Listen to this article in mp3 format: Population Genetics and Huntington’s Disease
Have you ever wondered where Huntington’s disease originated? Or why it’s predominantly found among Europeans and those of European descent? Population genetics, the study of the genetic makeup of populations and of changes over time in that makeup, attempts to answer such questions. In this chapter, we explore the origins of the HD allele, the variable frequency of HD around the world, and current theories for how the HD allele has “survived” through time in human populations.
- The Genetics of HD
- The Origin of HD
- The Frequency of HD
- The Maintenance of HD
The Genetics of HD^
It is important to understand the basic genetics behind Huntington’s disease (HD) before learning about its population genetics. This section is simply a brief refresher – to learn more, please visit The Basics of Huntington’s Disease and The Inheritance of HD.
- The Huntington gene is responsible for encoding the huntingtin protein. Although the biological function of the huntingtin protein is still unknown, it is known that the alteration of this protein ultimately results in HD.
- There are multiple versions, or alleles, of the Huntington gene. Some alleles, known as HD alleles, will result in Huntington’s disease. Other alleles, known as non-HD alleles, will not. Because Huntington’s disease is a dominant genetic disorder, a person only needs one copy of an HD allele to develop HD. For more on alleles or genetic dominance, click here.
- Specifically, the number of CAG codon repeats in the Huntington gene determines whether an allele will be an HD allele or a non-HD allele. Alleles with fewer than 35 CAG codon repeats are non-HD alleles; alleles with more than 40 CAG codon repeats are HD alleles. Alleles with between 35 and 40 CAG codon repeats are intermediate – sometimes they will result in HD, sometimes they will not
The Origin of HD^
WHERE DID THE HD ALLELE ORIGINATE?^
It is generally accepted that there have been multiple origins of the HD allele. Currently, it is thought that separate new mutations have taken place in Europe, Japan, and Africa.
Researchers came to this conclusion by comparing the genetic sequences of the Huntington gene. They have found that there are significant differences between the European, Japanese, and African HD genes. If one HD allele were responsible for all of the HD cases in the world, you would find strikingly similar HD alleles in all persons with HD – not the distinct varieties that are actually found. Such differences therefore suggest that the HD allele originated independently in these three regions.
IS IT COMMON FOR NEW HD ALLELES TO ARISE?^
Originally, it was thought that mutations from a non-HD allele to an HD allele were rare and accounted for only a very small proportion of HD cases. On an individual level, new mutations were not considered to be very frequent. (Please note: In this chapter, the term “new mutation” specifically refers to the mutation from a non-HD allele to an HD allele.)
On the population level, it was also assumed that new mutations did not significantly affect the frequency of HD. If an HD allele did develop, researchers thought the HD allele could mutate back to a non-HD allele just as easily – thereby not changing the overall frequency of HD alleles in the population.
Researchers realized this biased mutation tendency when they discovered that HD was a type oftrinucleotide repeat disorder. In such disorders, a high number of codon repeats is indicative of having the disease. Unfortunately, the expansion of a codon repeat is more likely to happen than the contraction of it – resulting in a relatively higher rate of new HD mutations.
A 1994 study confirmed the idea that codon repeat expansions were common by using computer simulations to investigate the evolution of the HD allele. The simulations suggested that the human HD allele expanded from a shorter non-human primate’s allele – suggesting that there is a mutational bias towards having longer and longer Huntington gene alleles. This study predicted that the expansion of codon repeats will continue and accelerate in the absence of any outside interference and lead to an ever-increasing incidence of HD.
A 2001 study used another approach to analyze genetic disorders in order to measure the rate of new mutation. When this approach was applied to HD, it was estimated that the new mutation rate in each generation was about 10%. In other words, this study suggested that about 10% of all HD cases did not inherit the HD allele from a parent, but received the HD allele from a newly formed mutation.
In British Columbia, another study discovered that of 141 patients with HD, 11 had no family history of HD. All 11 cases had reliable parental information with parents who lived well into old age with no signs of the disease. Thus, this study estimated the new mutation rate to be at least 8%.
