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.

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Created by Kate Stafford and Michael Mannor for ThinkQuest.
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