Arches. Photo by Daniel Chia
Feb
05
2011

Population Genetics Part II: The Future of Huntington’s Disease

In order to make predictions about the future spread or decline of Huntington’s Disease, we can draw upon scientific tools from the field of population genetics (see Part I for an introduction to this field). According to population genetics, genes that make it more difficult for an affected individual to survive to reproductive age will tend to decrease in frequency in a population over time. Such a decrease in frequency is an example of the more general process of natural selection—the elimination of variation that results from differential survival and reproduction. The gene for HD is a special case in that it primarily affects men and women once they have passed their reproductive years. As a result, those affected by HD as adults will already have reproduced and, by the normal laws of probability (as described here), may already have passed on the harmful gene to their children. This means that natural selection–which would normally lower the frequency of HD over generations of time–will have little or no effect.

So if natural selection plays little role, what other evolutionary forces act on Huntington’s Disease? There are three other evolutionary forces that may have an important effect on the prevalence of HD: Genetic DriftMutation, and Migration. These three forces have helped shape the current global distribution of HD and will influence the fate of HD in the future.

Genetic Drift

is defined as the effect of chance on whether or not a specific gene is passed on to the next generation. When our bodies make sex cells like sperm and eggs, they allocate genes to sex cells on a fairly random basis. This means that chance ‘decides’ if the gene for HD will, or will not, be passed on to the next generation. Both theory and empirical research suggest that the effect of drift on the frequency of a gene like the HD gene can be large in small populations. If only one person has HD to begin with and does not pass on the gene, then no one inherits the HD gene. But if that person by chance passes on the gene to several progeny, then the percentage of people in the population with HD could increase greatly.

Migration

is closely related to the concept of genetic drift. When people who happen to carry HD genes change locations and establish settlements in new countries, which happens at an increasing pace in today’s globalized society, they bring the genes for HD with them. The movement of these groups creates small populations with the HD gene in new places. Sometimes these small populations have elevated HD frequencies simply as an accidental byproduct of who moved and who didn’t: this is called founder’s effect.” Genetic drift can also influence the frequency of HD in these small populations as described above. As a result of this combination of migration and genetic drift, pockets of HD have appeared in various locations of the world, as described in the global prevalence section of the Population Genetics Overview.

Mutation

refers to spontaneous chemical change in a gene. Although such change often has no effect on the bearer’s ability to function, sometimes, as in the case of HD, it has dramatic consequences. As described elsewhere, HD occurs in people that have more than 36 CAG repeats in their gene for huntingtin protein. The repeating CAG segment of DNA is known as a microsatellite, that is, a short repeating segment of DNA. Many mutations occur at random, and if that were true of the HD gene, then the length of the microsatellite CAG repeats would increase or decrease randomly. However, as mentioned earlier in the Population Genetics section, a mutational bias has been demonstrated in the case of HD that tends to increase the length of the repeat, rather than decrease it. Recent discoveries indicate that this trend of increasing microsatellite length generally occurs with all microsatellites. This means that other microsatellite diseases such as myotonic dystrophy, Friedrich’s ataxia, and Machado-Joseph disease also have this property, not just Huntington’s Disease.

So what do all these evolutionary forces mean for the future of Huntington’s disease? The mutational bias towards longer microsatellite repeats will most likely have the greatest effect on the distribution of HD, causing the prevalence of HD to increase gradually over time. As migration increases, the disease has the potential to spread in clusters across the globe as it already has in parts of Venezuela, Tasmania, and India. These two forces would seem to paint a picture of slowly increasing HD frequencies across the generations; however, there are countervailing pressures for a decrease in the prevalence of HD.

Remember from the beginning of this section that natural selection would seem to have little negative impact on the spread of the HD allele. In contrast, modern reproductive technology has the potential to impose an artificial selection against the HD allele. Genetic counseling allows parents to find out if they carry the allele before they decide to have children. This could potentially mean a decrease in the number of children being born with HD, and thus reduce the prevalence over time. Furthermore, in vitro fertilization and pre-implantation genetic diagnosis (PGD) offer parents that carry the HD allele the opportunity to ensure that the child they raise does not carry the HD allele, as described in more detail here. Genetic testing allows the parents to determine which of their fertilized eggs contain the allele and to proceed with an embryo that will be HD-free. If enough parents and embryos are tested, these two practices could significantly reduce the number of new children born with Huntington’s Disease. In this way, contemporary technology may be able to step in and help where natural selection has failed.

Although these predictions of the future spread or decline of Huntington’s disease may seem far off in the future, in fact they may already be upon us. Genetic testing and PGD have already been shown to decrease the prevalence of other genetic diseases. In Taiwan, these technologies have reduced the prevalence of thalassaemia, a rare genetically-inherited blood disorder, in newborns from 5.6 in 100,000 to 1.21 over the course of 8 years. Such a five-fold decrease in the prevalence of HD would have a dramatic impact on the future of the disease. So even though the predictions of the growth of Huntington’s Disease may appear bleak without interventions, there is cause for hope. With current technologies and new innovations appearing every day, the potential to decrease the spread of HD seems just as likely as the potential increase. We who have the capacity now must make efforts to steer the course of Huntington’s Disease in the future.

For additional reading:

  • Rubensztein et al. “Microsatellite and trinucleotide-repeat evolution: evidence for mutational bias and different rates of evolution in different lineages.” Philosophical Transactions of the Royal Society of London. 1999 Vol. 354: 1095 – 1099.
  • Leroi, Armand. European Molecular Biology Organization. 2006 Vol. 7(12): 1184 – 1187.
  • Harper, Peter. “The epidemiology of Huntington’s Disease.” Human Genetics. 1992 Vol. 89: 365 – 376.
  • Rubensztein et al. “Mutational bias provides a model for the evolution of Huntington’s Disease and predicts a general increase in disease prevalence.” Nature Genetics. August 1994 Vol. 7: 525 – 530.

-J. Czaja, 7/25/03