Long-held assumptions about "silent" genetic mutations have been torn down, challenging a fundamental evolutionary theory.

Scattered throughout the human genome are thousands of mutations that biologists have treated mostly as footnotes. They’re hardly few in number—in coding regions of the genome, there are as many as 15,000—but biologists regard them as mutations that simply don’t change the way a cell functions. Both in name and effect, they have been accepted as “silent.” Now, however, new discoveries are showing that silent mutations appear to play an important role in dozens of human genetic diseases, a fact that is forcing biologists to discard a long-held evolutionary theory and to reexamine the very rules governing the transfer of information from DNA to proteins.

To understand the importance of this realization, it’s necessary to review how infrormation is transfered from genes to proteins. During protein synthesis the two strands of the double helix unravel, and the DNA template, composed of four nucleotide bases, is transcribed into messenger RNA (mRNA). Essentially, the information encoded in DNA is preserved in the alphabet of mRNA, which in turn is translated into amino acids, the basic building blocks of proteins. In this process, each group of three mRNA bases, called collectively a codon, signals for the addition of a particular amino acid to the growing protein. As this chain elongates, the protein spontaneously begins to fold into its final, three-dimensional conformation—a step that is essential for it to be biologically active.

A simple mutation within a gene, such as the substitution of one nucleotide for another (a “single nucleotide polymorphism,” or SNP), can modify which amino acid gets incorporated into the protein, altering the way it folds and functions. Though there are an estimated 30,000 SNPs in the human genome, which account for the genetic variation among humans, most are not harmful. Biologists consider these harmless mutations “neutral” because they do not affect the fitness of an organism.

Silent mutations are a subset of SNPs. They have no impact on the amino acid sequence of proteins and, therefore, were not expected to change their function. This belief has been a central tenet of biology for decades, but new research is eroding that orthodoxy. And an article in Science this past December substantially overturned it. Dr. Chava Kimchi-Sarfaty and her colleagues at the National Institutes of Health were trying to understand why certain silent mutations occurred with unusual frequency in a gene called multidrug resistance 1 (MDR1), found in human cancer cells. MDR1 codes for a protein that sits in the membrane and pumps chemotherapy drugs out of cells, rendering the cancer cells resistant to the drugs. The team discovered that a variant of the MDR1 gene, containing certain common silent mutations, made the cells even more effective at expelling cytotoxic drugs. The question was, how?

After further investigation, the team showed that the silent mutations in MDR1 were actually slowing down the protein-making process. And since the folding of a protein into its three-dimensional shape is partially speed-dependent, these mutations were able to alter the structure—and biological function—of the protein without changing its basic building blocks. Through a series of elegant experiments, the team put to rest the idea that silent mutations were neutral.

This mechanism, which they call “translational pausing,” is actually just one of several ways in which silent mutations have very recently been shown to affect protein function—and, more broadly, the fitness of an organism. It turns out that silent mutations can also change the stability of mRNA, one of the important intermediates in the transfer of information from DNA to proteins, and disrupt gene splicing, the process by which the DNA that contains genes is trimmed away from the rest of the genome.

Remarkably, it has now been shown that there are at least 40 silent mutations that cause disease in humans by changing the way a gene is spliced. One such example is CFTR, the gene that is linked to cystic fibrosis. Another example is FBN1, a gene linked to a common connective-tissue disorder called Marfan Syndrome. With this new understanding, we can now reexamine the basis of many inherited conditions for which no underlying cause has been identified.

Most fundamentally, the involvement of silent mutations in disease undermines the neutral theory of molecular evolution. This theory, posited by Motoo Kimura in the late 1960s and a powerful influence ever since, asserted that the vast majority of mutations were neutral, having no effect on the fitness of an organism, and spread through a population by chance. The fact that silent mutations are not harmless anomalies of nature means that they are not neutral. In contrast, some, if not all, silent sites must be subject to the forces of Darwinian natural selection.

Lindsay Borthwick is a writer living in Toronto.

Originally published March 18, 2007

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