Though the “true” new mutation rate for HD is still unclear, current estimates range anywhere from 1% to 14%.
WHO IS AT RISK FOR DEVELOPING NEW HD ALLELES?^
New mutations from non-HD alleles to HD alleles occur more frequently on chromosomes with a high number of CAG repeats. Therefore, people with CAG repeat lengths in the high range of normal (close to 35) or in the intermediate range (35-40) are more likely to develop an HD allele in their germ cells and pass this HD allele on to their children. In other words, a person whose parent has a higher than normal frequency is more likely to develop HD than a person whose parent has fewer CAG repeat lengths.
Also, it seems that paternal transmission of the Huntington gene is more prone to expansion of the CAG repeats than maternal transmission. Therefore, a person whose father has a high number of CAG repeats is more likely to develop HD than a person whose mother has a high number.
Interestingly, chromosomes with a high number of CAG repeats tend to be marked by other features, including seven repeats of the CCG codon next to the CAG repeats and a missing GAG codon within the Huntington gene. It has been hypothesized, though not proven, that these markers might contribute to the instability and expansion of the CAG repeats.
The Frequency of HD^
WHAT IS THE FREQUENCY OF HD AROUND THE WORLD?^
Huntington’s disease is currently found in many different countries and ethnic groups around the world. The highest frequencies of HD are found in Europe and countries of European origin, such as the United States and Australia. The lowest documented frequencies of HD are found in Africa, China, Japan, and Finland.
|Population||Frequency of HD
(cases per million people)
|South Africa (blacks)||0.6|
|Europe & countries
of European descent
|-Scotland (Grampian Region)||99.4|
Though it has been suggested that the frequency of HD is probably low among people of African origin, documentation remains poor and evidence is inconclusive. From the few known cases, however, it has been hypothesized that the HD mutation in Africa has a separate origin from the mutation in Europe or Japan.
- There is a substantial frequency of HD in the white and mixed-race populations of South Africa. Most of the families with HD have Dutch or British ancestry, which suggests that they inherited the European HD allele.
- A 1987 study revealed the HD prevalence among South African blacks to be very low – around 0.6 cases per million people.
While there have not been a lot of studies conducted in Asia, it is thought that HD may be relatively frequent in India, Turkey, and Central Asia. However, HD is relatively rare in China and Japan.
- In Hong Kong, the prevalence of HD between 1984 and 1991 was found to be 3.7 cases per million people. Since the ancestors of these families with HD can be connected to coastal provinces with histories of strong colonial presence, it has been proposed that these cases have a European origin.
- HD is notably rare in Japan, with a prevalence of 1-4 cases per million people – about one-tenth of the prevalence in most European and European-origin populations.
- It has been hypothesized that the HD mutation in Japan has a separate origin from the HD mutation in Europe or Africa.
Europe has a relatively high prevalence of HD in its population, with 40 to 100 cases per million people. The prevalence is rather uniform across almost all of Europe, except for Finland. The geographically even distribution of HD suggests that there has either been:
- one very ancient mutation responsible for all of the HD cases in Europe, or
- multiple, separate mutations responsible for the HD cases spread throughout Europe.
Recent studies suggest that multiple, separate mutations are more likely to explain Europe’s uniform HD prevalence rates. For example, a 1994 study suggested at least three origins of the HD allele in Sweden alone. Population geneticists also think that recurring mutations may be necessary to maintain the prevalence of HD at its relatively high level.
- Finland has always been recognized as having a genetically distinct population from the rest of Europe. Therefore, it is not surprising that the prevalence of HD in Finland (at six cases per million people) is drastically different – an order of magnitude less, in fact – than the rest of Europe. This remarkably lower prevalence rate suggests that the Finnish population must have diverged from the European stock before the HD mutation occurred and became widespread in Europe.
- Most, if not all, cases of HD in Finland can be traced to foreign connections. For example, the Aland archipelago near Sweden, which has an unusually high frequency of HD, has been exposed to other populations, including the British, for centuries. Also, a high percentage of Finnish families with HD had foreign ancestors or had Finnish ancestors that lived in border or trade regions.
