Download Mutations and Genetic Disease There are more than 4,000 genetic

Mutations and Genetic Disease
There are more than 4,000 genetic diseases currently identified - most are very rare,
but some are relatively widespread, especially within certain ethnic groups. In
addition, genetic predispositions toward conditions such as high cholesterol, heart
disease,
and
cancer
have
been
found.
Most genetic diseases are caused by mutations - differences in the DNA of an
individual as compared to normal human DNA. Sickle cell anemia, a recessive
disorder characterized by chronic anemia, episodic joint pain, and crescent-shaped red
blood cells, is a relatively simple example. Interestingly, it should be noted that
carriers of the sickle-cell trait (people that possess one copy of the recessive gene, as
opposed to the two required for full-fledged disease) are almost exclusively of African
descent and seem to have an increased resistance to malaria. Since malaria is
widespread in many parts of Africa, this is a striking example of evolutionary
adaptation
in
humans.
The sickle cell mutation. One amino
acid out of a total 287 differs in sickle
cell haemoglobin compared with
normal haemoglobin. In the latter, the
triplet GAG (guanine, adenine,
guanine) codes for the amino acid
glutamic acid (left-hand diagram). In
sickle
cell
haemoglobin,
the
corresponding three-base sequence is
GTG (guanine, thymine, guanine)
which codes for the amino acid valine.
This substitution occurs sixth in line
from one of the ends of the beta
haemoglobin chain. [Hemoglobin
consists of two chains of animo acids,
the
alpha
and
beta
chain.]
This image and caption from The Book of Man by Walter Bodmer and Robin McKie.
The type of mutation exemplified in sickle cell anemia is called a substitution,
because one nucleotide base is substituted for another. Other types of mutations
include insertions and deletions, both of which can have disastrous consequences,
since they "throw off" the entire sequence of triplet codes from the point of mutation
to
the
"STOP"
code
at
the
end
of
the
gene.
In an insertion mutation, an extra base pair not normally present is added to the
code. For example, a normal DNA sequence of ATTGGCGTA would be translated
into triplet codes, obviously, as ATT GGC GTA. If an insertion mutation was present,
causing the code to read AATTGGCGTA, then the triplet translation would read AAT
TGG CGT A.... The end result would be a change in all amino acids on the protein
chain after the mutation. Insertion mutations often arise as a result of randomly adding
genes
in
gene-therapy
tests.
A deletion mutation, in which a base pair is subtracted from the normal code, works
much the same way. To use the same example, if the mutated code read
ATGGCGTA, then it would be translated into triplet code as ATG GCG TA.... The
end result is similar to that of an insertion mutation, with the exception that deletion
mutations are more common. Deletions of one or more base pairs have been
associated with certain bowel cancers and with the most common form of cystic
fibrosis, a disease characterized by unusually viscous mucus that impedes normal
respiratory and digestive function.
Chromosomes and Genetic Disease
Some genetic diseases are caused by possession of too many or not enough
chromosomes. Down's Syndrome, a common form of mental retardation, is caused by
possession of three copies of chromosome 21, instead of the usual two. Turner's
Syndrome, a condition that causes infertility and immature sexual development in
women, is due to the possession of only one X chromosome, instead of the two
always present in normal women. These types of diseases are caused by
nondisjunction, a failure in the distribution of chromosomes during meiosis.
Other genetic diseases are
caused
by
chromosome
translocation, in which small parts
of chromosomes break and rejoin
other chromosomes. Translocation
has been pinpointed as the cause of
chronic myeloid leukemia, a type
of cancer. It may be linked to other
cancers in the future.
Sex-Linked Diseases
With the exception of Turner's Syndrome, all the diseases mentioned so far have
been autosomal, or related to chromosomes 1 - 22 (that is, not related to the sex
chromosomes - X and Y). Sex-linked disorders are the opposite - related to the sex
chromosomes. These disorders, (also called X-linked), are recessive, involve the X
chromosome, and affect males almost exclusively. Females are virtually never
affected by these disorders because they possess two X chromosomes, both of which
would have to carry the defective gene in order for it to be manifested. Since these
females' fathers would be affected by the disorder, which is usually debilitating or
fatal, this is a highly unlikely situation. (Note that Turner's Syndrome, while related to
the
sex
chromosomes,
is
not
a
true
sex-linked
disorder.)
Examples of sex-linked disorders include Duchenne muscular dystrophy, a
progressive degeneration of muscle tissue; fragile-X syndrome, a common form of
mental retardation in boys; and hemophilia, a disease in which a deficiency in one of
several blood-clotting factors causes uncontrollable bleeding. This disease was made
famous by Queen Victoria of England, who was a carrier of the disease and spread it
throughout the European royal lines. Part of her family pedigree is shown below. The
Empress Alexandra of Russia (not shown), a descendant of Victoria and a carrier of
the disease, married the last Czar of Russia, Nicholas Romanov. The couple had four
daughters and a son, Alexei, who was affected by hemophilia. The couple allowed the
Siberian mystic Rasputin to enter their court because he seemed to control their son's
bouts of bleeding, but Rasputin's political influence and personal habits contributed to
the Czar's downfall during the Russian Revolution of 1917.
Dominant Genetic Diseases
Without exception, all the diseases mentioned so far have been recessive. Dominant
inherited diseases are very rare, because victims of these diseases tend to die before
reproducing, and thus passing on the gene for the disease. As a result, the few
dominant inherited diseases that do exist rarely manifest themselves before late
middle age. One example, called Huntington's chorea, has been described as "the most
demonic of diseases". Its symptoms include depression, dementia, exhaustion,
extreme weight loss, and constant jerking movements of the limbs - the hallmark of
the disease. Because it is a dominant disorder, a child of a Huntington's victim has a
50% chance of also succumbing to it. This simple pattern of inheritance has allowed
scientists to study the disease in detail.
Ethnic Heritage and Genetic Disease
Certain genetic diseases are often associated with specific ethnic groups. Sickle cell
anemia, as discussed above, is almost exclusively present in people of African
descent. Tay-Sachs disease, a fatal disorder that causes blindness and mental
retardation, is most prevalent in people of Jewish descent. The highest concentrations
of Tay-Sachs victims are among Jews of German or East European origin. (This has
been linked to the high incidence of tuberculosis in these regions.) Cystic fibrosis,
also mentioned above, most often affects people of Caucasian ethnicity. As discussed
before in the example of sickle cell anemia, the concentration of victims in people
from a particular area can reflect human evolutionary adaptation.
In summary, genetic diseases are diverse and varied. They have very different
genetic causes and origins, and they affect different ethnic populations. In addition,
some genetic diseases are caused by multiple defective genes inherited together, or by
different genes in different victims. Often, disease-causing genes are spread out over a
large part of a chromosome, or even over different chromosomes. Also inheritable are
genetic predispositions to other diseases such as cancer, AIDS, heart disease, high
cholesterol, and high blood pressure. All these facts make it difficult for genetic
researchers to track the genes that cause these diseases. However, with the help of the
Human Genome Project and new technology being developed, the genes will finally
be identified, and help will be available for the tragic victims of genetic diseases.