Jon Krause

Key Concepts

• Scientists long assumed that any DNA mutation that does not change the final protein encoded by a gene is effectively “silent.”
• 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.
• Understanding the subtler dynamics of how genes work and evolve may reveal further insights into causes and cures for disease.

Biologists long thought they understood how genetic mutations cause disease. But recent work has revealed an important twist in the tale and uncovered surprising—even counterintuitive—ways that 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. Proteins function in virtually every process carried out by cells, from catalyzing biochemical reactions to recognizing foreign invaders. Hence, the thinking went, if a protein’s makeup ends up being correct, any small glitches in the process leading to its construction could not do a body harm.

Yet detective work occasionally traced a disorder to a silent mutation, even though researchers presumed that it could not possibly be the culprit. Similar mysteries popped up in studies of genome evolution, where patterns of changes in the DNA of various species indicated that many silent mutations were preserved over time—a sign that they were useful to the organisms possessing them. In many species, these changes seemed to help cells make proteins more efficiently, but not in people.

   
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