- A 1994 study in Sweden discovered 10 different variants or haplotypes of the HD allele. However, one of the ten haplotypes accounted for 89% of the families with HD, suggesting that the majority of Swedish families with HD are related through a single HD mutation in their ancestors. This study also suggested at least three origins of the HD mutation in Sweden alone.
- Studies in the UK have shown a high and relatively uniform prevalence of HD across the nation, with no obvious correlation with ethnic origin (Celtic, etc.)
- A 1981 study in South Wales found a prevalence of 76.1 HD cases per million people.
- A 1989 study in the Grampian region of NW Scotland revealed an unusually high HD prevalence of 99.4 cases per million people.
- In Northern Ireland (population 1.5 million), a 1994 study determined an HD prevalence of 64 cases per million people.
- Because there is no single “hot spot” of high prevalence, studies have suggested that there is no single origin of HD in the UK.
OTHER POPULATIONS OF EUROPEAN ORIGIN^
Most analysts agree that migration out of Europe has brought HD to North and South America, Australia, New Zealand, and other regions with European contact. The prevalence of HD in these regions is similar to that of Europe (40-100 cases per million people). HD patients in these areas have a wide range of European ethnic origins or contacts, suggesting that there were multiple introductions of the HD allele into these communities in all but the smallest and most isolated groups.
Australia & New Zealand
- Among the Caucasian populations of Australia and New Zealand, which include many people of southern ancestry, there is a uniform, widespread distribution of HD.
- Tasmania represents an exception to the uniform distribution of HD throughout Australia. In Tasmania, there is an unusually high frequency of HD in one large clan of English origin. These people are descendents of a single ancestor with HD from Somerset, England.
- There have been no documented cases of HD in the native populations of Australia or New Zealand. Reported occurrences of HD in the Aborigines have a European origin.
New Guinea & Small Pacific Island Groups
- At first glance, HD cases appeared to predate any European settlement. However, it has been suggested that the HD allele was introduced by crews of visiting whaling ships from North America in the first half of the 19th century.
- HD is widespread in most South American countries.
- The largest and best-studied concentration of HD is in Lake Maracaibo, Venezuela. This small community has over 100 living individuals with HD, all of whom are descendents from a single ancestor, probably of European origin. Studies in Lake Maracaibo have helped to localize the HD gene and document the etiology of HD. (To learn more about Lake Maracaibo, click here.)
- There have been no documented cases of HD in the native populations of South America.
- As of the year 2000, there were 30,000 cases of HD in the United States – indicating a prevalence rate of about 100 cases per million people.
- Among the European-American population, there is a uniform distribution across the United States. The ethnic origins of these families with HD can be traced to a variety of European countries.
- A 1987 study determined the prevalence of HD in African Americans to be 15 cases per million people – much lower than the prevalence in European Americans. In most of these affected families, the HD allele did not have a European origin.
- There have been no documented cases of HD among the Native American populations of North America.
WHAT EXPLAINS THE VARIATION IN HD PREVALENCE AROUND THE WORLD?^
European migration explains much of the variation in HD prevalence rates around the world. Europeans appear to have carried the HD allele with them wherever they settled: North and South America, Australia, New Zealand, etc. Prevalence rates in these populations resemble those of Europe and represent the highest frequencies of HD in the world. But, if the mutation responsible for HD also originated in Japan and Africa, why are the prevalence rates in those regions so much lower?
One theory holds that the different prevalence rates of HD around the world are due to differences in genetic risk factors. Before we take a look at these risk factors, however, let’s take a closer look at the Huntington gene itself:
There are many different versions, or alleles, of the Huntington gene. Perhaps the most noteworthy variation is in the number of CAG repeats (non-HD alleles have under 35 repeats; HD alleles have over 40). However, there are two other variations in the Huntington gene that we will mention here:
- Variation in the Number of CCG Codon Repeats
Most people either have either 7 or 10 CCG codon repeats adjacent to their CAG repeats. These alleles are either abbreviated (CCG)7 and (CCG)10 or simply “7” and “10.”
