Structural variation-associated expression changes are paralleled by chromatin architecture modifications

PLoS One. 2013 Nov 12;8(11):e79973. doi: 10.1371/journal.pone.0079973. eCollection 2013.


Copy number variants (CNVs) influence the expression of genes that map not only within the rearrangement, but also to its flanks. To assess the possible mechanism(s) underlying this "neighboring effect", we compared intrachromosomal interactions and histone modifications in cell lines of patients affected by genomic disorders and control individuals. Using chromosome conformation capture (4C-seq), we observed that a set of genes flanking the Williams-Beuren Syndrome critical region (WBSCR) were often looping together. The newly identified interacting genes include AUTS2, mutations of which are associated with autism and intellectual disabilities. Deletion of the WBSCR disrupts the expression of this group of flanking genes, as well as long-range interactions between them and the rearranged interval. We also pinpointed concomitant changes in histone modifications between samples. We conclude that large genomic rearrangements can lead to chromatin conformation changes that extend far away from the structural variant, thereby possibly modulating expression globally and modifying the phenotype.

Geo series accession number: GSE33784, GSE33867.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autistic Disorder / genetics
  • Cell Line
  • Chromatin / genetics*
  • Chromatin / metabolism*
  • Chromosomes, Human, Pair 7
  • DNA Copy Number Variations*
  • Epistasis, Genetic
  • Female
  • Gene Expression Regulation*
  • Histones / metabolism
  • Humans
  • Intellectual Disability / genetics
  • Quantitative Trait Loci
  • Williams Syndrome / genetics


  • Chromatin
  • Histones

Associated data

  • GEO/GSE33784
  • GEO/GSE33867

Grant support

This work was supported by the European Commission anEUploidy Integrated Project (grant 037627), the Swiss National Science Foundation and a SNSF Sinergia grant to AR. RMW was supported by a fellowship from the doctoral school of the Faculty of Biology and Medicine, University of Lausanne. NG is a grantee of the Marie Heim Vögtlin and the Pro-Women programs of the SNSF and the Faculty of Biology and Medicine, University of Lausanne, respectively.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.