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Huntington's Chorea: Evolution and Genetic Disease
http://evolution.berkeley.edu/evolibrary/article/_0_0/
medicine_05
Huntington's chorea is a devastating human
genetic disease. A close look at its genetic origins
and evolutionary history explains its persistence
and points to a potential solution to this
population-level problem.
People who inherit this genetic disease have an
abnormal dominant allele that disrupts the
function of their nerve cells, slowly eroding their
control over their bodies and minds and
ultimately leading to death. In the fishing villages
located near Lake Maracaibo in Venezuela (see
map at left), there are more people with
Huntington's disease than anywhere else in the
world. In some villages, more than half the people may develop the disease.1
The people of Lake
Maracaibo.
How is it possible that such a devastating genetic disease is so common in some populations? Shouldn't
natural selection remove genetic defects from human populations? Research on the evolutionary genetics of
this disease suggests that there are two main reasons for the persistence of Huntington's in human
populations: mutation coupled with weak selection.
The diagram at left shows how the Huntington's allele is passed down. Since it is the dominant allele,
individuals with just one parent with Huntingtons's chorea have a 50-50 chance of developing the disease
themselves.
Mutation
In 1993, a collaborative research group discovered the culprit responsible for Huntington's: a stretch of DNA
that repeats itself over and over again, CAGCAGCAGCAG... and so on. People carrying too many CAGs in the
Huntington's gene (more than about 35 repeats) develop the disease. In most cases, those affected by
Huntington's inherited a disease-causing allele from a parent. Others may have no family history of the
disease, but may have new mutations which cause Huntington's.
If a mutation ends up inserting extra CAGs into the Huntington's gene, new Huntington's alleles may be
created. Of course it's also possible for a mutation to remove CAGs. But research suggests that for
Huntington's, mutation is biased; additions of CAGs are more likely than losses of CAGs.
Selection
As though that weren't bad enough, Huntington's belongs to a class of genetic diseases that largely escape
natural selection. Huntington's is often "invisible" to natural selection for a very simple reason: it generally
does not affect people until after they've reproduced. In this way, the alleles for late-onset Huntington's may
evade natural selection, "sneaking" into the next generation, despite its deleterious effects. Early-onset cases
of Huntington's are rare; these are an exception, and are strongly selected against.
Persistence
These mechanisms of evolution, mutation and selection, can help us understand the persistence of
Huntington's in populations. In general, Huntington's is rare — 30-70 cases per million people in most
Western countries — but it is not entirely eliminated because selection does a relatively poor job of weeding
these alleles out, while mutation continues creating new ones.
Dr. Nancy Wexler (shown at right tracking geneologies) has been studying
the remarkably high frequency of Huntington's in Lake Maracaibo since the
1970s. She has found that the high incidence of this disease there is
explained by an evolutionary event called the founder effect. About 200
years ago, a single woman who happened to carry the Huntington's allele
bore 10 children — and today, many residents of Lake Maracaibo trace their
ancestry (and their disease-causing gene) back to this lineage. A simple
fluke of history, high-birth rates, and weak selection are responsible for the
genetic burden shouldered by this population.
Solutions?
Currently, physicians don't have any cures for Huntington's disease — there's
no miracle pill that will stop the progress of the disease. However,
understanding the evolutionary history of the disease — a recurrent mutation
that is often "missed" by natural selection — points out a way to reduce the
frequency of the disease in the long term: allowing people to make more
informed reproductive choices.
Today, genetic testing can identify people who carry a Huntington's allele
long before the onset of the disease and before they have made their
reproductive choices. The genetic test that identifies the Huntington's allele
works sort of like DNA fingerprinting. A DNA sample is copied and cut into
pieces. The pieces are then spread out on a gel (see right). The banding
pattern can tell researchers whether a person carries an allele that is likely to
cause Huntington's.
Having this information could allow people to make more-informed
reproductive decisions. For example, at Lake Maracaibo, researchers and
health workers have tried to make contraception available to the local
population so that they can make reproductive choices based on their own
family history with the disease. But whatever people eventually decide to do
with this knowledge, a deep understanding of the disease would not be
possible without the historical perspective offered by evolution.
Comparing the banding patterns
in a genetic test can tell
researchers whether a person
carries an allele that is likely to
cause Huntington's.