![]() This reasoning follows the principle of a sign test of phenotypes ( 17, 18), although it uses the actual values and not just the sign. Thus, TFBSs evolving adaptively are expected to accumulate substitutions that consistently change the phenotype to stronger or to weaker binding, whereas TFBSs evolving under purifying selection are expected to accumulate substitutions that increase or diminish binding in approximately equal measure, around a constant optimum. RESULTS Detecting positive selection on TFBSsĪdaptive evolution on TFBSs is expected to push them from a suboptimal toward an optimal binding strength or from an old optimum to a new one (e.g., in response to changing environment). Thus, we provide evidence for adaptive evolution of gene regulation in the human brain. The same analysis in mouse found the highest positive selection in the lung, with no special signal in the brain. We found the highest positive selection in brain samples, followed by male reproductive system. Then, we used this method to detect positive selection of CTCF binding sites in 29 human tissues or cell types. We validated it with three independent lines of evidence: Our evidence of positive selection is associated to higher empirical binding affinity, higher substitution-to-polymorphism ratio in sequence, and lower variance in expression of neighboring genes. ![]() As a proof of principle, we first applied this method to well-known transcription factors, such as CEBPA and CTCF, in species triples focused on human, mouse, or fly. We have developed a new method to detect adaptive evolution of transcription factor binding sites (TFBSs) on the basis of predicted binding affinity changes. ![]()
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