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

Author

Listed:
  • Magali Naville

    (Ecole Normale Supérieure, Institut de Biologie de l’ENS, IBENS
    CNRS
    Inserm)

  • Minaka Ishibashi

    (Brain and Mind Research Institute, Sydney Medical School, University of Sydney)

  • Marco Ferg

    (Institute of Toxicology and Genetics and European Zebrafish Resource Centre, Karlsruhe Institute of Technology)

  • Hemant Bengani

    (MRC Human Genetics Unit, MRC Institute of Medical Genetic and Molecular Medicine, University of Edinburgh)

  • Silke Rinkwitz

    (Brain and Mind Research Institute, Sydney Medical School, University of Sydney)

  • Monika Krecsmarik

    (Paris-Saclay Institute for Neuroscience (Neuro-PSI), UMR9197 CNRS-Université Paris Sud)

  • Thomas A. Hawkins

    (Anatomy building, UCL)

  • Stephen W. Wilson

    (Anatomy building, UCL)

  • Elizabeth Manning

    (Brain and Mind Research Institute, Sydney Medical School, University of Sydney)

  • Chandra S. R. Chilamakuri

    (The Norwegian Radium Hospital)

  • David I. Wilson

    (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)

  • Alexandra Louis

    (Ecole Normale Supérieure, Institut de Biologie de l’ENS, IBENS
    CNRS
    Inserm)

  • F. Lucy Raymond

    (Cambridge Institute for Medical Research, University of Cambridge)

  • Sepand Rastegar

    (Institute of Toxicology and Genetics and European Zebrafish Resource Centre, Karlsruhe Institute of Technology)

  • Uwe Strähle

    (Institute of Toxicology and Genetics and European Zebrafish Resource Centre, Karlsruhe Institute of Technology)

  • Boris Lenhard

    (Institute of Clinical Sciences, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus)

  • Laure Bally-Cuif

    (Paris-Saclay Institute for Neuroscience (Neuro-PSI), UMR9197 CNRS-Université Paris Sud)

  • Veronica van Heyningen

    (MRC Human Genetics Unit, MRC Institute of Medical Genetic and Molecular Medicine, University of Edinburgh)

  • David R. FitzPatrick

    (MRC Human Genetics Unit, MRC Institute of Medical Genetic and Molecular Medicine, University of Edinburgh)

  • Thomas S. Becker

    (Brain and Mind Research Institute, Sydney Medical School, University of Sydney
    University of Bergen)

  • Hugues Roest Crollius

    (Ecole Normale Supérieure, Institut de Biologie de l’ENS, IBENS
    CNRS
    Inserm)

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.

Suggested Citation

  • 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. , 2015. "Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7904
    DOI: 10.1038/ncomms7904
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