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Nat Commun. 2015 Apr 24;6:6904. doi: 10.1038/ncomms7904.

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

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1] Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, 46 rue d'Ulm, Paris F-75005, France [2] CNRS, UMR 8197, Paris F-75005, France [3] Inserm, U1024, Paris F-75005, France.
Brain and Mind Research Institute, Sydney Medical School, University of Sydney, Camperdown, New South Wales 2050, Australia.
Institute of Toxicology and Genetics and European Zebrafish Resource Centre, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany.
MRC Human Genetics Unit, MRC Institute of Medical Genetic and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Paris-Saclay Institute for Neuroscience (Neuro-PSI), UMR9197 CNRS-Université Paris Sud, Avenue de la Terrasse, Gif-sur-Yvette 91190, France.
C.D.B. Division of Biosciences, Anatomy building, UCL, Gower street, London, WC1E 6BT, UK.
Department of Tumor Biology, The Norwegian Radium Hospital, 0310 Oslo, Norway.
University of Southampton and University Hospital Southampton NHS Foundation Trust, Centre for Human Development, Stem Cells and Regeneration, MP808, Faculty of Medicine, Southampton General Hospital, Tremona Road, Southampton 16 6YD, UK.
Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 OXY, UK.
Institute of Clinical Sciences, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
1] Brain and Mind Research Institute, Sydney Medical School, University of Sydney, Camperdown, New South Wales 2050, Australia [2] Department of Clinical Medicine, University of Bergen, Bergen 5009, Norway.


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.

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