Chromatin features constrain structural variation across evolutionary timescales

Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2175-2180. doi: 10.1073/pnas.1808631116. Epub 2019 Jan 18.


The potential impact of structural variants includes not only the duplication or deletion of coding sequences, but also the perturbation of noncoding DNA regulatory elements and structural chromatin features, including topological domains (TADs). Structural variants disrupting TAD boundaries have been implicated both in cancer and developmental disease; this likely occurs via "enhancer hijacking," whereby removal of the TAD boundary exposes enhancers to new target transcription start sites (TSSs). With this functional role, we hypothesized that boundaries would display evidence for negative selection. Here we demonstrate that the chromatin landscape constrains structural variation both within healthy humans and across primate evolution. In contrast, in patients with developmental delay, variants occur remarkably uniformly across genomic features, suggesting a potentially broad role for enhancer hijacking in human disease.

Keywords: CTCF; Hi-C; chromatin; comparative genomics; evolution.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / genetics
  • Chromatin / chemistry*
  • Chromatin / genetics*
  • Chromatin / metabolism
  • Developmental Disabilities / genetics
  • Evolution, Molecular*
  • Gene Duplication
  • Genetic Variation*
  • Genome
  • Genomics / methods
  • Hominidae / genetics
  • Humans
  • Sequence Deletion
  • Transcription Initiation Site


  • Chromatin