High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity

Elisa Närvä; Reija Autio; Nelly Rahkonen; Lingjia Kong; Neil Harrison; Danny Kitsberg; Lodovica Borghese; Joseph Itskovitz-Eldor; Omid Rasool; Petr Dvorak; Outi Hovatta; Timo Otonkoski; Timo Tuuri; Wei Cui; Oliver Brüstle; Duncan Baker; Edna Maltby; Harry D. Moore; Nissim Benvenisty; Peter W. Andrews; Olli Yli-Harja; Riitta Lahesmaa

doi:10.1038/nbt.1615

High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity

Elisa Närvä, Reija Autio, Nelly Rahkonen, Lingjia Kong, Neil Harrison, Danny Kitsberg, Lodovica Borghese, Joseph Itskovitz-Eldor, Omid Rasool, Petr Dvorak, Outi Hovatta, Timo Otonkoski, Timo Tuuri, Wei Cui, Oliver Brüstle, Duncan Baker, Edna Maltby, Harry D. Moore, Nissim Benvenisty, Peter W. AndrewsOlli Yli-Harja, Riitta Lahesmaa^*

^*Corresponding author for this work

Department of Genetics

Research output: Contribution to journal › Article › peer-review

243 Scopus citations

Abstract

Prolonged culture of human embryonic stem cells (hESCs) can lead to adaptation and the acquisition of chromosomal abnormalities, underscoring the need for rigorous genetic analysis of these cells. Here we report the highest-resolution study of hESCs to date using an Affymetrix SNP 6.0 array containing 906,600 probes for single nucleotide polymorphisms (SNPs) and 946,000 probes for copy number variations (CNVs). Analysis of 17 different hESC lines maintained in different laboratories identified 843 CNVs of 50 kb-3 Mb in size. We identified, on average, 24% of the loss of heterozygosity (LOH) sites and 66% of the CNVs changed in culture between early and late passages of the same lines. Thirty percent of the genes detected within CNV sites had altered expression compared to samples with normal copy number states, of which 44% were functionally linked to cancer. Furthermore, LOH of the q arm of chromosome 16, which has not been observed previously in hESCs, was detected.

Original language	English
Pages (from-to)	371-377
Number of pages	7
Journal	Nature Biotechnology
Volume	28
Issue number	4
DOIs	https://doi.org/10.1038/nbt.1615
State	Published - Apr 2010

Bibliographical note

Funding Information:
We are grateful to everyone who has taken care of sample collection and handling: T. Golan-Lev, A. Urrutikoetxea-Uriguen, S. Haupt, P. Koch, I. Laufenberg, B. Ley, A. Hampl, M. Vodinska, K. Koudelkova, S. Ström, F. Holm, A.-M. Strömberg, C. Olsson, M. Mikkola, S. Vuoristo, P. Junni and M. Hakkarainen. We especially acknowledge M. Linja, T. Heinonen and the Finnish DNA Microarray Centre for their excellent technical assistance. We acknowledge the Turku Graduate School of Biomedical Sciences. This study is supported by funding for the ESTOOLS consortium under the Sixth Research Framework Programme of the European Union, Juvenile Diabetes Research Foundation, The Academy of Finland and the Finnish Cancer Organizations, The Improving Outcomes Guidance Trust, The Ministry of Education, Youth, and Sport of the Czech Republic, Ida Montin Foundation, The Academy of Finland, projects no. 129657 (Finnish Centre of Excellence program 2006-11) and no. 134117 and the Medical Research Council, UK.

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Närvä, E., Autio, R., Rahkonen, N., Kong, L., Harrison, N., Kitsberg, D., Borghese, L., Itskovitz-Eldor, J., Rasool, O., Dvorak, P., Hovatta, O., Otonkoski, T., Tuuri, T., Cui, W., Brüstle, O., Baker, D., Maltby, E., Moore, H. D., Benvenisty, N., ... Lahesmaa, R. (2010). High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity. Nature Biotechnology, 28(4), 371-377. https://doi.org/10.1038/nbt.1615

