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Transcription Factor Influences Codon Choice & Protein Evolution

John Stamatoyannopoulos, M.D.
University of Washington
NIEHS Grant U01ES017156

Research partially supported by an NIEHS grant funded by the NIH Common Fund, revealed that complex genomes simultaneously code for amino acids and regulatory information. The work adds a transcription factor “binding code” to the spectrum of other regulatory codes that have been proposed to influence protein evolution by influencing codon choice.

Genomes contain protein-coding regions as well as regulatory code that influences gene expression by specifying recognition sequences for transcription factors. Scientists have assumed that the genetic code and regulatory codes were physically and operationally independent. To find out if these codes intersect, the researchers created a nucleotide-resolution map showing where protein-coding regions of the human genome were occupied by a transcription factor. They looked at 81 diverse cell types and found that approximately 15 percent of human codons simultaneously specify both proteins and transcription factor recognition sites. These dual-use codons, or duons, are highly conserved, and constraint from the transcription factors appears to be a major driver of codon usage bias. The researchers found that more than 17 percent of single-nucleotide variants within duons directly altered transcription factor binding.

The researchers conclude that widespread dual encoding of amino acid and regulatory information appears to be a fundamental feature of genome evolution.

Citation: Stergachis AB, Haugen E, Shafer A, Fu W, Vernot B, Reynolds A, Raubitschek A, Ziegler S, LeProust EM, Akey JM, Stamatoyannopoulos JA. 2013. Exonic transcription factor binding directs codon choice and affects protein evolution. Science 342(6164):1367-1372.

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