Another strikingly unique feature of TF evolution is the positive trend relating TF evolutionary rate to regulatory in-degree, while other proteins show a negative trend.
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Regulatory network structure as a dominant determinant of transcription factor evolutionary rate.
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As shown in Table 2 , both the significance of the activating edge relations and the lack of a significant trend for repressive edge relations were confirmed using the literature curated network.
For example a strong trend was discovered relating protein-protein interaction (PPI) degree to evolutionary rate [7] , [8] , which suggests that physical interactions lead to evolutionary constraints on the protein sequence.