- The Presence or Absence of a GAG Codon at Residue 2642
Huntington genes that have a GAG codon at the specific location in the DNA called “residue 2642” are known as “A alleles;” genes without this codon are known as “B alleles.”
As mentioned in Part 4 above, alleles with a high number of CAG repeats are more likely to be the source of new HD mutations. Interestingly, the B7 allele—the allele that has both the B allele and the (CCG)7 allele—usually has a high number of CAG repeats, while the A10 allele usually has a low number of CAG repeats. It has been suggested, though not proven, that the B allele and the (CCG)7 allele may contribute to the instability and expansion of the CAG repeats.
Populations with a high prevalence of HD (i.e., Europeans and those of European ancestry) have a relatively high number of B7 alleles, which are associated with a high number of CAG repeats. This finding suggests that in these populations, new HD mutations may be more frequent, thus making HD more prevalent.
On the other hand, populations with a low prevalence of HD (i.e., in the populations of Africa, China, Finland, and Japan) have a relatively high number of A10 alleles, which are associated with a low number of CAG repeats. This indicates that new HD mutations may be less frequent in these populations, making HD less prevalent. The (CCG)7 allele is relatively underrepresented in these populations, and the B allele is not even found in Africa and Asia
The Maintenance of HD^
HOW DOES HD AFFECT FERTILITY AND REPRODUCTIVE FITNESS?^
Currently, there are conflicting findings on the effect of HD on one’s fertility and reproductive fitness. Many studies have found that people with HD, compare to general population, have an increased fertility and fitness before they develop symptoms. Most notably, studies in Canada, Minnesota, England, Wales, and Tasmania have found an increased fertility and reproductive fitness in presymptomatic persons with HD. However, some studies, like one performed in Queensland, Australia, found an identical fertility and fitness among persons with HD and the general population. In addition, other studies carried out in Michigan and Japan found decreased fertility and fitness among persons with HD.
In general, most studies find an increase in fertility and reproductive fitness among presymptomatic people with HD. It has been hypothesized that some early features of HD – possibly increased sexual drive, loss of impulse control, and impaired cognition and judgment – may be responsible for this increased reproduction. At this time, however, there is no published evidence to support these possible mechanisms for increased fertility. The hypothesis of increased fertility and reproduction among presymptomatic individuals remains speculative.
One study in Tasmania, Australia found that the increased fertility was especially prevalent in people with late-onset HD. People with early-onset HD did not exhibit a similar increase. Logically, if people start to develop HD symptoms before they complete their families, the early symptoms of HD could well decrease their chances of pregnancy and children. Such an effect has been found in the case of juvenile HD, in which HD symptoms develop in childhood or adolescence and significantly reduce a person’s reproductive ability. (To learn more about Juvenile HD, click here.) Given enough time to complete their families, though, it seems that presymptomatic people with HD could well have, on average, more children than people without HD. Keep in mind, however, that there is contradictory evidence from some locations and that none of the hypothetical mechanisms have been confirmed.
WHAT HAS KEPT THE HD ALLELE FROM BEING ELIMINATED?^
Part of the answer may lie in the fact that HD is a late-onset disorder. Symptoms normally arise in the fourth or fifth decade of life, usually after a person has already started a family. A parent could therefore pass on the HD allele to his children before he even realized that he carried the allele. In this way, the HD allele is able to survive, even though its human carrier will not.
This explanation, however, doesn’t fully answer the question. After all, not all cases of HD are late-onset. Sometimes symptoms arise during the reproductive years. Other times, symptoms arise as early as childhood.
Currently, there are two hypotheses that attempt to explain how the HD allele has reached and been maintained at such high frequencies, especially in Europe:
Early on, researchers did not think that new mutations could account for the global persistence of HD because, in most cases, mutations have little effect on large populations. However, as described in Part 3, the new mutation rate may be much higher than previously thought.
It is estimated that anywhere from 1%-14% of persons with HD did not inherit the HD allele from a parent, but instead acquired the HD allele from a newly formed mutation. Therefore, despite its deleterious nature, HD might be maintained in high frequencies due to the relatively high rate of new mutations.
