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

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 Straehle; Boris Lenhard; Laure Bally-Cuif; Veronica van Heyningen; David R. FitzPatrick; Thomas S. Becker; Hugues Roest Crollius

doi:10.1038/ncomms7904

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

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 Straehle, Boris Lenhard, Laure Bally-Cuif, Veronica van Heyningen, David R. FitzPatrick, Thomas S. Becker^*Hugues Roest Crollius

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	6904
Number of pages	9
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7904
Publication status	Published - 24 Apr 2015

Keywords

IN-SITU HYBRIDIZATION
HUMAN CELL-TYPES
GENOMIC SEQUENCES
CONSERVED SYNTENY
GENE-EXPRESSION
ELEMENTS
ENHANCERS
DATABASE
DISEASE
TOOLS

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10.1038/ncomms7904

Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome
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Naville, M., Ishibashi, M., Ferg, M., Bengani, H., Rinkwitz, S., Krecsmarik, M., Hawkins, T. A., Wilson, S. W., Manning, E., Chilamakuri, C. S. R., Wilson, D. I., Louis, A., Raymond, F. L., Rastegar, S., Straehle, U., Lenhard, B., Bally-Cuif, L., van Heyningen, V., FitzPatrick, D. R., ... Crollius, H. R. (2015). Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome. Nature Communications, 6, [6904]. https://doi.org/10.1038/ncomms7904

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title = "Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome",

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.",

keywords = "IN-SITU HYBRIDIZATION, HUMAN CELL-TYPES, GENOMIC SEQUENCES, CONSERVED SYNTENY, GENE-EXPRESSION, ELEMENTS, ENHANCERS, DATABASE, DISEASE, TOOLS",

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

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Naville, M, Ishibashi, M, Ferg, M, Bengani, H, Rinkwitz, S, Krecsmarik, M, Hawkins, TA, Wilson, SW, Manning, E, Chilamakuri, CSR, Wilson, DI, Louis, A, Raymond, FL, Rastegar, S, Straehle, U, Lenhard, B, Bally-Cuif, L, van Heyningen, V, FitzPatrick, DR, Becker, TS & Crollius, HR 2015, 'Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome', Nature Communications, vol. 6, 6904. https://doi.org/10.1038/ncomms7904

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AU - Naville, Magali

AU - Ishibashi, Minaka

AU - Ferg, Marco

AU - Bengani, Hemant

AU - Rinkwitz, Silke

AU - Krecsmarik, Monika

AU - Hawkins, Thomas A.

AU - Wilson, Stephen W.

AU - Manning, Elizabeth

AU - Chilamakuri, Chandra S. R.

AU - Wilson, David I.

AU - Louis, Alexandra

AU - Raymond, F. Lucy

AU - Rastegar, Sepand

AU - Straehle, Uwe

AU - Lenhard, Boris

AU - Bally-Cuif, Laure

AU - van Heyningen, Veronica

AU - FitzPatrick, David R.

AU - Becker, Thomas S.

AU - Crollius, Hugues Roest

PY - 2015/4/24

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N2 - 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.

AB - 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.

KW - IN-SITU HYBRIDIZATION

KW - HUMAN CELL-TYPES

KW - GENOMIC SEQUENCES

KW - CONSERVED SYNTENY

KW - GENE-EXPRESSION

KW - ELEMENTS

KW - ENHANCERS

KW - DATABASE

KW - DISEASE

KW - TOOLS

U2 - 10.1038/ncomms7904

DO - 10.1038/ncomms7904

M3 - Article

C2 - 25908307

VL - 6

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 6904

ER -

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

Abstract

Keywords

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