Dynamic changes in gene copy number: where signalling meets epigenetics

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Copy number variations (CNVs) in the human genome are linked to a plethora of conditions such as schizophrenia and obesity. CNVs are common in the population and even between different cells within an individual, suggesting that copy number change occurs frequently. CNVs can have major effects on physiology and can aid cell survival; for example, we have shown that amplification of oncogenes in tumour cells drives resistance to protein kinase inhibitors [1]. Similarly, yeast can use CNV to survive environmental stress.
The frequent occurrence of some CNVs suggests that they may not arise entirely at random. A clear example of controlled CNV occurs in the yeast ribosomal DNA, which normally contains 180 copies of the ribosomal RNA genes and is amplified if the copy number drops. We have shown that the ribosomal DNA is amplified by an unusual mechanism independent of the normal recombination machinery [2,3], and have data indicating this mechanism acts at other CNVs in the genome. We have now identified the signalling pathway that controls amplification of the ribosomal DNA, providing the first demonstration that cells can orchestrate copy number changes in response to the environment. Notably, recombination of the yeast ribosomal DNA is controlled by non-coding RNAs, suggesting that such RNAs could mediate CNVs throughout the genome.

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