A method for optimizing the coding sequence of a polynucleotide that encodes a polypeptide, the method comprising (a) identification of at least one codon within said coding sequence which is susceptible to amino acid residue misincorporation at a position within the encoded polypeptide that corresponds to said codon; (b) identification of at least one codon within said coding sequence which is susceptible to amino acid residue misincorporation at a position within the encoded polypeptide that corresponds to said codon and selecting an alternative codon to the at least one codon so as to change the degree or type of amino acid residue misincorporation; (c) changing at least one codon within said coding sequence to an alternative codon, wherein said at least one codon is susceptible to amino acid residue misincorporation at a position within the encoded polypeptide that corresponds to said codon so as to change the degree or type of amino acid residue misincorporation; or (d) identification of at least one codon within said coding sequence which is susceptible to amino acid residue misincorporation at a position within the encoded polypeptide that corresponds to said codon and changing said codon to an alternative codon so as to change the degree or type of amino acid residue misincorporation, wherein the amino acid residue misincorporation is the result of at least one non-Watson-Crick base mismatch during transcription or translation, and wherein the at least one non-Watson-Crick base mismatch is selected from the group consisting of (a) a C*A mismatch between a DNA template strand and an mRNA being transcribed from said DNA template strand; (b) a G*U mismatch between the mRNA codon and an anticodon of an amino-acyl tRNA during translation; (c) an A*C mismatch between a DNA template strand and an mRNA being transcribed from said DNA template strand; (d) an U*G mismatch between the mRNA codon and an anticodon of an amino-acyl tRNA during translation; (e) an A*A mismatch between a DNA template strand and an mRNA being transcribed from said DNA template strand; or (f) an U*U mismatch between the mRNA codon and an anticodon of an amino- acyl tRNA during translation. (a) identification of at least one codon within said coding sequence which is susceptible to amino acid residue misincorporation at a position within the encoded polypeptide that corresponds to said codon; (b) identification of at least one codon within said coding sequence which is susceptible to amino acid residue misincorporation at a position within the encoded polypeptide that corresponds to said codon and selecting an alternative codon to the at least one codon so as to change the degree or type of amino acid residue misincorporation; (c) changing at least one codon within said coding sequence to an alternative codon, wherein said at least one codon is susceptible to amino acid residue misincorporation at a position within the encoded polypeptide that corresponds to said codon so as to change the degree or type of amino acid residue misincorporation; or (d) identification of at least one codon within said coding sequence which is susceptible to amino acid residue misincorporation at a position within the encoded polypeptide that corresponds to said codon and changing said codon to an alternative codon so as to change the degree or type of amino acid residue misincorporation, (a) a C*A mismatch between a DNA template strand and an mRNA being transcribed from said DNA template strand; (b) a G*U mismatch between the mRNA codon and an anticodon of an amino-acyl tRNA during translation; (c) an A*C mismatch between a DNA template strand and an mRNA being transcribed from said DNA template strand; (d) an U*G mismatch between the mRNA codon and an anticodon of an amino-acyl tRNA during translation; (e) an A*A mismatch between a DNA template strand and an mRNA being transcribed from said DNA template strand; or (f) an U*U mismatch between the mRNA codon and an anticodon of an amino- acyl tRNA during translation.