particular the most evolutionarily conserved ones, can be efficiently buffered at the binding level. We do not know the exact nature of these buffering mechanisms, and whether their prevalence at highly conserved sites is evolutionarily driven or is merely a side effect of the increasing complexity of regulatory networks [53,54]. It can be expected that such buffering effects would be, at least in part, due to interactions with heterologous proteins. Given the multifaceted functions of CTCF, it is very likely that such interactions will involve different partners, depending on specific regulatory context. Studies of more 'specialized' TFs may therefore be more appropriate to address these questions. For example, analyses of individual variation at human NFκB [15] and yeast Ste12 [17] pinpointed candidate interaction partners that affect the binding in the absence of mutations at the analyzed TF's own binding sites. We attempted to use the NFκB data to ask the reverse question, that is, look for factors that may help maintain the binding when mutations at conserved TFBSs are present; unfortunately, the number of such cases was extremely low, prohibiting this analysis. It is possible that mutations at conserved NFκB sites are poorly tolerated, implying that they are less efficiently
