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Gene Silencing in Mammalian Cells

Robin Holliday, Thu Ho, Richard Paulin


In the early genetic studies of mammalian cells in culture there was ongoing controversy about the sources of heritable variability (for review, see Holliday 1991). On the one hand, it was believed that mammalian cells could be handled essentially in the same way as microorganisms; that is, by the isolation and study of gene mutations. On the other hand, it was maintained that these cells were derived from tissues containing specialized genes, most of which were not transcribed, as well as standard housekeeping genes. Changes in the activity of specialized genes in cells in culture would be expected to have an epigenetic basis. This controversy was apparently ended by two definitive reviews (De Mars 1974; Siminovitch 1976), which established beyond doubt that classic mutations could be induced in cultured mammalian cells and that these had the inherited stability expected of such mutations. There was still a problem, because established cell lines had at least a diploid number of chromosomes, and often a higher number. It would be expected that autosomal recessive mutations would be expressed only rarely, and yet when particular mutants were sought they were often easily obtained. To resolve this problem, at least for the Chinese hamster ovary (CHO) cell line, Siminovitch suggested that these cells were “functionally hemizygous,” that they were haploid for a considerable part of their genome, owing to chromosome rearrangements, which, in effect, produced monosomy either for whole chromosomes or for parts of chromosomes.

The situation changed when it was discovered that a silent...

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