All About Mutations
Part 4

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

The Unequal Crossing Over Model

Sperm and egg cells reproduce by a process called meiosis. During meiosis, homologous chromosomes line up, enabling alleles to switch places between the chromosomes in an event described as crossing over. During equal crossing over, the alleles are exchanged equally. For instance, say that originally allele "A" is on chromosome "4A" and allele "B" is on chromosome "4B." During equal crossing over, if allele A and allele B were to switch places, then allele A would move to chromosome 4B, while allele B would move to chromosome 4A. However, during unequal crossing over, the position switching of allele A and allele B might not be quite so smooth. Instead of whole alleles switching places, only a certain segment of each may switch, leaving the rest behind to act as a neighbor for the new inhabitant (the allele coming from the other chromosome). In the case of HD, the segments being cut unequally are often the repeating CAG regions of each Huntington allele. After the crossover, one of the chromosomes will have a Huntington allele with fewer CAGs than before. This is the “contracted allele” due to the contraction of the number of CAGs. The other chromosome will have a Huntington allele with more CAGs than before. This expansion results in the “expanded allele.”

Once meiosis is complete, the two homologous chromosomes are split apart. In males, one of the chromosomes goes to one sperm, and the other chromosome goes to a different sperm. In females, one of the chromosomes goes to one egg, and the other to a different egg. The end result is that, should a baby be created from an egg or sperm with a chromosome housing the contracted Huntington allele, then the baby will have a reduced number of CAGs on his or her Huntington gene (in comparison to the parent). If the baby’s number of CAGs is below threshold for HD (see Table A-1 for the rough threshold numbers), the baby is unlikely to develop HD. However, should the expanded Huntington allele be present, then the baby will have a greater number of CAGs than the parent. If there are enough CAGs (again, see Table A-1 for the rough threshold numbers), then the child will develop HD. (For a general discussion of the probability of passing HD to one’s children, click here. For more about how expansion affects passing HD to one’s children, see Part 2 of this chapter.)

The unequal crossing over model does not perfectly represent the expansion mechanism in HD. Its most important flaw is that it suggests that expansion occurs during meiosis, which happens before sperm and eggs are developed. In reality, however, researchers have found little evidence of expansion during meiosis. Instead, they believe that expansion happens during mitosis, which takes place in the developing embryo after fertilization (when a mature sperm and a mature egg have fused together). Another phenomenon that is unexplained by the unequal crossover model is that in real life, expansion occurs much more often than contraction. One study demonstrated that 52.1% of parent-child transmissions of HD result in expansion, compared to only 18% for contraction. Say the unequal crossing over happens in the father’s body: According to the model and our discussion of homologous chromosomes, his child should have a 50% chance of being made from a sperm with chromosome 4A and a 50% chance of being made from a sperm with chromosome 4B. If one of these chromosomes has an expanded Huntington allele and the other has a contracted Huntington allele, then the chances of expansion and contraction should be 50/50, like calling heads or tails with a coin. The same argument can be made for a mother and her eggs. With a 50/50 prediction and 52.1/18 results, the model clearly is not a perfect fit for what actually occurs to cause expansion in HD. This certainly does not mean that the model plays no role in expansion; it simply suggests that, if the model does play a role, there are also others players involved.

Another model, polymerase slippage (also known as "DNA slippage"), is the one that is receiving the highest amount of attention with regard to HD mutation research. We discuss this model next.

Last Modified: 1-28-04

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