Genome-wide data provide important insights into the rates of functional polymorphism in the non-coding genome. For example, we consider motifs matching the consensus for transcriptional repressor CTCF, which has a well-characterised and highly conserved binding motif21. Within CTCF-binding peaks experimentally defined by chromatin-immunoprecipitation sequencing (ChIP-seq), average levels of conservation within the motif are comparable to third codon positions, while outside peaks there is no conservation (Fig. 4c). Within peaks levels of genetic diversity are typically reduced 25-75%, depending on the position in the motif (Fig. 4c). Unexpectedly, the reduction in diversity at some degenerate positions, for example position 8 in the motif, is as great as that at nondegenerate positions, suggesting that motif degeneracy may not have a simple relationship with functional importance. Variants within peaks show a weak but consistent excess of rare variation (proportion with frequency <0.5% is 61% within peaks compared to 58% outside peaks, Fig. S12) supporting the hypothesis that regulatory sequences harbour substantial amounts of weakly deleterious variation.
