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

Magali Naville (1) , Minaka Ishibashi (2) , Marco Ferg (3) , Hemant Bengani (4) , Silke Rinkwitz , Monika Krecsmarik (5) , Thomas A Hawkins , Stephen W Wilson , Elizabeth Manning , Chandra S R Chilamakuri , David I Wilson (6) , Alexandra Louis (1) , F Lucy Raymond (7) , Sepand Rastegar (3) , Uwe Strähle (3) , Boris Lenhard (8) , Laure Bally-Cuif (5) , Veronica van Heyningen , David R Fitzpatrick , Thomas S Becker (9) , Hugues Roest Crollius (1)

1 IBENS - Institut de biologie de l'ENS Paris
2 The University of Sydney
3 KIT - Karlsruhe Institute of Technology
4 Edin. - University of Edinburgh
5 NeuroPSI - Institut des Neurosciences Paris-Saclay
6 University of Southampton
7 CIMR - Cambridge Institute for Medical Research
8 Imperial College London
9 UiB - University of Bergen

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.

Domaines: Génétique humaine; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Neurobiologie

Magali Naville, Minaka Ishibashi, Marco Ferg, Hemant Bengani, Silke Rinkwitz, et al.. Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome.. Nature Communications, 2015, 6, pp.6904. ⟨10.1038/ncomms7904⟩. ⟨hal-01156469⟩