To understand the role of CNVs in human disease, it is important to consider how these genomic variants may affect phenotype. Deletion or duplication of dosage-sensitive genes, or their regulatory regions, could have adverse phenotypic effects, and copy number changes correlate with expression of affected genes (Henrichsen et al. 2009; Stranger et al. 2007 ). The majority of common CNVs are much smaller than the subset investigated by Stranger et al. (2007) , leading them to propose that a substantial proportion of heritable variation in gene expression may be explained by copy number variation. In addition to direct copy number effects, CNVs may also exert positional effects, for example by shifting them closer to or further away from heterochromatin. Furthermore, adverse phenotypic effects may result from interactions between CNVs and other variants, for example a deletion on one chromosome may unmask a harmful recessive allele on the other. Conversely, a genomic duplication that incorporates a harmful mutation may have a double gain-of-function effect: a duplication of the PRSS1 and PRSS2 genes along with a missense mutation was recently shown to cause hereditary pancreatitis (Masson et al. 2008) .