Sickle-cell anemia is the classic example of a disease of a disease caused by a gene that is also useful. Normal hemoglobin in red blood cells carries oxygen from the lungs to the rest of the body, and picks up carbon dioxide and carries it back to the lungs. People with sickle-cell disease, hemoglobin doesn’t hold onto oxygen well (Christensen 2000).

Sickle-cell anemia is a hereditary disease that affects the blood in males and females and occurs mainly in the African race. Aside from Africa, the disease also occurs in the Middle East, the Mediterranean area, India, and in the black communities of the United States and a few other areas in the Western Hemisphere. Sickle-cell anemia is caused by the inheritance of an abnormal hemoglobin (Hb S) gene from both parents. A person who inherits the sickle-cell gene from one parent and a normal hemoglobin gene (Hb A) from the other parent is a carrier of the sickle-cell trait. Furthermore, when two people who carry the trait have a child together, there are three possible gene pair combinations that could be passed to their offspring:

The sickle-cell allele is unusual for three reasons. First, it is not widely distributed, being originally found almost exclusively in people of tropical African descent. Second, the hemoglobin alteration is a simple sort of adaptation. Most adaptations, such as color vision or the capacity for fever, are complex, closely regulated systems whose assembly requires many genes.

The order of the gene synthesized two 19-base-long oligonucleotides, 1 complementary to the 5-prime end of the normal beta-globin gene and 1 complementary to the sickle cell gene. By contrast, the sickle-cell allele differs from that for normal hemoglobin only by a single-cell allele differs from that for normal hemoglobin only by a single T substituted from a single A. When this genetic code is translated into the protein hemoglobin, the amino acid valine ends up where glutamic acid should be causing a mutation. It is this molecular change that gives the blood cell its abnormal shape and other properties. Third, there is extraordinarily strong selection acting on one gene locus. It may well be that heterozygote advantage is common in human populations, but when selection against homozygotes is weak, the effect is hard to demonstrate. Normal red blood cells live about 120 days, whereas sickle-shaped red cells don’t live nearly as long – only 15-25 days (Accordant 2000)

By high-resolution chromosome sorting of human chromosomes carrying segements of chromosome 11 and by spot blotting with various gene-specific probes, it was concluded that the loci for parathyroid homone, beta-globin, and insulin were all located on 11p15. By in situ hybridization studies of chromosome 11 rearrangements, HBB was also assigned to 11p15. The beta hemoglobin structure can be seen here along with the helix one-letter amino acid sequence.
 

The gene that causes sickle-cell disease occurs mostly in people from parts of Africa where malaria has been prevalent. A person who is heterozygous for this gene gets substantial protection from malaria because the gene changes the hemoglobin structure in a way that speeds the removal of infected cells from the circulation. Homozygotes, however, get sickle-cell disease. Their red blood cells twist into a crescent or sickle shape that cannot circulate normally, thus causing bleeding, shortness of breath, and pain in bones, muscles, and the abdomen. Because of their resistance to malaria, heterozygotes are favored over both kinds of homozygotes. Homozygotes for the sickle-cell disease, while homozygotes for the normal allele have low fitness resulting from their vulnerability to malaria. The relative strength of these two selective forces determines the allelic frequencies. Thus, a gene that causes a lethal childhood illness and a gene that makes one susceptible to malaria can both be maintained at high frequencies in the population. Malaria was probably endemic in southern Italy from ancient times until the 1940’s, when the Anopheles mosquitoes that carry it were largely eradicated with DDT (Cochran and Ewald 1999).

In areas where malaria is rare, you would expect the sickle-cell allele to decrease in frequency. Indeed, African Americans, many of whom have lived in malaria-free regions for ten generations, show a lower sickle-cell frequency than Africans, lower than any admixture with Caucasian genes would explain. It appears that selection has been decreasing the frequency of the sickle-cell gene in regions where malaria is unimportant, as would be expected from evolutionary theory.

Like sickle-cell anemia, hemoglobin C in northwest Africa and hemoglobin E in Southeast Asia are scorched-earth defenses- they defend against malaria and are also caused by a change in a single amino acid on the hemoglobin molecule. Another malarial defense, Melanesian ovaloctosis, is caused by a mutation that alters red blood cell membranes.
 