As mentioned in Part 7 above, there is evidence in some populations that presymptomatic people with HD have a higher average fertility than the general population. If generally true, this increased fertility could also account for the persistence of HD in our world. However, this hypothesis presently lacks conclusive evidence.
As this section shows, the history of the HD allele in human populations has not been fully unraveled. While geneticists have some idea where the allele originated, and how it spread through human migration, they are still trying to understand how the allele has been maintained at such high frequencies in certain parts of the world and what the genetic risks are of developing a new mutation. Although the study of population genetics may at first seem to be a matter of purely historical interest, clues revealed by this kind of inquiry will surely help clinicians better understand the HD mutation and Huntington’s disease itself.
For Further Reading^
- Almqvist, E, et al. “Ancestral differences in the distribution of the delta 2642 glutamic acid polymorphism is associated with varying CAG repeat lengths on normal chromosomes: Insights into the genetic evolution of Huntington disease.” Human Molecular Genetics, February 1995, 4 (2): 207-14.
A technical paper on the GAG deletion, the CAG repeat lengths, and their distributions around the world.
- Almqvist E, et al. “Geographical distribution of haplotypes in Swedish families with Huntington’s disease.” Human Genetics, August 1994, 94 (2): 124-8.
A technical paper on the Huntington gene alleles found in Sweden and their implications for the multiple-origin hypothesis in Europe.
- Andrew, SE and MR Hayden. “Origins and evolution of Huntington disease chromosomes.”Neurodegeneration, September 1995, 4 (3): 239-44.
A technical paper on the relationship between CAG repeat lengths and development of new HD alleles.
- Harper, PS. “The epidemiology of Huntington’s disease.” Human Genetics, 1992, 89: 365-76.
A fairly easy-to-read paper on the epidemiology of HD around the world as of 1992. Though a bit outdated, this is probably the best overall review article on this list.
- “Genetic background of Huntington’s disease in Croatia: molecular analysis of CAG, CCG, and Δ2642 (E2642del) polymorphisms.” Human Mutation, September 2002, 20 (3): 233.
A technical but clear explanation of the CAG, CCG, and GAG deletion patterns found in Croatia. Includes useful discussion of the varying Huntington gene alleles around the world.
- Morrison, PJ, et al. “The epidemiology of Huntington’s disease in Northern Ireland.” Journal of Medical Genetics, 1995, 32: 524-30.
A technical paper that discusses the prevalence of HD in Northern Ireland, the theory of HD origin in Europe, and the increased fertility among HD patients.
- Pridmore, SA and GC Adams. “The fertility of HD-affected individuals in Tasmania.” Australian and New Zealand Journal of Psychiatry, June 1991, 25 (2): 262-4.
A fairly technical paper on the increased fertility among presymptomatic HD patients in Tasmania, Australia.
- Rubinsztein, DC, et al. “Haplotype analysis of the delta 2642 and (CAG)n polymorphisms in the Huntington’s disease (HD) gene provides an explanation for an apparent ‘founder’ HD haplotype.”Human Molecular Genetics, February 1995, 4 (2): 203-6.
A technical paper on the GAG deletion, the CAG repeat lengths, and the chromosomes that are at risk for CAG codon expansion.
- Squitieri, F, et al. “DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence.” Human Molecular Genetics, December 1994, 3 (12): 2103-14.
A technical paper on the different Huntington gene alleles and their different ancestries around the world.
- Stine, OC and KD Smith. “The estimation of selection coefficients in Afrikaners: Huntington Disease, Prophyria Variegata, and Lipoid Proteinosis.” American Journal of Human Genetics, 1990, 46: 452-458.
A technical paper discussing the decreased fertility found among Afrikaners with HD.
- Walker, DA, et al. “Huntington’s chorea in South Wales: mutation, fertility, and genetic fitness.”Journal of Medical Genetics, 6 February 1983, 20 (1): 12-17.
A fairly technical paper on the increased fertility and fitness among presymptomatic HD patients in South Wales.
J. Czaja, 7/25/03