A complementary way to analyze the relationship between sequence and function is to explore intra-species (that is, polymorphic) variation of functional elements. Variation at DNA regulatory elements is relatively common and at least a fraction of it falls directly at TFBSs [13,14]. While some regulatory variants have been associated with major changes in transcription factor binding [15-17], gene expression [18,19] and disease phenotypes [20], many others do not result in apparent aberrations in function. This difference in itself suggests that analyzing TFBS variability in the context of the same species may lead to insights into cis-regulatory logic. For example, high tolerance of a binding site to deleterious variation may indicate that such variation is effectively 'buffered', either at the level of the same regulatory module or elsewhere in the system.
