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 A105 Human Origins and Prehistory
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Sickle Cell Anemia Text

CASE STUDIES OF NATURAL SELECTION
 This section provides several examples of natural selection in human populations. Because natural selection operates differently on different loci, the focus will be on individual loci or traits rather than on specific populations.

Hemoglobin, Sickle Cell, and Malaria

     Perhaps the best-known example of natural selection operating on a discrete genetic trait is the relationship of hemoglobin variants to malaria. One of the proteins in red blood cells is hemoglobin. which functions to transport oxygen to body tissues. The normal structure of the beta chain of hemoglobin is coded for by an allele usually called hemoglobin A.

    In many human populations, the A allele is the only one present, and as a result everyone has the AA, or normal adult hemoglobin, genotype.

HEMOGLOBIN VARIANTS. Many hemoglobin variants are produced by the mutation of an A allele to another form. The most widely studied mutations include hemoglobin S, C, and E. The S allele is also known as the sickle cell allele. A person who has two S alleles (genotype SS) has sickle cell anemia, a condition whereby the structure of the red blood cells is altered and oxygen transport is severely impaired.  Roughly, only 15 percent of those with genotype SS survive to adulthood. An estimated 100,000 deaths per year throughout the world are from sickle cell anemia. 

   If the S allele is harmful in homozygotes, we expect natural selection to eliminate S alleles from the population in such a way that the frequency of S should be relatively low. Mutation introduces the S allele, but natural selection eliminates it. Indeed, in many parts of the world the frequency of S is extremely low, fitting the model of mutation balanced by selection. In a number of populations, however, the frequency of S is much higher – often up to 10 to 20 percent. Such high frequencies seem paradoxical, given the harmful effect of the S allele in the homozygous genotype. Why does S reach such high frequencies? Genetic drift might seem likely, except for the definite association of geography and higher frequencies of S. That is, higher frequencies of S occur only in certain environments. Genetic drift is random and influenced by population size, not environment. If genetic drift were responsible for the high frequencies of S, we would expect to see high frequencies in isolated groups in many different environments.

DISTRIBUTION OF THE SICKLE CELL ALLELE AND MALARIA. T'he distribution of the sickle cell allele is related to the prevalence of a certain form of malaria. Malaria is an infectious disease – that is, a disease caused by the introduction into the body of an organic foreign substance, such as a virus or parasite (a disease that is not caused by an organic foreign substance is a noninfectious disease). Malaria is caused by a parasite that enters an organism's body, and four different species of the malarial parasite can affect humans. Malaria remains one of the major infectious diseases in the world today. In the late 1970s, as many as 120 million people in the world had some form of malaria (Encyclopaedia Britannica 1988).

     The Old World shows a striking correspondence between higher frequencies of the S allele and the prevalence of malaria caused by the parasite Plasmodium falciparum. This parasite is spread through the bites of certain species of mosquitoes. Except for blood transfusions, humans cannot give malaria to one another directly. Those areas with frequent cases of malaria such as Central Africa, also have the highest frequencies of the sickle cell allele. The falciparum form of malaria, the most serious of all forms of malaria, is often fatal.

   The strong geographic correspondence suggests that sickle cell anemia and malaria are both related to the high frequencies of the S allele. Further experimental work has confirmed this hypothesis. Because the S allele affects the structure of the red blood cells, it makes the blood an inhospitable place for the malaria parasite.

       In a malarial environment, people who are heterozygous (genotype AS) actually have an advantage. The presence of one S allele does not give the person sickle cell anemia, but it does change the blood cells sufficiently so that the malaria parasite does not have as serious an effect. Overall, the heterozygote has the greatest fitness in a malarial environment. As discussed in Chapter 3, this is a case of balancing selection, in which selection occurs for the heterozygote (AS) and against both homozygotes (AA from malaria and SS from sickle cell anemia).

       In addition to greater survival of the heterozygote in malarial environments, it has also been suggested that women with genotype AS have greater fertility. If so, then is selection for the heterozygote in environments with malaria a function of differential mortality, differential fertility, or both? Madrigal (1989) studied this problem by examining the hemoglobin genotype and reproductive histories of women in Limon, Costa Rica. She found that there was no difference between AA and AS women for a number of measures of differential fertility (family size, number of pregnancies, number of live births, and number of spontaneous abortions).

      If the effects of sickle cell anemia and malaria were equal, then we would expect the frequencies of the normal allele (A) and the sickle cell allele (S) ultimately to reach equal frequencies. The two diseases, however, are not equal in their effects. Sickle cell anemia is much worse. The balance between these two diseases is such that the maximum fitness of an entire population occurs when the frequency of S is somewhere between 10 and 20 percent.

     An analysis of one African population suggests that for every 100 people with AS who survive to adulthood, 88 people with AA survive and only 14 of those with SS (Bodmer and Cavalli-Sforza 1976). Clearly, the relationship between hemoglobin, sickle cell anemia, and malaria represents a very strong case of natural selection. Instead of a difference in survival between genotypes of only several percent, the differences are quite striking. Such differences can lead to major changes in allele frequencies in a very short period of time. To illustrate the rapidity of such change, Figure 14.10 shows a hypothetical example of changes in the frequency of the sickle cell allele. In this example, the initial frequency of S from mutation was set equal to a reasonable estimate of 0.00001. The fitness values mentioned earlier were used to examine the kind of change in the frequency of S that could take place. Because the initial allele frequency is low, there is little change for the first 40 generations or so. (Of course, if the initial allele frequency were higher, the rate of change would be greater; a higher initial frequency could occur due to genetic drift or the initial occurrence of the mutation in a small population.) As the frequency of S increases, change takes place more rapidly because there are more people with the AS genotype to be selected for. After 100 generations, there is little change in the frequency of the S allele because it has reached an equilibrium based on the balance between the effects of sickle cell anemia and malaria. In this example, the sickle cell allele would reach an equilibrium frequency of 0.122. Of course, this simple illustration does not take other evolutionary forces into account, but it does show how quickly allele frequencies can change under strong natural selection.

    The sickle cell example clearly shows the importance of the specific environment on the process of natural selection. In a nonmalarial environment, the AS genotype has no advantage, and the AA genotype has the greatest evolutionary fitness. In such cases, the frequency of the S allele is very low, approaching zero. In a malarial environment, however, the situation is different, and the heterozygote has the advantage. Clearly, we cannot label the S allele as intrinsically "good" or "bad"; it depends on circumstances.

      The example of sickle cell also shows that evolution has a price. The equilibrium is one in which the fitness for the entire population is at a maximum. The cost of the adaptation, however, is an increased proportion of individuals with sickle cell anemia because the frequency of S has increased. People with the heterozygous genotype AS have the greatest fitness, but they also carry the S allele. When two people with the AS genotype mate, they have a 25 percent chance of having a child with sickle cell anemia (in the previous example, 1.5 percent of all children in a population is expected to have the SS genotype). This is not advantageous from the perspective of the indi. vidu;il with the disease. From the perspective of the entire population, however, it is the most adaptive outcome. Every benefit in evolution is likely to carry a price.