Exonic Transcription Factor Binding Directs Codon Choice and Affects Protein Evolution

• Published in: Science (American Association for the Advancement of Science) Vol. 342; no. 6164; pp. 1367 - 1372
• Main Authors: Stergachis, Andrew B., Haugen, Eric, Shafer, Anthony, Fu, Wenqing, LeProust, M., Akey, Joshua M., Stamatoyannopoulos, John A.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 13.12.2013; The American Association for the Advancement of Science
• Subjects: Amino acids; Binding; Cells; Coding; Codon - genetics; Codons; Deoxyribonuclease I - chemistry; DNA Footprinting; Evolution; Evolution, Molecular; Evolutionary; Evolutionary biology; Exome; Exons; Genes; Genetic code; Genome, Human; Genomes; Genomics; Human; Humans; Nucleic acids; Open reading frames; P values; Polymorphism, Single Nucleotide; Proteins; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1243490

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 exorne 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.