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Wednesday, July 1, 2009

Silent mutations can also be harmful

Single-letter changes to the DNA, known as point mutations, can therefore change a codon to one that specifies the wrong amino acid (known as a missense mutation) or to a stop signal (nonsense mutation), causing the final protein to be truncated. A single-base change can also alter a stop codon so that it then encodes an amino acid (sense mutation), resulting in a lengthened protein. And a final change is possible: a mutation that alters a nucleotide but yields a synonymous codon. These mutations are the ones termed “silent.”
The classic view assumed that what are termed “silent” mutations were inconsequential to health, because such changes in DNA would not alter the composition of the proteins encoded by genes.
Only in the 1980s did scientists realize that silent mutations could also affect protein production—at least in bacteria and yeast. A key discovery at the time was that the genes of those organisms did not use synonymous codons in equal numbers. When the bacterium Escherichia coli specifies the amino acid asparagine, for instance, the codon AAC appears in its DNA much more often than AAT. The reason for this biased usage of codons soon became apparent: cells were preferentially employing certain codons because those choices enhanced the rate or accuracy of protein synthesis.
It turned out that tRNAs corresponding to those synonymous codons typically are not equally abundant within the cell. Most important, then, a gene that contains more of the codons matching the relatively abundant tRNAs would be translated faster, because the higher concentration of those tRNAs would make them more likely to be present when needed. In other cases, a single tRNA variety matches more than one synonymous codon but binds more readily to one codon in particular, so the use of that codon maximizes the accuracy of translation. Consequently, a cell has good reasons not to use all codons equally. As expected, in bacteria and yeast the genes that encode especially abundant proteins exhibit the greatest codon bias, with the preferred codons matching the most common or better-binding tRNAs.
Lately, studies of human disease have indicated that silent disease-causing mutations interfere with several stages of the protein-making process, from DNA transcription all the way through to the translation of mRNA into proteins.
One example involves silent mutations changing how a gene transcript is edited. Shortly after a gene is transcribed into RNA form, that transcript is trimmed to remove noncoding regions (introns) and then splice the coding regions (exons) together to produce the final mRNA version of the gene. Research over the past few years has revealed that exons not only specify amino acids, they also contain within their sequences cues necessary for intron removal. Chief among these are exonic splicing enhancer (ESE) motifs—short sequences of about three to eight nucleotides that sit near the ends of the exons and define the exon for the cellular splicing machinery. The need for such motifs can in fact explain a preference for certain nucleotides in human genes. Although the codons GGA and GGG, which encode glycine, can both occur in splicing enhancers, the former codon acts as a more potent enhancer, leading to more efficient splicing. GGA is also correspondingly more common close to the ends of exons.

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