Exonic Transcription Factor Binding Directs Codon Choice and Affects Protein Evolution

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Science  13 Dec 2013:
Vol. 342, Issue 6164, pp. 1367-1372
DOI: 10.1126/science.1243490

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Transcription Factor Binding Sites

Transcription factors (TFs) are proteins that bind to DNA to control gene transcription. Stergachis et al. (p. 1367; see the Perspective by Weatheritt and Babu) examined TF binding within the human genome in more than 80 cell types. Nearly 15% of coding regions simultaneously specify both amino acid sequence and TF recognition sites. The distribution of the TF binding sites evolutionarily constrains how codons within these regions can change, independent of encoded protein function. Thus, TF binding may represent a widespread and strong evolutionary force in coding regions.


Genomes contain both a genetic code specifying amino acids and a regulatory code specifying transcription factor (TF) recognition sequences. We used genomic deoxyribonuclease I footprinting to map nucleotide resolution TF occupancy across the human exome in 81 diverse cell types. We found that ~15% of human codons are dual-use codons (“duons”) that simultaneously specify both amino acids and TF recognition sites. Duons are highly conserved and have shaped protein evolution, and TF-imposed constraint appears to be a major driver of codon usage bias. Conversely, the regulatory code has been selectively depleted of TFs that recognize stop codons. More than 17% of single-nucleotide variants within duons directly alter TF binding. Pervasive dual encoding of amino acid and regulatory information appears to be a fundamental feature of genome evolution.

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