Why don't transcription factors exploit inter-nucleotide correlations in binding motifs? Evolution of information encoding strategies on DNA

Single locus information (SI) encoding in TF-DNA binding motifs is intrinsically more robust to mutation than correlation-based multi-locus encodings, biasing evolution toward SI.

• Why it matters: The field lacks an explanation for why transcription factors largely ignore nucleotide correlations despite motifs being able to store information through position dependencies.
• What they did: The authors combine analytical derivations, numerical methods, and evolutionary simulations to compare SI versus correlation-based encodings under selection in functional transcriptional regulatory networks.
• The result: SI is linked to a smoother affinity landscape and greater evolvability of regulatory interactions, and a similar SI bias appears in the genetic code, implying a general information-storage strategy under mutational noise.

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