Cis-regulatory mutations in human disease

Abstract

Cis-acting regulatory sequences are required for the proper temporal and spatial control of gene expression. Variation in gene expression is highly heritable and a significant determinant of human disease susceptibility. The diversity of human genetic diseases attributed, in whole or in part, to mutations in non-coding regulatory sequences is on the rise. Improvements in genome-wide methods of associating genetic variation with human disease and predicting DNA with cis-regulatory potential are two of the major reasons for these recent advances. This review will highlight select examples from the literature that have successfully integrated genetic and genomic approaches to uncover the molecular basis by which cis-regulatory mutations alter gene expression and contribute to human disease. The fine mapping of disease-causing variants has led to the discovery of novel cis-acting regulatory elements that, in some instances, are located as far away as 1.5 Mb from the target gene. In other cases, the prior knowledge of the regulatory landscape surrounding the gene of interest aided in the selection of enhancers for mutation screening. The success of these studies should provide a framework for following up on the large number of genome-wide association studies that have identified common variants in non-coding regions of the genome that associate with increased risk of human diseases including, diabetes, autism, Crohn's, colorectal cancer, and asthma, to name a few.

Figure 1:

Cis-regulatory sequences implicated in gene expression. Schematic showing the location of proximal and distal regulatory elements with respect to the transcriptional TSS of a given gene. Abbreviations: BE, boundary element (gray oval); CP, core promoter (orange oval); E, enhancer (green oval); IE, intronic enhancer (green oval); PP, proximal enhancer (blue oval); R, repressor (red oval). Exons are represented by black boxes.

Figure 2:

Long-range regulation of SHH expression in the developing limb and its disruption in PPD. (A) Schematic of human chromosome 7 showing the location of the zone of polarizing regulatory sequence (zrs) in LMBR1 intron 5, approximately 1 Mb upstream of the SHH promoter (orange oval). Sequences in the zrs are required to activate (green oval) and repress (red oval) SHH expression in the posterior and anterior limb bud, respectively. (B) Mutations in the zrs result in PPD in humans, mice and cats. Wild-type zrs activates SHH in the posterior limb bud (blue) and is responsible for growth and patterning of distal limb elements along the anteroposterior axis. In cases of PPD, mutations in the zrs result in the ectopic expression of SHH in the anterior limb bud and ectopic digit formation (asterisk). The location of PPD causing mutations in the zrs of human (H), mice and feline (F) is indicated in red. Colour version of this figure available at BFGP Online: http://bfgp.oxfordjournals.org/