Genome-wide inference of natural selection on human transcription factor binding sites

Nat Genet. 2013 Jul;45(7):723-9. doi: 10.1038/ng.2658. Epub 2013 Jun 9.


For decades, it has been hypothesized that gene regulation has had a central role in human evolution, yet much remains unknown about the genome-wide impact of regulatory mutations. Here we use whole-genome sequences and genome-wide chromatin immunoprecipitation and sequencing data to demonstrate that natural selection has profoundly influenced human transcription factor binding sites since the divergence of humans from chimpanzees 4-6 million years ago. Our analysis uses a new probabilistic method, called INSIGHT, for measuring the influence of selection on collections of short, interspersed noncoding elements. We find that, on average, transcription factor binding sites have experienced somewhat weaker selection than protein-coding genes. However, the binding sites of several transcription factors show clear evidence of adaptation. Several measures of selection are strongly correlated with predicted binding affinity. Overall, regulatory elements seem to contribute substantially to both adaptive substitutions and deleterious polymorphisms with key implications for human evolution and disease.

Publication types

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

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites / genetics
  • Chromosome Mapping
  • Computer Simulation
  • Genome, Human* / genetics
  • Genome-Wide Association Study
  • Humans
  • Models, Genetic
  • Models, Statistical
  • Mutation / physiology
  • Regulatory Sequences, Nucleic Acid / genetics
  • Selection, Genetic / genetics*
  • Substrate Specificity
  • Transcription Factors / metabolism*


  • Transcription Factors