Because of natural selection, different
alleles are more likely to confer a survival advantage in different environments. Cycles
of infectious disease prevalence and virulence often reflect natural selection.
If natural selection eliminates individuals with detrimental phenotypes from a population,
then why do harmful mutant alleles persist in a gene pool? A disease can remain prevalent
when heterozygotes have some other advantage over individuals who have two copies of the
wild type allele. When carriers have advantages that allow a detrimental allele to persist
in a population, balanced polymorphism is at work. This form of polymorphism often
entails heterozygosity for an inherited illness that protects against an infectious
illness. Examples are fascinating.
Sickle Cell Disease
Sickle Cell disease is an autosomal recessive disorder that causes anemia, joint pain, a
swollen spleen, and frequent, severe infections. It illustrates balanced polymorphism
because carriers are resistant to malaria, an infection by the parasite Plasmodium
falciparum that causes cycles of chills and fever. The parasite spends the first stage
of its life cycle in the salivary glands of the mosquito Anopheles gambiae. When an
infected mosquito bites a human, the malaria parasite enters the red blood cells, which
transport it to the liver. The red blood cells burst, releasing the parasite throughout
In 1949, British geneticist Anthony Allison found that the frequency of
sickle cell carriers in tropical Africa was higher in regions where malaria raged all year
long. Blood tests from children hospitalized with malaria found that nearly all were
homozygous for the wild type of sickle cell allele. The few sickle cell carriers among
them had the mildest cases of malaria. Was the presence of malaria somehow selecting for
the sickle cell allele by felling people who did not inherit it? The fact that sickle cell
disease is far less common in the United States, where malaria is rare, supports the idea
that sickle cell heterozygosity provides a protective effect.
Further evidence of a sickle cell carrier's advantage in a
malaria-ridden environment is the fact that the rise of sickle cell disease parallels the
cultivation of crops that provide breeding grounds for Anopheles mosquitoes. About
1,000 B.C., Malayo-Polynesian sailors from southeast Asia traveled in canoes to East
Africa, bringing new crops of bananas, yams, taros, and coconuts. When the jungle was
cleared to grow these crops, the open space provided breeding ground for mosquitoes. The
insects, in turn, offered a habitat for part of the life cycle of the malaria parasite.
The sickle cell gene may have been brought to Africa by people
migrating from Southern Arabia and India, or it may have arisen by mutation directly in
East Africa. However it happened, people who inherited one copy of the sickle cell allele
had red blood cell membranes that did not admit the parasite. Carriers had more children
and passed the protective allele to approximately half of them. Gradually, the frequency
of the sickle cell allele in East Africa rose from 0.1 percent to a spectacular 45 percent
in thirty-five generations. Carriers paid the price for this genetic protection, whenever
two produced a child with sickle cell disease.
A cycle set in. Settlements with large numbers of sickle cell carriers
escaped debilitating malaria. They were therefore strong enough to clear even more land to
grow food- and support the disease-bearing mosquitoes. Even today, sickle cell disease is
more prevalent in agricultural societies than among people who hunt and gather their food.
Glucose-6-Phosphate Dehydrogenase Deficiency
G6PD deficiency is a sex-linked enzyme deficiency that affects 400 million people
worldwide. It causes life-threatening hemolytic anemia, in which red blood cells burst.
However, it develops only under specific conditions- eating fava beans, inhaling certain
types of pollen, taking certain drugs, or contracting certain infections. Studies on
African children with severe malaria show that heterozygous females and hemizygous males
for G6PD deficiency are underrepresented. This suggests that inheriting the enzyme
deficiency gene somehow protects against malaria.
The fact that G6PD deficiency is sex-linked introduces a possibility we
do not see with sickle cell disease, which is autosomal recessive. Because both
heterozygotes and hemizygotes are selected for, the mutant allele should eventually
predominate in a malaria-exposed population. However, this doesn't happen- there are still
males hemizygous and females homozygous for the wild type allele. The reason again relates
to natural selection. People with the enzyme deficiency- hemizygous males and homozygous
females- are selected out of the population by the anemia. Therefore, natural selection
acts in two directions on the hemizygous males- selecting for the mutant allele
because it protects against malarial infection, yet selecting against it because an
enzyme deficiency. This is the essence of balanced polymorphism.
Phenylketnonuria is an inborn error of metabolism in which a missing enzyme causes the
amino acid phenylalanine to build up, with devastating effects on the nervous system
unless the individual follows a restrictive diet. Carriers of this autosomal recessive
condition have elevated phenylalanine levels- levels that are not sufficiently high to
cause symptoms, but that are high enough that they may have a protective effect during
pregnancy. Physicians have observed that women who are PKU carriers have a much
lower-thanŠaverage incidence of miscarriage. One theory is that excess phenylalanine
somehow inactivates a poison, called ochratoxin A, that certain fungi produce and that is
known to cause spontaneous abortion.
History provides the evidence that links PKU heterozygosity to
protection against a fungal toxin. PKU is most common in Ireland and western Scotland, and
many affected families living elsewhere trace their roots to this part of the world. If
PKU carriers were most likely to have children than non-carriers because of the protective
effects of the PKU gene, over time, the disease-causing allele would increase the
Carrying Tay-Sachs disease may protect against tuberculosis (TB). In Ashkenazim
populations, up to 11 percent of the people are Tay-Sachs carriers. During World War II,
TB ran rampant in Eastern European Jewish settlements. Often, healthy relatives of
children with Tay-Sachs disease did not contact TB, even when repeatedly exposed. The
protection against TB that Tay-Sachs disease heterozygosity apparently offered remained
among the Jewish people because they were prevented from leaving the ghettos. The mutant
allele increased in frequency as TB selectively felled those who did not carry it and the
carriers had children with each other. Genetic drift may also have helped isolate the
Tay-Sachs allele, by chance, in groups of holocaust survivors. Precisely how lowered
levels of the gene product, an enzyme called hexoseaminidase A, protect against TB isn't
Balanced polymorphism may explain why cystic fibrosis is so common- the anatomical defect
that underlies CF protects against diarrheal illnesses, such as cholera.
Cholera epidemics have left their mark on human populations, causing
widespread death in just days. In the summer of 1831, an epidemic killed 10 percent of the
population of St. Louis, and in 1991, an epidemic swept Peru. Cholera bacteria causes
diarrhea, which rapidly dehydrates the body and can lead to shock and kidney and heart
failure. The bacterium produces a toxin that opens chloride channels in the small
intestine. As salt (NaCl) leaves the cells, water follows, in a natural chemical tendency
to dilute the salt. Water rushing out of intestinal cells leaves the body as diarrhea.
In 1989, when geneticists identified the CF gene and described its
protein product as a regulator of a chloride channel in certain secretory cells, a
possible explanation for the prevalence of the inherited disorder emerged. Cholera opens
chloride channels, letting chloride and water leave cells. The CFTR protein does just the
opposite, closing chloride channels and trapping salt and water in cells, which dries out
mucus and other secretions. A person with CF cannot contract cholera, because the toxin
cannot open the chloride channels in the small intestine.
Carriers of CF enjoy the mixed blessing of a balanced polymorphism.
They do not have enough abnormal chloride channels to cause the labored breathing and
clogged pancreas of cystic fibrosis, but they do have enough of a defect to prevent the
cholera from taking hold. During the devastating cholera epidemics that have peppered
history, individuals carrying mutant CF alleles had a selective advantage, and they
disproportionately transmitted those alleles to future generations. However, because CF
arose in Western Europe and cholera in Africa, perhaps an initial increase in CF
herterozygosity was a response to a different diarrheal infection.