All About Mutations
Part 5

What it means to have a mutation and what role mutations play in Huntington’s disease.

The Polymerase Slippage Model

Most cells reproduce by a process called mitosis, in which a cell copies (or replicates) its DNA and then splits into two identical daughter cells, each containing a complete copy of the original DNA. If a cell divided during mitosis without undergoing DNA replication first, the two daughter cells would each have a serious deficiency of DNA. This deficiency of essential information would have catastrophic results for the organism involved. Thus, DNA replication is essential not only for creating identical cells, but also for the organism as a whole. DNA polymerase (we will call this just "polymerase" for short) is the enzyme that replicates the DNA. Working with other compounds, it takes each of the two initial strands in the double helix and uses it as a template for creating a new strand. The polymerase elongates this new strand by attaching new nitrogenous bases to the template bases. For instance, if the template strand has an adenine (A), polymerase attaches its partner, a thymine (T); if the template strand has a guanine (G), polymerase attaches a cytosine (C). This matching of corresponding bases occurs on both of the initial strands in the double helix, with the result that polymerase pairs each initial strand with a new strand. While polymerase is working, another enzyme, helicase, unwinds the initial double helix, thus releasing the initial strands from each other’s grasp. As the initial strands are paired with their respective new strands, what began as one double helix ends up as two identical double helices.

Sometimes the polymerase slips from the template strand during replication. It is this event, called polymerase slippage, that many researchers believe holds the key to codon expansions. According to the polymerase slippage model, if the polymerase slips, it causes the new strand to unpair (release) from the template strand. If the slip occurs at the template’s codon repeat region of the Huntington gene, then when the new strand tries to reattach to the template strand, it will have many identical copies of the codon to choose from. With so many identical codon copies to reattach to, the new strand may reattach to the template at the wrong copy, usually one more distant than the copy that was adjacent to the polymerase before it slipped. As a result of this misplacement, the new strand forms a bubble of unpaired bases, which represents the expansion of the new strand. Once DNA replication is complete, an unknown mechanism allows the template strand to realign with the new strand and bring the bases from the bubble back into line with the template strand. The bases are then paired with their corresponding partner bases (cytosine (C) to guanine (G); adenine (A) to thymine (T)). In the end, the brand new double helix of DNA contains more CAGs in the repeat region of the Huntington gene than existed before. Polymerase slippage has caused expansion.

Like the unequal crossing over model, the polymerase slippage model also has its flaws. One criticism rests on the fact that, of all the codons in DNA, very few of them have been known to expand in human disease. According to the polymerase slippage model, the codon GGA should be just as likely to expand as CAG. However, in reality, we see no evidence of GGA expanding and the model cannot explain why. Another criticism of the polymerase slippage model is its inability to explain why some expansions are quite large. Small codon expansions (say, less than 5 copies of CAG) require little energy and are easily accounted for by the slippage model. However, many of the expansions that researchers see are quite large, sometimes in the hundreds of repeats. Slippage as the cause of these large expansions would be energetically unfavorable. This simply means that for the DNA, the energy costs of long-range slippage far outweigh the energy benefits. Since nature always seeks the "easiest route," an inefficient mechanism like this should either not occur, or it should continue with the aid of other events that make it more energetically efficient. In the case of polymerase slippage, most researchers believe that the latter is true: Polymerase slippage does play a role in codon expansion but it requires something else to make it happen. That something else appears to be what researchers call hairpins, which we will discuss next.

Last Modified: 1-28-04

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