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Keywords:

  • regulatory sequences;
  • NGS;
  • molecular diagnostics;
  • functional genomics

Abstract

With the successful identification of many protein-coding genes, the focus has now shifted toward deciphering functions of non-protein-coding regions that direct spatiotemporal and quantitative aspects of protein expression. Recent advances in our understanding of the regulatory architecture of the human genome coincide with growing evidence that changes in regulatory sequences are associated with human disease. Several recent reviews have highlighted disease-causing potential of aberrations in transcriptional and splicing regulatory elements as well as non-protein-coding RNA. Although changes in regulatory sequences generally produce milder biological effects than their protein-coding counterparts, many act as independent risk factors for common complex disorders or as genetic modifiers for “primary” disease-causing loci. Here, we review bioinformatics and experimental approaches that are used to identify regulatory sequences and assess pathogenicity of regulatory changes. We describe the current state of knowledge on disease-causing changes in regulatory sequences, challenge protein-centric views, and discuss complexities and solutions pertaining to the interpretation of regulatory changes in the next-generation sequencing era. Hum Mutat 33:1021–1030, 2012. © 2012 Wiley Periodicals, Inc.