by Monya Baker

Copy number variants crop up in routine ES cell culture

Individual mouse embryonic stem cell lines likely encompass more genetic variety than researchers can control for. A recent publication in the Proceedings of the National Academy of Sciences shows that mouse embryonic stem cells accumulate gains and losses of millions of base pairs in routine culture.


The particular type of genetic variability described is known as copy number variation (CNV). Though harder to study than differences in single nucleotides, such variation means that one cell can have several more copies of a particular region of the genome (encompassing one or many genes) than another cell. In humans, CNV has been associated with a range of diseases.

 Allan Bradley and colleagues at the Sanger Institute in Cambridge, UK examined 50 clonally isolated embryonic stem (ES) cell populations from 3 ES cell lines derived from 3 different strains of mice. These included two widely used lines, AB2.2 and E14, plus the JM8 line that is being used in two large government-funded initiatives aimed at creating mouse lines to determine the function of mammalian genes (the European Conditional Mouse Mutagenesis Program and U.S. Knockout Mouse Project). Within those 50 populations, the team detected over 28 instances of CNV that involved more than 1,200 different genes. Moreover, the mechanism used to identify differences in copy numbers, an array relying on bacterial artificial chromosomes, could detect differences only larger than 100 kilobases. The researchers concluded that many smaller CNVs remained undetected.

Though some of the CNVs had been identified previously, the researchers showed that CNVs can arise anew after only a limited number of mitotic divisions in culture. Though the effect of this variation on the behaviour of the cells was not explored, the researchers point out that the variation could be a confounding factor when studying the cells and the knockout mice derived from them. Induced pluripotent cells will also reflect this variation, says Bradley.

The concerns will most likely extend to studies and applications of human ES cell lines, says Michael Teitell of the University of California, Los Angeles, who has identified CNV within human ES cells. He says the work is further evidence of the need to systematically detect and assess CNVs not only within individuals, but also within stem cell lines.


Source: Nature

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