Everyone whose life has been turned upside down by Huntington's Disease has to wonder why such a horrific disease should burden so many people. Students of philosophy may well conclude that the question is one that we cannot answer. Students of genetics, however, are not content with that conclusion. Evolution has shaped the distribution of our genes, and some evolutionary process must have led to the current situation in which as many as 1 in 10,000 persons carries the gene for HD. What has kept such a harmful gene from being eliminated by natural selection? Examination of the gene has revealed the answer to the question. How that answer was arrived at is an interesting story. The following assumes some familiarity with the language of population genetics.

According to classical population genetics, there are four forces that influence gene frequency in populations: Genetic drift; immigration/emigration; mutation; and selection. Genetic drift and immigration/emigration influence gene frequencies in isolated populations (together they explain the unusually high incidence of HD on Lake Maracaibo, for example), but neither could account for global persistence of a deleterious gene. Mutation is usually considered to have little effect. There is no a priori reason to expect a normal gene to mutate to a disease gene at a higher frequency than the reverse.

Selection is known to contribute to the maintenance of disease genes in populations if the gene is recessive. The vast majority of people who carry a recessive gene will be unaffected (or weakly affected) "carriers", and if they enjoy some selective advantage the gene will be maintained. This may be the case for the genes that cause sickle cell anemia and cystic fibrosis in that carriers of those genes may have enhanced resistance to certain infectious diseases. The gene for HD, however, is dominant, so an argument for heterozygous advantage cannot be given.

Years ago, there was speculation that persons who carried the HD gene might enjoy some reproductive advantage. Perhaps the gene led to increased fertility so that persons who carried the gene left more children than those who did not. Population studies comparing family sizes of persons with HD with those of their unaffected siblings failed to confirm this.

The textbook explanation for how the gene for HD is maintained in human populations is illustrated with this quote from a popular college biology textbook, Raven & Johnson: "Since the allele is dominant, every individual that carries the allele expresses the disorder. Nevertheless, the disorder persists in human populations because its symptoms usually do not develop until the affected individuals are more than 30 years old, and by that time most of those individuals have already had children." In other words, the standard explanation is that the gene for HD persists because there is no selection against it. Consideration of the facts of HD reveals this to be an inadequate explanation. A significant number of people carrying the gene for HD develop symptoms before they are able to have children, and so there should be significant selection against the gene. Furthermore, even if HD were always a late onset disorder, lack of negative selection would only explain how it has failed to be eliminated. It would offer no clue as to how the gene arrived at its high frequency in the first place. For that, genetic drift is sometimes invoked, though unconvincingly.

We had a paradox, then: A disease gene that should be selected against persists in human populations at a relataively high frequency. The solution was arrived at once the nature of the gene as a trinucleotide repeat expansion was revealed. The gene for HD is maintained by a force that previously had been dismissed: Mutation. For the huntingtin gene, mutation from the normal to the disease gene does indeed occur at a higher frequency than the reverse. This is because expansion of the CAG repeat between generations is more likely to occur than contraction. As copies of the disease gene are being lost to negative selection, new copies are coming into the population by expansion of the CAG repeat from the normal into the disease range. It has been estimated that as many as 1% of persons with HD express such new mutations.

This realization that the persistence of HD is due to an unusually high mutation frequency has practical meaning for society's approach to the disease. It is sometimes assumed that HD could be eliminated if everybody who knew of a family history of the disease remained childless. In fact, many people who carry the HD gene have no family history of the disease because their copy of the gene represents a new mutation. Huntington's Disease can be understood as a tragic consequence of the structure of the human genome, and the only rational approach to controlling its incidence is to develop effective therapies that will allow gene carriers to live full lives.