Common DNA mutation

In human DNA, guanine and thymine, are able to change shape in order to form an inconspicuous rung on the helical DNA "ladder." This allows them to survive by avoiding the body's natural defenses against genetic mutations.When these two bases form a hydrogen bond by accident, at first, they don't fit quite right," explained Zucai Suo, professor of chemistry and biochemistry at The Ohio State University and co-corresponding author of the study. They stick out along the DNA helix, so normally it's easy for the enzymes that replicate DNA to detect them and fix them. But once in a while, before they can be detected, they change shape.

The discovery provides a foundation for work on other types of DNA mutations, which are responsible for diseases as well as normal aging and evolution. The four bases of DNA each have their own size and shape, and are supposed to fit together in just the right way. Adenine (A) is always supposed to pair with thymine (T), and cytosine (C) is always supposed to pair with guanine (G). The two "Watson-Crick" base pairs, A-T and C-G, form the DNA sequences of all life.

However, if G were to somehow mispair with T, for example, that would be a mutation. In fact, the G-T mutation is the single most common mutation in human DNA. It occurs about once in every 10,000 to 100,000 base pairs-which doesn't sound like a lot, until its consider that the human genome contains 3 billion base pairs.

Though scientists had long speculated that the G-T mispair shape-shifted in order to resemble a normal G-C or A-T pair, researchers used a form of nuclear magnetic resonance imaging to reveal that these Watson-Crick-like G-T mispairs form in so-called "naked" DNA. Researchers used a DNA polymerase, an enzyme that replicates DNA, to insert a G-T mispair into a DNA strand. By stopping the chemical reaction at different times and analyzing the resulting DNA molecules, they were able to measure how efficiently the polymerase could form the G-T mispair.

Researchers discovered that the G and T bases would pair, but in a misshapen way that stuck out from the DNA helix. Then, in a fraction of a second, the bases would re-arrange their chemical bonds so that they could "snap" into the shape of a normal base pair and fool the polymerase into completing the chemical reaction.

The mutation's survival is a real feat, since it has to overcome a good bit of basic physics. Bases pair in a certain way because of how the protons and electrons in their atoms are arranged. Base pairing requires some amount of energy, and the easiest, most energy-efficient pairs to form are the "right" ones -- A-T and C-G. In effect, the G-T pair has to overcome an energy barrier to form and maintain itself. It turns out that when the G and T bases change shape, they make themselves more energy efficient, less efficient than a normal base pair, but efficient enough.
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