Determining aetiology of genetic disorders caused by damaging mutations in protein-coding genes is well established. However, understanding how mutations in the vast stretches of the noncoding genome contribute to genetic abnormalities remains a huge challenge. Cis-regulatory elements (CREs) or enhancers are an important class of noncoding elements. CREs function as the primary determinants of precise spatial and temporal regulation of their target genes during development by serving as docking sites for tissue-specific transcription factors. Although a large number of potential disease-associated CRE mutations are being identified in patients, lack of robust methods for mechanistically linking these mutations to disease phenotype is currently hampering the understanding of their roles in disease aetiology. Here, we have described the various systems available for testing the CRE potential of stretches of noncoding regions harbouring mutations implicated in human disease. We highlight advances in the field leading to the establishment of zebrafish as a powerful system for robust and cost-effective functional assays of CRE activity, enabling rapid identification of causal variants in regulatory regions and the validation of their role in disruption of appropriate gene expression.
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