So what accounts for the evolution of such seemingly crude and self-destructive defenses? Sometimes a crude defense may be better than none at all, and crude defenses are easy to generate. While most adaptations involve an orchestration of several genes, self-destructive defenses typically consist of a simple change that interferes with only one gene’s primary function. Even though such mutations may harm us by altering biological machinery fine-tuned over millennia by natural selection, they help us by interfering with the similarly finely calibrated mechanisms of an infectious adversary. When the sickle-cell gene first appears, it is beneficial to the host, who may then pass on single copies of the new mutant to a few offspring. Those who inherit it have a survival advantage because they cannot be felled by a widespread cause of death-malaria. Even though the genetic basis of this disease have been well established, it has been difficult to develop gene therapy-based treatment because globin gene expression is highly regulated and has been difficult to recapitulate after gene transfer (Lan et al. 1998).

If only one in ten carries the defense gene, there may be little or no selection pressure favoring a mutant form of the pathogen. The malarial parasite continues to perpetuate itself by infecting the 90 percent of people who lack the defense gene entirely. To some people, sickle-cell anemia demonstrates that natural selection is such a feeble process that it cannot generate an effective defense against malaria without botching up the blood system. However, the evolutionary reasoning offers an alternative viewpoint showing that selection may be continually presenting effective defenses against many terrible diseases, but such defenses are not apparent because selection is acting powerfully on both host and pathogen. As a consequence, the effective defense of one era becomes the impotent defense of a later era. In addition, because the malaria protozoa are more damaging than most other parasites, the defenses against them offer greater fitness benefits; hence, more incidental harm can be tolerated. Self-destructive defenses against milder pathogens may also exist, but scientists may have overlooked them because so few people have two copies of the defense genes.

Many genes that cause disease such as the sickle-cell allele have actually been selected for because they provide benefits, either to the bearer or to other individuals with the gene in other combinations (Neese and Williams 1994). For this reason, it is important to educate people about this allele.Marked differences exist across the United States in mortality of young black children with sickle cell disease. To improve survival for children with the disease in high mortality areas, evaluations should be made of the accessibility and quality of medical care, and of parents’ health care seeking behavior and compliance with antibiotic prophylaxis. In addition, efforts should be made to understand and duplicate the success of treatment programs in low mortality areas (Davis 1997).

The evolutionary relationships among a group of different animals can be examined by comparing the sequence of amino acids that compose a common protein, for example, the beta subunit of hemoglobin. As the evolutionary distance between two animals increases, so does the number of differences in the amino acid seqeuence of the beta-globin protein.

A comparison of the amino acid sequence of the beta-globin protein of a human with that of seven other animals (gorilla, rabbit, cow, mouse, goat, chicken and carp) is shown here. Based on these differences, it is possible to construct a "phylogenetic tree" that illustrates the relatedness of these different animals:

From this tree it is possible to see that the Human and Gorilla beta globin proteins diverged from a common ancestor comparatively recently, indeed there is only one amino acid difference between the two proteins. This process can be continued down to Carp beta globin which is only 53% identical to the human protein, indicating they are much less related to one another.

Christensen, Damaris. “No news: Nitric oxide may help treat sickle cell anemia.”

Science News. 29 Jan 2000. 157(5):78-79.

Cochran, Gregory and Paul W. Ewald. “High-risk defenses.” Natural History. 1999 Feb. 108(1): 40-43.

Davis, Harold, Peter J. Gergen, and Roscoe M. Moore, Jr. “Geographic differences in mortality of young children with sickle cell disease in the United States.” Public Health Reports. 1997 Jan. 112(1):52-58.

Helix and Turns. Swiss-Prot. Cited 15 April 2001.
http://www.expasy.ch/cgi-bin/niceprot.pl?P02023

Huskey, Robert J. Beta Globin Gene Sequence. Cited 15 April 2001. http://www.people.virginia.edu/~rjh9u/bglobin.html.

Lan, Ning, Richard P. Howrey, Lee Seong-Wook, Clayton A. Smith, and Bruce A. Sullenger.

Ribozyme-mediated repair of sickle (beta-globin) mRNAs in erythrocyte precursors.Science. 5 June 1998. 280(5369): 1593-1596.

Neese, Randolph M. and George C. Williams. Why We Get Sick: The New Science of Darwinian Medicine. Random House, Inc. New York. 1994. Pg. 10, 98-99.

Pairwise Alignments of Human vs Animal Beta Globin." Cited 2 May 2001.
   

Serjeant, Graham R. “Sickle-cell disease.” Lancet. 6 Sept 1997. 350(9079): 725-730.

“Sickle-cell Anemia.” Accordant Health Services. http://www.help4sickecellanemia.com Cited 21 March 2001.