Correspondence

Lack of Population Diversity in Commonly Used Human Embryonic Stem-Cell Lines

N Engl J Med 2010; 362:183-185January 14, 2010

Article

To the Editor:

Human embryonic stem-cell research may lead to new methods of drug discovery, insights into mechanisms of disease, and eventually, cellular therapies. The potential benefit to patient populations may depend partially on the diversity of the stem-cell lines that are available for research and clinical use. However, investigators have been unable to target their research to diverse subgroups of existing lines or to ensure the inclusion of lines from the human populations most relevant to their diseases of interest, because almost no information has been available on the human population origin of existing stem-cell lines.

Therefore, with the approval of the University of Michigan's Human Pluripotent Stem Cell Research Oversight Committee, we determined the genetic ancestry of a large collection of stem-cell lines, including the most commonly used lines that were approved for federally funded research under the Bush administration's policy, other lines derived in the United States that have been widely distributed,1 and additional lines derived in other countries (for details, see the table in the Supplementary Appendix, available with the full text of this letter at NEJM.org).

Using the Illumina 660W genotyping platform, we genotyped genomewide single-nucleotide polymorphisms (SNPs) in each stem-cell line. Control experiments showed that the presence of mouse embryonic feeder cells did not affect the SNP genotypes (>99.99% identity of SNP genotypes between stem-cell lines that were grown with or without feeder cells) or the inferred ancestry (data not shown). Genotypes of the stem-cell lines were compared with previously obtained genotypes on a reference set of 2001 subjects from the HapMap Project and the Human Genome Diversity Project,2,3 comprising 63 populations with worldwide representation. We analyzed 483,304 high-quality SNPs that had been genotyped in all sets of samples.

A cluster analysis4 of combined stem-cell and worldwide reference genotypes showed that nearly all the stem-cell lines clustered exclusively with reference subjects of known European and Middle Eastern origin (Figure 1Figure 1Cluster Analysis of Combined Stem-Cell and Worldwide Reference Genotypes.). Two stem-cell lines clustered with East Asians. Using a European and Middle Eastern subgroup of the reference data, we found that most lines clustered primarily with subjects of northern and western European ancestry. The remaining lines clustered with Middle Eastern and southern European populations, a finding that was compatible with the derivation of some of these lines from embryos with likely origins in Israel and Spain. Interestingly, an analysis of genotype sharing identified several sets of lines for which all lines in a given set had the same gamete donors (Figure 1).

We have found that widely distributed stem-cell lines lack population diversity and that none of these lines derive from populations with recent African ancestry. Other existing lines that we did not analyze probably derive from populations that were not represented in our study, but most published stem-cell studies have used the lines that we investigated.5

Efforts to derive and disseminate new stem-cell lines should now emphasize underrepresented populations, to allow researchers to assess the extent to which the ancestry of stem-cell lines influences disease models, cellular therapies, and drug screening with the use of stem cells. Availability of more diverse lines will reduce the risk that the potential benefits of stem-cell research will be limited to patients with certain ancestries. Another promising approach to increasing the diversity of pluripotent human cell lines is to derive induced pluripotent stem-cell lines from diverse donors. It is not yet clear, however, whether certain types of studies and therapies will be more readily performed with human embryonic stem cells.

Jack T. Mosher, Ph.D.
Trevor J. Pemberton, D.Phil.
Kristina Harter
Chaolong Wang, B.S.
Erkan O. Buzbas, Ph.D.
University of Michigan, Ann Arbor, MI

Petr Dvorak, Ph.D.
Masaryk University, Brno, Czech Republic

Carlos Simón, M.D., Ph.D.
Valencia University, Valencia, Spain

Sean J. Morrison, Ph.D.
Noah A. Rosenberg, Ph.D.
University of Michigan, Ann Arbor, MI
seanjm@umich.edu

Supported by the Howard Hughes Medical Institute, the Alfred P. Sloan Foundation, the Generalitat Valenciana, the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias grant P1081134, and donors to the University of Michigan's Center for Stem Cell Biology, especially the Jeffrey and Susan Liss Fund for the Life Sciences.

Financial and other disclosures provided by the authors are available with the full text of this letter at NEJM.org.

This letter (10.1056/NEJMc0910371) was published on December 16, 2009, at NEJM.org.

