Download Case Study: Genetic Disorders as Models for Evolution

Case Study: Genetic Disorders as Models for Evolution
Background Information:
Human genetic disorders are useful models for studying evolution. Because of their implications
for human populations, there is more incentive to study genetic disorders than to study the
inheritance and evolution of normal characteristics. Individuals with genetic disorders are often
readily identifiable in the larger population. Many disorders are associated with specific
populations, reflecting not only differences in lifestyle, but often differences in patterns of genetic
inheritance as well. Furthermore, studies of genetic disorders frequently provide evidence of long
periods of geographic and genetic isolation within the human population. Examples of disorders
that place certain groups and their descendants at a higher risk than others are: cystic fibrosis
and European whites; diabetes and Pacific Islanders; sickle-cell anemia and African blacks; and
Tay-Sachs and eastern European Jews.
Many of the well known inherited disorders are classified as autosomal, recessive disorders. They
result from point, or gene, mutations that cause errors in the body’s metabolism. The recessive
alleles can persist at fairly high frequencies in populations because heterozygous members may
still survive and reproduce; only one normal allele is necessary to carry out the specific function.
Two extensively studied recessive disorders are sickle-cell anemia and Tay-Sachs disorder. In
both cases, the condition is expressed in homozygous, recessive individuals and is usually fatal.
The heterozygotes (or carriers) are usually symptom-free but contain some advantage to being
heterozygous.
Sickle-Cell Anemia:
Discovered by a Chicago physician in the early 1900s, this disease gets its name from the sickleshaped red blood cells found in the blood of those who have the condition. While rare in most
human populations, it is common in certain groups of African blacks and in those of African
descent. Sickle-cell anemia causes general body pains, loss of appetite, yellowish eyes, a low
resistance to infection, and shortness of breath. Death usually occurs in early childhood, but a
few cases are known to have survived to adulthood.
It was Dr. Linus Pauling, a noted chemist and double Nobel prizewinner, who uncovered the
reason for the presence of sickle cells in individuals with the disorder. By analyzing the
hemoglobin molecules from patients’ blood, he concluded that the sickle cells occur when on
amino acid (valine) is substituted for another (glutamic acid) in one of the four chains of the
hemoglobin molecule. He determined that the change in the shape of red blood cells occurs when
oxygen levels are low (e.g., at high altitudes, during physical exertion, and so on) and is
irreversible.
Since specific amino acids can only be produced from the existing genes within a gene pool,
Pauling’s work demonstrates the importance of the gene to the production of variation (change) in
a population. The shuffling of genes in the process of inheritance provides great variation in gene
combinations. The sickle-cell trait, like other genetic traits, is inherited by a simple Mendelian
A
S
pattern. The genotype of the carrier with the defective gene is written Hb Hb where Hb is the
symbol for hemoglobin and the subscripts A and S represent the genes for normal hemoglobin
and the sickle-cell gene respectively.
a) Write the genotypes of the offspring from a cross between two carriers of the sickle-cell
gene. Complete a punnett square for the following cross. What is the probability that the
couple will have a normal child and what is the probability that they will have a child with
the sickle-cell disorder?
b) What is the probability that a child born of a normal parent and a carrier parent would be
a normal child? A child with the sickle-cell disorder?
c) Why would there be no concern about the offspring of two homozygous individuals
having the sickle-cell disorder?
d) How does Pauling’s discovery provide an answer to the observation that carriers
experience mild “sickling” during exercise?
One biological deduction from this information might be that the recessive allele will eventually
disappear from the population through natural selection. However, this has not happened. As
many as 40% of the population in certain parts of Africa and 10% of Americans of African descent
still carry the trait. What accounts for the frequency of the sickle-cell gene remaining relatively
constant over the years? Interestingly, areas with high levels of sickle-cell anemia also display a
high incidence of the parasite responsible for malaria. The mild sickling trait expressed by
heterozygous individuals might provide some measure of protection against the malaria parasite.
e) What selective advantage is afforded heterozygous individuals in certain African
populations?
f) What might happen to the frequency of the sickle-cell gene if malaria were eliminated in
Africa?
g) Estimates suggest that the frequency of the sickle-cell gene in North American blacks
has decreased from 22% in the early slavery period to a current value of 10% or less.
What might explain this difference?
