Researchers should consider a new layer of genetic variability
In the past few years, with the development of new tools for examining the human genome, researchers have found large segments of DNA that are copied or deleted in different individuals so that some people have more than two copies, only one copy or no copies of certain genes. Just like other genetic changes, these differences (termed copy number variations) influence physical traits, including susceptibility to disease.
Until now, it was unclear how common copy number variants (CNVs) were in human embryonic stem cells (hESCs) — and whether they had any effect. Researchers from the University of California, Los Angeles have just discovered at least nine CNVs in two stem cell lines using a technique known as array comparative genomic hybridization (aCGH)1. Their work suggests that stem cell lines need to be better characterized for use in research and therapies.
Led by Michael Teitell, the study is the first to use aCGH to detect copy number changes in hESCs. The technique provides a higher-resolution snapshot of the stem cell genome than other commonly used methods, such as karyotyping. As a result, researchers can detect smaller genetic changes (on the order of a thousand to a million bases), including CNVs, that haven't been seen before.
In the study, the researchers wondered whether changes in copy number could explain the differing ability of stem cells lines to proliferate or differentiate into cells with particular functions. So they examined the HSF1 and HSF6 stem cell lines, which have been previously shown to preferentially become different kinds of neurons under identical culture conditions2. Using aCGH, the team identified 4 variable regions in HSF1 and 5 in HSF6, plus 70 other candidate CNVs in the two lines. These regions contain numerous genes, but the researchers have not determined whether the amplification or deletion of the genes contained within the nine CNVs affects the differentiation and function of cells from the HSF1 and HSF6 lines. They also don't know whether the CNVs are inherited or arise in the laboratory.
Nonetheless, their results suggest that CNVs are an important variable affecting the phenotype and quality of stem cells — and any therapeutic cells or tissues derived from them. They also suggest that one cell line may not be as good as another when it comes to making particular cell types. As researchers and clinicians come to understand the differences between lines, they may be able to select cells' most appropriate tissue for a given stem cell experiment or therapy.
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References
Wu, H. et al. Copy number variant analysis of human embryonic stem cells. Stem Cells doi:10.1634/stemcells.2007-0993 (published online 27 March 2008).
Wu, H. et al. Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines. Proc. Natl. Acad. Sci. USA 10.1073/pnas.0706199104 (published online 10 August 2007).
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Borthwick, L. Some human embryonic stem cells have more gene copies than others. Nat Rep Stem Cells (2008). https://doi.org/10.1038/stemcells.2008.60
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DOI: https://doi.org/10.1038/stemcells.2008.60