Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome
Year: 2015
Type: article
Abstract: 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.
Source: Nature Communications
DOI: 10.1038/ncomms7904
Authors: Magali Naville, Minaka Ishibashi, Marco Ferg, Hemant Bengani, Silke Rinkwitz, Monika Krecsmarik, Thomas A. Hawkins, Stephen W. Wilson, Elizabeth Manning, Chandra S. R. Chilamakuri, David I. Wilson, Alexandra Louis, F. Lucy Raymond, Sepand Rastegar, Uwe Strähle, Boris Lenhard, Laure Bally-Cuif, Veronica van Heyningen, David R. FitzPatrick, Thomas S. Becker, Hugues Roest Crollius
Institutions: Centre National de la Recherche Scientifique, Inserm, École Normale Supérieure - PSL, Institut de Biologie de l'École Normale Supérieure, The University of Sydney, Karlsruhe Institute of Technology, MRC Human Genetics Unit, University of Edinburgh, Université Paris-Sud, Institut des Neurosciences Paris-Saclay, University College London, Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, University of Southampton, University of Cambridge, Hammersmith Hospital, Imperial College London, University of Bergen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,670
Awards: G1449229046, INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE, How is brain asymmetry established and what is it good for?., G1742243815, G196500007, G2079521050, Genomic Regulatory Systems of Human X-linked neurological diseases, Generation of an interactive online atlas of developmental neuroanatomy of the zebrafish brain, G282959247, G4866930200, Cellular Medicine at the Cambridge Institute for Medical Research., G7240651115, G7376787254, G782245399
OpenAlex ID: W2005653484