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Citing Articles (10)

Citing Articles

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   Jason Owen-Smith, Christopher Thomas Scott, Jennifer B. McCormick. (2012) Expand and Regularize Federal Funding for Human Pluripotent Stem Cell Research. Journal of Policy Analysis and Managementn/a-n/a
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   Katherine Amps, Peter W Andrews, George Anyfantis, Lyle Armstrong, Stuart Avery, Hossein Baharvand, Julie Baker, Duncan Baker, Maria B Munoz, Stephen Beil, Nissim Benvenisty, Dalit Ben-Yosef, Juan-Carlos Biancotti, Alexis Bosman, Romulo Martin Brena, Daniel Brison, Gunilla Caisander, María V Camarasa, Jieming Chen, Eric Chiao, Young Min Choi, Andre B H Choo, Daniel Collins, Alan Colman, Jeremy M Crook, George Q Daley, Anne Dalton, Paul A De Sousa, Chris Denning, Janet Downie, Petr Dvorak, Karen D Montgomery, Anis Feki, Angela Ford, Victoria Fox, Ana M Fraga, Tzvia Frumkin, Lin Ge, Paul J Gokhale, Tamar Golan-Lev, Hamid Gourabi, Michal Gropp, Lu Guangxiu, Ales Hampl, Katie Harron, Lyn Healy, Wishva Herath, Frida Holm, Outi Hovatta, Johan Hyllner, Maneesha S Inamdar, Astrid Kresentia Irwanto, Tetsuya Ishii, Marisa Jaconi, Ying Jin, Susan Kimber, Sergey Kiselev, Barbara B Knowles, Oded Kopper, Valeri Kukharenko, Anver Kuliev, Maria A Lagarkova, Peter W Laird, Majlinda Lako, Andrew L Laslett, Neta Lavon, Dong Ryul Lee, Jeoung Eun Lee, Chunliang Li, Linda S Lim, Tenneille E Ludwig, Yu Ma, Edna Maltby, Ileana Mateizel, Yoav Mayshar, Maria Mileikovsky, Stephen L Minger, Takamichi Miyazaki, Shin Yong Moon, Harry Moore, Christine Mummery, Andras Nagy, Norio Nakatsuji, Kavita Narwani, Steve K W Oh, Sun Kyung Oh, Cia Olson, Timo Otonkoski, Fei Pan, In-Hyun Park, Steve Pells, Martin F Pera, Lygia V Pereira, Ouyang Qi, Grace Selva Raj, Benjamin Reubinoff, Alan Robins, Paul Robson, Janet Rossant, Ghasem H Salekdeh, Thomas C Schulz, Karen Sermon, Jameelah Sheik Mohamed, Hui Shen, Eric Sherrer, Kuldip Sidhu, Shirani Sivarajah, Heli Skottman, Claudia Spits, Glyn N Stacey, Raimund Strehl, Nick Strelchenko, Hirofumi Suemori, Bowen Sun, Riitta Suuronen, Kazutoshi Takahashi, Timo Tuuri, Parvathy Venu, Yuri Verlinsky, Dorien Ward-van Oostwaard, Daniel J Weisenberger, Yue Wu, Shinya Yamanaka, Lorraine Young, Qi Zhou. (2011) Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nature Biotechnology 29:12, 1132-1144
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   Ana Maria Fraga, Érica Sara Souza de Araújo, Raquel Stabellini, Naja Vergani, Lygia V. Pereira. (2011) A Survey of Parameters Involved in the Establishment of New Lines of Human Embryonic Stem Cells. Stem Cell Reviews and Reports 7:4, 775-781
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   Christopher Thomas Scott, Jennifer B. McCormick, Mindy C. DeRouen, Jason Owen-Smith. (2011) Democracy Derived? New Trajectories in Pluripotent Stem Cell Research. Cell 145:6, 820-826
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   E. Stephenson, C. M. Ogilvie, H. Patel, G. Cornwell, L. Jacquet, N. Kadeva, P. Braude, D. Ilic. (2010) Safety paradigm: genetic evaluation of therapeutic grade human embryonic stem cells. Journal of The Royal Society Interface 7:Suppl_6, S677-S688
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   Linda F. Hogle. (2010) Characterizing Human Embryonic Stem Cells: Biological and Social Markers of Identity. Medical Anthropology Quarterly 24:4, 433-450
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   B. Arabadjiev, R. Petkova, S. Chakarov, A. Momchilova, R. Pankov. (2010) Do We Need More Human Embryonic Stem Cell Lines?. Biotechnology & Biotechnological Equipment 24:3, 1921-1927
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    Kouichi Hasegawa, Jordan E. Pomeroy, Martin F. Pera. (2010) Current Technology for the Derivation of Pluripotent Stem Cell Lines from Human Embryos. Cell Stem Cell 6:6, 521-531
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