Molecular Medicine News Analyses

In the scientific literature:

Meaningful silence

The most common of the millions of single nucleotide polymorphisms (SNPs) in the human genome are the so-called “silent” SNPs, or changes that do not affect the amino acid sequence of the protein they encode. These SNPs have been useful as tags for combing through the genome for disease-associated genes, but now it appears that they may be players in disease in their own right.

In the January 26, 2007 issue of the journal Science, Michael Gottesman and his colleagues at NCI’s Center for Cancer Research describe a series of experiments that demonstrate that “silent” SNPs in the Multidrug Resistance 1 (MDR1) gene change the structural conformation of the pump protein encoded by the gene, altering its functionality. This change is probably a result of the protein folding machinery of the cell being affected by the translation of the unusual base codon (even if the amino acid is unchanged).

These observations can go a long way toward potentially explaining differences between patients’ rates of metabolism of drugs. If born out by further research, they also have ramifications for future genetic association studies and clinical translation:

1) Science needs to revisit old SNP friends.

Researchers need to examine silent SNPs that were previously seen in genes of interest for various diseases, but were dismissed as irrelevant because of their apparent lack of functional significance.

2) Proteomics will get even more complicated.

The already high complexity of proteomic analyses will need to expand to include detecting subtle structural changes.

3) Further work must prove silent SNP relevance to human disease biology.

These findings will need to be verified in human populations and, if valid, in the context of clinical trials of specific drugs.

4) Communications will require a more subtle exposition of the molecular causes of disease.

These findings hold the potential of even further personalization of diagnosis and treatment. Communicating these results requires a more sophisticated yet accessible understanding of the many different kinds of genetic alterations that can contribute to disease development and treatment options.