The regulatory landscape where a gene resides is of utmost importance. Chromosomal aberrations that change a gene's location will alter that landscape and can affect the regulation of the gene. Lettice et al. (Hum Mutat 32: 1492–1499, 2011) show a compelling example for the importance of gene location in the case of a child with features of a holoprosencephaly spectrum (HPES) disorder. By characterizing the regulatory landscape near the chromosomal breakpoints of an inversion in this child, they demonstrate how a gene could be abnormally regulated by an enhancer in this novel landscape, a phenomenon which they term “enhancer adoption.”

The inversion breakpoints are between 7q22.1 and 7q36.3 and move the Sonic Hedgehog (SHH) gene away from several of its regulatory elements including its limb enhancer (ZPA regulatory sequence, or ZRS) to a new regulatory landscape. In this new genomic region, the authors characterize a novel limb enhancer, highly conserved non-coding element 2 (HCNE2), and show that it can drive ectopic expression of SHH in the limb. They suggest that in the child with the HPES disorder, SHH has ‘adopted’ this enhancer, which leads to altered SHH limb expression and ultimately the limb malformation in this child.

This altered gene and regulatory element configuration needs to be taken into account on several levels. Because SHH was removed from several of its regulatory elements, these elements could now regulate other genes. In addition, the region where SHH relocated to could contain genes whose regulation is now altered. For example, the HCNE2 limb enhancer would normally drive expression of some other gene in that genomic region, but the addition of SHH to this genomic landscape could interfere with HCNE2's normal function. Lettice et al. nicely illustrate some of the potential phenotypic consequences of gene relocation as it relates to the changed regulatory landscape. All of these changes need to be considered when attempting to link a phenotype to chromosomal aberrations or copy number variations.