Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome

• Published in: Nature communications Vol. 6; no. 1; p. 6904
• Main Authors: Naville, Magali, Ishibashi, Minaka, Ferg, Marco, Bengani, Hemant, Rinkwitz, Silke, Krecsmarik, Monika, Hawkins, Thomas A., Wilson, Stephen W., Manning, Elizabeth, Chilamakuri, Chandra S. R., Wilson, David I., Louis, Alexandra, Lucy Raymond, F., Rastegar, Sepand, Strähle, Uwe, Lenhard, Boris, Bally-Cuif, Laure, van Heyningen, Veronica, FitzPatrick, David R., Becker, Thomas S., Roest Crollius, Hugues
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.04.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 42/109; 42/34; 631/181/2474; 631/208/2489/144; Animals; Animals, Genetically Modified; Biochemistry, Molecular Biology; Chromosomes, Human, X - genetics; Enhancer Elements, Genetic - genetics; Evolution, Molecular; Gene expression; Gene Expression - genetics; Gene Rearrangement - genetics; Genetic Linkage - genetics; Genetics; Genomes; Genomics; Hospitals; Human genetics; Humanities and Social Sciences; Humans; Life Sciences; Medicine; multidisciplinary; Neurobiology; Neurons and Cognition; Science; Science (multidisciplinary); Selection, Genetic - genetics; X chromosomes; Zebrafish; United Kingdom > UK; France; Norway
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7904

Enhancers can regulate the transcription of genes over long genomic distances. This is thought to lead to selection against genomic rearrangements within such regions that may disrupt this functional linkage. Here we test this concept experimentally using the human X chromosome. We describe a scoring method to identify evolutionary maintenance of linkage between conserved noncoding elements and neighbouring genes. Chromatin marks associated with enhancer function are strongly correlated with this linkage score. We test >1,000 putative enhancers by transgenesis assays in zebrafish to ascertain the identity of the target gene. The majority of active enhancers drive a transgenic expression in a pattern consistent with the known expression of a linked gene. These results show that evolutionary maintenance of linkage is a reliable predictor of an enhancer’s function, and provide new information to discover the genetic basis of diseases caused by the mis-regulation of gene expression. Enhancers regulate the transcription of genes over long genomic distances. Here, the authors show that enhancer function is correlated with maintenance of linkage between non-coding elements and neighbouring genes in the human X chromosome and that enhancers in zebrafish drive expression in a pattern consistent with the expression of a linked gene.