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

Abstract

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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Figure 1: Population structure of the human ES cell lines analyzed.
Figure 2: Cytogenetic changes occurring during prolonged passage of human ES cells.
Figure 3: Ideogram demonstrating the chromosome changes found in this study.
Figure 4: Copy number variation occurrence in human ES cell lines during prolonged passage.
Figure 5: Cumulative distribution function of methylation changes in human ES cells in this study.
Figure 6: Recent pericentric inversion associated with 20q11.

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Acknowledgements

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).

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Contributions

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.

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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

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Notes 1 and 2. (PDF 649 kb)

Supplementary Table 1

Full details of cell line samples provided. (XLS 265 kb)

Supplementary Table 2

ES-associated structural variants. (XLSX 224 kb)

Supplementary Table 3

The extent of DNA methylation changes in ES cell lines in relation to the difference between early and late passage levels. (PDF 40 kb)

Supplementary Table 4

Polycomb array manifest. (XLS 431 kb)

Supplementary Table 5

Cell line availability. (XLSX 24 kb)

Supplementary Data Set 1

.bed file of all LOH calls for all samples in the ISCI-2 sample set (XLS 7081 kb)

Supplementary Data Set 2

LOH calls for all samples in the ISCI-2 sample set (ZIP 3089 kb)

Supplementary Data Set 3

.bed file of CNV calls from karyotypically normal samples in the ISCI-2 sample set. (TXT 6779 kb)

Supplementary Data Set 4

Complete β-scores (methylation level) of all ISCI-2 samples (ZIP 1435 kb)

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The International Stem Cell Initiative. Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat Biotechnol 29, 1132–1144 (2011). https://doi.org/10.1038/nbt.2051

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