Multiple alleles

SIGNIFICANCE: Alleles are alternate forms of genes at the same locus. When three or more variations of a gene exist in a population, they are referred to as multiple alleles. The human ABO blood groups provide an example of multiple alleles.

The Discovery of Alleles and Multiple Alleles

Although Gregor Mendel, considered to be the father of genetics, did not discover multiple alleles, an understanding of his work is necessary to understand their role in genetics. In the 1860s, Mendel formulated the earliest concepts of how traits or characteristics are passed from parents to their offspring. His work on pea plants led him to propose that there are two factors, since renamed “genes,” that cause each trait that an individual possesses. A particular form of the gene, called the “dominant” form, will enable the characteristic to occur whether the offspring inherits one or two copies of that allele. The alternate form of the gene, or allele, will be exhibited only if two copies of this allele, called the “recessive” form, are present. For example, pea seeds will be yellow if two copies of the dominant, yellow-causing gene are present and will be green if two copies of the recessive gene are present. However, since yellow is dominant to green, an individual plant with one copy of each allele will be as yellow as a plant possessing two yellow genes. Mendel discovered only two alternate appearances, called phenotypes, for each trait he studied. He found that violet is the allele dominant to white in causing flower color, while tall is the allele dominant to short in creating stem length.

Early in the twentieth century, examples of traits with more than an either/or caused by only two possible alleles were found in a variety of organisms. Coat color in rabbits is a well-documented example of multiple alleles. Not two but four alternative forms of the gene for coat color exist in rabbit populations, with different letters used to designate those colors. The gene producing color is labeled c; thus, c⁺ produces full, dark color;c^ch produces mixed colored and white hairs; c^h produces white on the body but black on the paws; and c creates a pure white rabbit. It is important to note that although three or more alternative forms can exist in a population, each individual organism can possess only two, acquiring only one from each of its parents. What, then, of Mendel’s principle of one allele being dominant to the other? In the rabbit color trait, c⁺ is dominant to c^ch, which is dominant to c^h, with c, the gene for pure white, recessive to the other three.

If mutation can create four possible color alleles, is it not also possible that successive mutations might cause a much larger number of multiple alleles? Numerous examples exist of genes with many alleles. For example, sickle-cell disease, and related diseases called thalassemias, are all caused by mutations in one of the two genes that code for the two protein subunits of hemoglobin, the protein that carries oxygen in the blood. Dozens of different types of thalassemia exist, all caused by mutations in the same gene.

Blood Types

One of the earliest examples of discovered in humans concerns the ABO system. In 1900, the existence of four blood types (A, B, AB, and O) was discovered. The study of pedigrees (the family histories of many individuals) revealed by 1925 that these four blood types were caused by multiple alleles. The alleles are named I^A, I^B, I^O, or simply A, B, and O. Both A and B are dominant to O. However, A and B are codominant to each other. Thus, if both are present, both are equally seen in the individual. A person with two A alleles or an A and an O has type A blood. Someone with two B alleles or a B and an O has type B. Two O alleles result in type O blood. Because A and B are codominant, the individual with one of each allele is said to have type AB blood.

To say people are “type A” means that they have an antigen (a glycoprotein or protein-sugar molecule) of a particular type embedded in the membrane of all red blood cells. The presence of an A allele causes the production of an that transfers the sugar galactosamine to the glycoprotein. The B allele produces an enzyme that attaches a different sugar, called galactose, and the O allele produces a defective enzyme that cannot add any sugar. Because of codominance, people with type AB blood have both antigens on their red blood cells.

Transfusion with blood from a donor with a different blood type from the recipient can cause death, due to the potential presence of A or B antibodies in the recipient’s blood. Antibodies are chemical molecules in the plasma (the liquid portion of the blood). If, by error, type A blood is given to a person with type B blood, the recipient will produce antibodies against the type A red blood cells, which will attach to them, causing them to agglutinate, or form clumps. By this principle, people with type O blood can donate it to people with any blood type, because their blood cells have neither an A nor a B antigen. Thus, people with type O blood are often referred to as universal donors because no antibodies will be formed against type O red blood cells. Likewise, people with type AB blood are often referred to as universal recipients because they have both types of antigens and therefore will not produce antibodies against any of the blood types. Medical personnel must carefully check the blood type of both the recipient and the donated blood to avoid agglutination and subsequent death.

Blood types have been used to establish paternity because a child’s blood type can be used to determine what the parents’ blood types could and could not be. Since a child receives one allele from each parent, certain men can be eliminated as a child’s potential father if the alleles they possess could not produce the combination found in the child. However, this proves only that a particular person could be the father, as could millions of others who possess that blood type; it does not prove that a particular man is the father. Current methods of analyzing the DNA in many of the individual’s genes now make the establishment of paternity a more exact science.

Impact and Applications

The topic of multiple alleles has implications for many human disease conditions. One of these is cystic fibrosis (CF), the most common deadly inherited disease afflicting Caucasians. Characterized by a thick mucus buildup in the lungs, pancreas, and intestines, it frequently brings about death by age twenty. Soon after the gene that causes CF was found in 1989, geneticists realized there may be as many as one hundred multiple alleles for this gene. The extent of the mutation in these alternate genes apparently causes the great variation in the severity of symptoms from one patient to another.

The successful transplantation of organs is also closely linked to the existence of multiple alleles. A transplanted organ has antigens on its cells that will be recognized as foreign and destroyed by the recipient’s antibodies. The genes that build these cell-surface antigens, called human leukocyte antigen (HLA), occur in two main forms. HLA-A has nearly twenty different alleles, and HLA-B has more than thirty. Since any individual can have only two of each type, there is an enormous number of possible combinations in the population. Finding donors and recipients with the same or a very close combination of alleles is a very difficult task for those arranging successful organ transplantation.

Geneticists are coming to suspect that multiple alleles, once thought to be the exception to the rule, may exist for the majority of human genes. If this is so, the study of multiple alleles for many disease-producing genes should shed more light on why the severity of so many genetic diseases varies so widely from person to person.

Key terms

• blood typeone of the several groups into which blood can be classified based on the presence or absence of certain molecules called antigens on the red blood cells
• codominant allelestwo contrasting alleles that are both fully functional and fully expressed when present in an individual
• dominant allelean allele that masks the expression of another allele that is considered recessive to it
• recessive allelean allele that will be exhibited only if two copies of it are present

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