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

Adam Siepel and colleagues find that natural selection has exerted a significant influence on transcription factor binding sites in the human lineage using a new probabilistic method, INSIGHT. They analyzed whole-genome sequences from 54 individuals, as well as from several non-human primates, combined with chromatin immunoprecipitation and sequencing data sets to identify transcription factor binding sites and evidence of selection. 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.