and data curation: A. Ford and P.J.G. Data analysis and manuscript drafting: P.W.A., S.A., D.B., N.B., R.M.B., P.J.G., K.H., L.H., B.B.K., Y. Mayshar, S.K.W.O., M.F.P. and P.R. The scientific management of the ISCI project was provided by a steering committee comprising: P.W.A., N.B., B.B.K., S.K.W.O., M.F.P., J.R. and G.N.S. Sample contribution: A. Colman, A. Robins, A. Hampl, A. Bosman, A.M. Fraga, A. Nagy, A.B.H. Choo, A.L. Laslett, A. Feki, A. Kuliev, A. Kresentia Irwanto, B. Reubinoff, B. Sun, C. Denning, C. Mummery, C. Li, C. Olson, C. Spits, D. Ben-Yosef, D. Collins, D.J. Weisenberger, D. Ryul Lee, D. Ward-van Oostwaard, E. Chiao, E. Sherrer, Fei Pan, F. Holm, G. Anyfantis, G.Q. Daley, G.H. Salekdeh, G. Selva Raj, G. Caisander, H. Gourabi, H. Moore, H. Skottman, H. Suemori, H. Baharvand, H. Shen, I. Mateizel, In-Hyun Park, J. Sheik Mohamed, J. Downie, J. Eun Lee, J.M. Crook, J. Chen, J. Hyllner, J.-C. Biancotti, J. Baker, K. Sermon, K. Amps, K. Narwani, K. Takahashi, K. Sidhu, L. Ge, L.S. Lim, L. Young, Q. Zhou, L. Guangxiu, L.V. Pereira, L. Armstrong, M. Lako, M.S. Inamdar, M.A. Lagarkova, M.B. Munoz, M. Mileikovsky, M.V. Camarasa, M. Jaconi, M. Gropp, N. Lavon, N. Strelchenko, N. Nakatsuji, O. Kopper, O. Hovatta, O. Qi, P. Venu, P.A. De Sousa, P. Dvorak, R. Strehl, R. Suuronen, S. Kiselev, S. Yong Moon, S. Yamanaka, S. Sivarajah, S. Beil, S.L. Minger, S.K.W. Oh, S. Pells, S. Kyung Oh, S. Kimber, T. Miyazaki, T.E. Ludwig, T. Ishii, T.C. Schulz, T. Otonkoski, T. Tuuri, T. Frumkin, V. Kukharenko, V. Fox, W. Herath, Y. Jin, Y. Min Choi, Y. Ma, Y. Wu and Y. Verlinsky.

    Competing interests

    G. Caisander, J. Hyllner and R. Strehl are employees of Cellartis AB. E. Chiao is an employee of Hoffmann-LaRoche. D. Collins and J. Downie are employees of Roslin Cells Ltd. P.A. De Sousa is CSO of Roslin Cells Ltd. S.L. Minger is an employee of GE Healthcare. B. Reubinoff holds shares and is the CSO of CellCure Neurosciences Ltd. A. Robins, T.C. Schulz and E. Sherrer are employees of Viacyte. S. Yamanaka is a member of the scientific advisory board of iPierian Inc and iPS Academia Japan, Inc. without salary

    Supplementary information

    PDF files

    1. 1.

      Supplementary Text and Figures

      Supplementary Figures 1–5 and Supplementary Notes 1 and 2.

    2. 2.

      Supplementary Table 3

      The extent of DNA methylation changes in ES cell lines in relation to the difference between early and late passage levels.

    Excel files

    1. 1.

      Supplementary Table 1

      Full details of cell line samples provided.

    2. 2.

      Supplementary Table 2

      ES-associated structural variants.

    3. 3.

      Supplementary Table 4

      Polycomb array manifest.

    4. 4.

      Supplementary Table 5

      Cell line availability.

    5. 5.

      Supplementary Data Set 1

      .bed file of all LOH calls for all samples in the ISCI-2 sample set

    Zip files

    1. 1.

      Supplementary Data Set 2

      LOH calls for all samples in the ISCI-2 sample set

    2. 2.

      Supplementary Data Set 4

      Complete β-scores (methylation level) of all ISCI-2 samples

    Text files

    1. 1.

      Supplementary Data Set 3

      .bed file of CNV calls from karyotypically normal samples in the ISCI-2 sample set.

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