Synthetic Gene Design with a Large Number of Hidden Stop Codons

Hidden stop codons are nucleotide triples TAA, TAG, and TGA that appear in the second and third reading frames of a protein coding gene. Recent studies reported biological evidence suggesting that hidden stop codons are important in preventing misread of mRNA, which is often detrimental to the cell. We study the problem of designing protein-encoding genes with large number of hidden stop codons under biological constraints including GC content and codon usage of individual organism. In simpler models, we obtained provably optimal results. In more complex models, the designed genes have many more hidden stop codons than wild-type genes do, as observed in an experiment with 8 genomes with a wide range of GC content and codon usage.