Silent Mutations Are Not Always Silent
A silent mutation is a mutation that changes DNA but not the amino acid incorporated. For example, if the DNA coding strand has a UUC, it codes for phenylalanine. If a mutation in the DNA changes the sequence to UUU, then the DNA has undergone a silent mutation because both UUU and UUC code for the same amino acid. At least that is what scientists believed for decades. Recent evidence, however, has shown that this is not always true. Researchers at the National Cancer Institute were studying a gene called MDR1, which is named for its association with multiple drug resistance in tumor cells. They had sequences of this gene and knew that there were some common silent mutations. Interestingly, they discovered that there was a phenotypic response to silent mutations of this gene that influenced patientsâ€™ response to certain drugs. This was striking, as a silent mutation should have no effect on the final product.
Apparently, not all codons are translated equally. Different codons may require alternate versions of the tRNA for a particu-lar amino acid. Even though the amino acid incorporated is the same, the pace with which the ribosome is able to incorporate the amino acid differs depending on which codon it is. This is a situation reminiscent of transcription attenuation. As shown in the figure, translation kinetics can affect the form of the final protein. If the wild-type codon is used, then translation proceeds normally and produces the normal confor-mation of the protein. However, if a silent mutation changes the pace of the movement of the ribosome, then because of folding differences, an abnormal protein conformation is created.