Identification of Lineage-Specific Cis-Regulatory Modules Associated with Variation in Transcription Factor Binding and Chromatin Activity Using Ornstein-Uhlenbeck Models

Mol Biol Evol. 2015 Sep;32(9):2441-55. doi: 10.1093/molbev/msv107. Epub 2015 May 4.


Scoring the impact of noncoding variation on the function of cis-regulatory regions, on their chromatin state, and on the qualitative and quantitative expression levels of target genes is a fundamental problem in evolutionary genomics. A particular challenge is how to model the divergence of quantitative traits and to identify relationships between the changes across the different levels of the genome, the chromatin activity landscape, and the transcriptome. Here, we examine the use of the Ornstein-Uhlenbeck (OU) model to infer selection at the level of predicted cis-regulatory modules (CRMs), and link these with changes in transcription factor binding and chromatin activity. Using publicly available cross-species ChIP-Seq and STARR-Seq data we show how OU can be applied genome-wide to identify candidate transcription factors for which binding site and CRM turnover is correlated with changes in regulatory activity. Next, we profile open chromatin in the developing eye across three Drosophila species. We identify the recognition motifs of the chromatin remodelers, Trithorax-like and Grainyhead as mostly correlating with species-specific changes in open chromatin. In conclusion, we show in this study that CRM scores can be used as quantitative traits and that motif discovery approaches can be extended towards more complex models of divergence.

Keywords: Drosophila species; FAIRE-Seq; Ornstein–Uhlenbeck; cis-regulatory evolution; eye development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Chromatin / genetics*
  • Compound Eye, Arthropod / growth & development
  • Conserved Sequence
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / growth & development
  • Gene Expression Regulation, Developmental
  • Genes, Insect
  • Genetic Speciation
  • Markov Chains
  • Models, Genetic
  • Phylogeny
  • Protein Binding
  • Regulatory Elements, Transcriptional*
  • Sequence Analysis, DNA
  • Species Specificity
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Chromatin
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Transcription Factors
  • grh protein, Drosophila

Associated data

  • GEO/GSE59706