Tay-Sachs Disorder:
Tay-Sachs disorder is also helping scientists understand how genetic disorders evolve, as well as
providing insight into precisely how genes (even lethal ones) can persist and spread over the
centuries. Tay-Sachs, which occurs in the general population in one out of every 400 000 births,
was co-discovered by W. Tay, a British Ophthalmologist, and B. Sachs in 1880. A notable
exception to its occurrence is found in the eastern European Jewish population known as the
Ashkenazim. In this group, the Tay-Sachs disorder is 100 times more frequent – about one in
3600 births.
The condition causes a deterioration of the central nervous system and becomes noticeable in
infants at about six months after birth. Babies with the disorder lose much of their motor control,
have convulsions, and usually die between the ages of two and four years. As with sickle-cell
anemia, the genotypes of individuals with Tay-Sachs are homozygous recessive. Carriers of the
trait are generally unaffected by the presence of the defective gene.
The cause of the disorder was not determined until 1962, when researchers discovered that
people with Tay-Sachs lacked a gene that produces the enzyme B-N-hexo-saminidase A (Hex A).
Hex A is required to control excessive accumulation of a fatty substance in body cells, especially
nerve cells. Normally, fat is present only in modest levels in cell membranes because it is
constantly being broken down by Hex A. A deficiency of the enzyme alters the metabolism of the
fat, which then accumulates around the nerve sheath and in time destroys the nerve cells.
h) Illustrate a cross between two parents that are carriers for the Tay-Sachs condition and
predict what percentage of their potential offspring will have the disorder.
i) Why can scientists be certain that each parent must have had at least one good copy of
the gene along with the defective copy?
j) What similarities exist between the biochemical abnormalities that cause sickle-cell
anemia and those that cause Tay-Sachs disorder?
k) Explain how scientists recognize that the selection pressure against Tay-Sachs disorder
is high?
To understand why there is an excessively high risk of Tay-Sachs disorder among the
Ashkenazim, two unique features associated with the group must be examined. One concerns
history and lifestyle, and the other relates to a potential selective advantage bestowed by the
gene on carriers of the disease.
The lifestyle of the Ashkenazim has been unique among the world’s ethnic groups. As a result of
certain events over the past several thousand years, including war and various forms of
persecution, the population has remained isolated from the general European population. Some
reports suggest that this lifestyle has kept intermarriage with other groups down to a mere 15%.
Another manifestation of the population’s isolation is their susceptibility to 10 other genetic
disorders that do not occur to the same extent in other Jews or eastern European non-Jews.
The most plausible hypothesis put forward to explain the high frequency of the Tay-Sachs gene
suggests a potential selective advantage conferred upon carriers of the disorder. In 1972, a
questionnaire administered to parents of Tay-Sachs children in the USA produced a surprising
piece of valuable information. The majority of the children’s grandparents who did not emigrate
from the old country died of common causes such as stroke or heart attack. Only one of the 306
grandparents died of tuberculosis, even though TB was a common killer during their youth. A
follow-up study, a decade later, on the distribution of TB and Tay-Sachs gene within Europe
revealed that the Tay-Sachs gene was three-times more frequent among the eastern European
Jews (9% to !0% of the population were heterozygous) than among other populations of
European Jews. If the recessive gene did lend some measure of protection against TB, then the
gene should occur more in areas with a high incidence of TB.
The ghetto conditions in which the eastern European Jews were forced to live is also an
environment in which TB thrives. With little or no intermarriage, some investigators believe that
the ghetto-bound population was under the strongest pressure to evolve genetic resistance to TB.
l) What are the two selection pressures acting on the eastern European Jewish population?
m) The Tay-Sachs recessive gene has survival value in areas where there is a high
incidence of TB. How does natural selection operate in its favor in these areas?
n) What significance can be attached to the fact that eastern European Jews are
susceptible to 10 other genetic disorders that are not found in other Jewish and nonJewish populations?
o) How does this case illustrate that evolution results from the interaction between an
organism’s genetic makeup and its environment?
Case Study Application Questions:
1. How are the factors in the evolutionary process illustrated in this case study? In your
answer consider the ideas of mutation, natural selection, and survival value.
2. What advice should a genetics counselor give to carriers who are contemplating giving
birth to a child?
3. What is the meaning of the statement, “Recessive genetic disorders can be both a
blessing and a curse?”