How Trivial DNA Changes Can Hurt Health

http://www.scientificamerican.com/article.cfm?id=the-price-of-silent-mutations&sc=WR_20090602

1. Scientists long assumed that any DNA mutation that does not change the final protein encoded by a gene is effectively “silent.”
   
2. Mysterious exceptions to the rule, in which silent changes seemed to be exerting a powerful effect on proteins, have revealed that such mutations can affect health through a variety of mechanisms.
3. Understanding the subtler dynamics of how genes work and evolve may reveal further insights into causes and cures for disease.

• Alterations in DNA can make people sick. 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.

• 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.”
• Examples certainly abound of the first three types of point mutations having a major impact on human health. Three different point mutations in the genes encoding proteins that make up the hemoglobin molecules in red blood cells are responsible for three separate and grave diseases, for instance. In the case of sickle cell anemia, a missense mutation exchanges a water-loving (hydrophilic) amino acid for a water-avoiding one (hydrophobic), causing the proteins to clump together and produce characteristic sickle-shaped blood cells. In polycythemia disorders, a nonsense mutation truncates one of the hemoglobin proteins, resulting in thickened blood. And in thalassemia, a sense mutation changes a stop codon (TAA) to the codon for glutamine (CAA), creating a much longer and nonfunctional protein.
  

• 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.

•  Analyses of mammalian genes did indeed reveal tendencies toward favoring certain codons. The similarity between simple organisms and mammals, however, proved to be only superficial. For reasons not yet fully understood, mammalian genomes are organized into large blocks, each with a distinctively skewed nucleotide content: some regions are rich in G and C bases, whereas others are enriched for A and T. As a result, genes residing in a GC-rich region of the genome tend to have many codons containing those bases. Our genes, then, do show a bias for using certain codons, but unlike simpler organisms, the mammalian pattern does not obviously suggest that the reason is to optimize protein synthesis.
  
  
  

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