Which Genetics Variants in DNase-Seq Footprints Are More Likely to Alter Binding?

PLoS Genet. 2016 Feb 22;12(2):e1005875. doi: 10.1371/journal.pgen.1005875. eCollection 2016 Feb.


Large experimental efforts are characterizing the regulatory genome, yet we are still missing a systematic definition of functional and silent genetic variants in non-coding regions. Here, we integrated DNaseI footprinting data with sequence-based transcription factor (TF) motif models to predict the impact of a genetic variant on TF binding across 153 tissues and 1,372 TF motifs. Each annotation we derived is specific for a cell-type condition or assay and is locally motif-driven. We found 5.8 million genetic variants in footprints, 66% of which are predicted by our model to affect TF binding. Comprehensive examination using allele-specific hypersensitivity (ASH) reveals that only the latter group consistently shows evidence for ASH (3,217 SNPs at 20% FDR), suggesting that most (97%) genetic variants in footprinted regulatory regions are indeed silent. Combining this information with GWAS data reveals that our annotation helps in computationally fine-mapping 86 SNPs in GWAS hit regions with at least a 2-fold increase in the posterior odds of picking the causal SNP. The rich meta information provided by the tissue-specificity and the identity of the putative TF binding site being affected also helps in identifying the underlying mechanism supporting the association. As an example, the enrichment for LDL level-associated SNPs is 9.1-fold higher among SNPs predicted to affect HNF4 binding sites than in a background model already including tissue-specific annotation.

Publication types

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

MeSH terms

  • Alleles
  • Binding Sites
  • Computational Biology
  • DNA Footprinting*
  • Deoxyribonucleases / metabolism*
  • Genes, Reporter
  • Genome-Wide Association Study
  • Humans
  • Molecular Sequence Annotation
  • Nucleotide Motifs / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Protein Binding
  • Regulatory Sequences, Nucleic Acid / genetics
  • Reproducibility of Results
  • Transcription Factors


  • Transcription Factors
  • Deoxyribonucleases