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title = "High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity",

abstract = "Prolonged culture of human embryonic stem cells (hESCs) can lead to adaptation and the acquisition of chromosomal abnormalities, underscoring the need for rigorous genetic analysis of these cells. Here we report the highest-resolution study of hESCs to date using an Affymetrix SNP 6.0 array containing 906,600 probes for single nucleotide polymorphisms (SNPs) and 946,000 probes for copy number variations (CNVs). Analysis of 17 different hESC lines maintained in different laboratories identified 843 CNVs of 50 kb-3 Mb in size. We identified, on average, 24% of the loss of heterozygosity (LOH) sites and 66% of the CNVs changed in culture between early and late passages of the same lines. Thirty percent of the genes detected within CNV sites had altered expression compared to samples with normal copy number states, of which 44% were functionally linked to cancer. Furthermore, LOH of the q arm of chromosome 16, which has not been observed previously in hESCs, was detected.",

author = "Elisa N{\"a}rv{\"a} and Reija Autio and Nelly Rahkonen and Lingjia Kong and Neil Harrison and Danny Kitsberg and Lodovica Borghese and Joseph Itskovitz-Eldor and Omid Rasool and Petr Dvorak and Outi Hovatta and Timo Otonkoski and Timo Tuuri and Wei Cui and Oliver Br{\"u}stle and Duncan Baker and Edna Maltby and Moore, {Harry D.} and Nissim Benvenisty and Andrews, {Peter W.} and Olli Yli-Harja and Riitta Lahesmaa",

note = "Funding Information: We are grateful to everyone who has taken care of sample collection and handling: T. Golan-Lev, A. Urrutikoetxea-Uriguen, S. Haupt, P. Koch, I. Laufenberg, B. Ley, A. Hampl, M. Vodinska, K. Koudelkova, S. Str{\"o}m, F. Holm, A.-M. Str{\"o}mberg, C. Olsson, M. Mikkola, S. Vuoristo, P. Junni and M. Hakkarainen. We especially acknowledge M. Linja, T. Heinonen and the Finnish DNA Microarray Centre for their excellent technical assistance. We acknowledge the Turku Graduate School of Biomedical Sciences. This study is supported by funding for the ESTOOLS consortium under the Sixth Research Framework Programme of the European Union, Juvenile Diabetes Research Foundation, The Academy of Finland and the Finnish Cancer Organizations, The Improving Outcomes Guidance Trust, The Ministry of Education, Youth, and Sport of the Czech Republic, Ida Montin Foundation, The Academy of Finland, projects no. 129657 (Finnish Centre of Excellence program 2006-11) and no. 134117 and the Medical Research Council, UK.",

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Närvä, E, Autio, R, Rahkonen, N, Kong, L, Harrison, N, Kitsberg, D, Borghese, L, Itskovitz-Eldor, J, Rasool, O, Dvorak, P, Hovatta, O, Otonkoski, T, Tuuri, T, Cui, W, Brüstle, O, Baker, D, Maltby, E, Moore, HD, Benvenisty, N, Andrews, PW, Yli-Harja, O & Lahesmaa, R 2010, 'High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity', Nature Biotechnology, vol. 28, no. 4, pp. 371-377. https://doi.org/10.1038/nbt.1615

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AU - Närvä, Elisa

AU - Autio, Reija

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AU - Kong, Lingjia

AU - Harrison, Neil

AU - Kitsberg, Danny

AU - Borghese, Lodovica

AU - Itskovitz-Eldor, Joseph

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AU - Dvorak, Petr

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AU - Otonkoski, Timo

AU - Tuuri, Timo

AU - Cui, Wei

AU - Brüstle, Oliver

AU - Baker, Duncan

AU - Maltby, Edna

AU - Moore, Harry D.

AU - Benvenisty, Nissim

AU - Andrews, Peter W.

AU - Yli-Harja, Olli

AU - Lahesmaa, Riitta

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N2 - Prolonged culture of human embryonic stem cells (hESCs) can lead to adaptation and the acquisition of chromosomal abnormalities, underscoring the need for rigorous genetic analysis of these cells. Here we report the highest-resolution study of hESCs to date using an Affymetrix SNP 6.0 array containing 906,600 probes for single nucleotide polymorphisms (SNPs) and 946,000 probes for copy number variations (CNVs). Analysis of 17 different hESC lines maintained in different laboratories identified 843 CNVs of 50 kb-3 Mb in size. We identified, on average, 24% of the loss of heterozygosity (LOH) sites and 66% of the CNVs changed in culture between early and late passages of the same lines. Thirty percent of the genes detected within CNV sites had altered expression compared to samples with normal copy number states, of which 44% were functionally linked to cancer. Furthermore, LOH of the q arm of chromosome 16, which has not been observed previously in hESCs, was detected.

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High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity

Abstract

Bibliographical note

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