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

Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome
Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome
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.
Naville, Magali
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Ishibashi, Minaka
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Ferg, Marco
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Bengani, Hemant
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Rinkwitz, Silke
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Krecsmarik, Monika
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Hawkins, Thomas A.
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Wilson, Stephen W.
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Manning, Elizabeth
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Chilamakuri, Chandra S. R.
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Wilson, David I.
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Louis, Alexandra
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Lucy Raymond, F.
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Rastegar, Sepand
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Strähle, Uwe
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Lenhard, Boris
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Bally-Cuif, Laure
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van Heyningen, Veronica
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FitzPatrick, David R.
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Becker, Thomas S.
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Roest Crollius, Hugues
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Naville, Magali
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Ishibashi, Minaka
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Ferg, Marco
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Bengani, Hemant
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Rinkwitz, Silke
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Krecsmarik, Monika
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Hawkins, Thomas A.
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Wilson, Stephen W.
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Manning, Elizabeth
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Chilamakuri, Chandra S. R.
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Wilson, David I.
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Louis, Alexandra
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Lucy Raymond, F.
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Rastegar, Sepand
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Strähle, Uwe
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Lenhard, Boris
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Bally-Cuif, Laure
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van Heyningen, Veronica
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FitzPatrick, David R.
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Becker, Thomas S.
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Roest Crollius, Hugues
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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. and Roest Crollius, Hugues (2015) Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome. Nature Communications, 6, [6904]. (doi:10.1038/ncomms7904).

Record 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.

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Accepted/In Press date: 12 March 2015
Published date: 24 April 2015
Organisations: Human Development & Health

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Local EPrints ID: 376597
URI: http://eprints.soton.ac.uk/id/eprint/376597
PURE UUID: 2ee3e3fe-8ae6-40dc-b4b2-9c98c859e5be

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Date deposited: 05 May 2015 14:08
Last modified: 14 Mar 2024 19:46

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Contributors

Author: Magali Naville
Author: Minaka Ishibashi
Author: Marco Ferg
Author: Hemant Bengani
Author: Silke Rinkwitz
Author: Monika Krecsmarik
Author: Thomas A. Hawkins
Author: Stephen W. Wilson
Author: Elizabeth Manning
Author: Chandra S. R. Chilamakuri
Author: David I. Wilson
Author: Alexandra Louis
Author: F. Lucy Raymond
Author: Sepand Rastegar
Author: Uwe Strähle
Author: Boris Lenhard
Author: Laure Bally-Cuif
Author: Veronica van Heyningen
Author: David R. FitzPatrick
Author: Thomas S. Becker
Author: Hugues Roest Crollius

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