Since the discovery of trisomy 21, it has been hypothesised that genes present in three copies are over-expressed Shaikh et al. (2009) by 1.5-fold relative to the euploid state, but this has subsequently been shown to not always be the case. Some genes are over expressed, some are expressed at euploid levels while other genes appear to be down-regulated (Li et al. 2006; Prandini et al. 2007 ). This may, of course, reflect adaptive regulatory control, but may also reflect the effects of local copy number variation on chromosome 21, which will result in deviations from the predicted three copies of each gene, as shown in Fig. 1 .