Briefings in Functional Genomics and Proteomics Advance Access originally published online on July 29, 2009
Briefings in Functional Genomics and Proteomics 2009 8(4):310-316; doi:10.1093/bfgp/elp021
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This article appears in the following Briefings in Functional Genomics and Proteomics issue: Special Issue: Non-Coding Regulatory Regions in Genomes [View the issue table of contents]
Special Issue Papers |
Cis-regulatory mutations in human disease
Corresponding author. D. J. Epstein, Department of Genetics, University of Pennsylvania School of Medicine, Clinical Research Bldg, Room 470, 415 Curie Blvd, Philadelphia, PA 19104, USA. Tel: +1 215 573 4810; Fax: +1 215 573 5892; E-mail: epsteind{at}mail.med.upenn.edu
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.
Keywords: cis regulation, transcription, gene expression, human disease