We saw in chapter 10 that selection has little effect on recessive disease traits because carriers do not exhibit the trait and therefore are not selected against. For example, in the case of PKU, 99 percent of the PKU genes are found in heterozygote carriers who are phenotyp-ically normal. This means that it takes an extremely long time for recessive traits, even lethal ones, to be eliminated from the population. Indeed, as the recessive form of the gene is eliminated in the form of unfit, homozygous affected individuals, a greater percentage of the disease gene is carried by phenotypically normal heterozygous individuals. Was there a reason for such disease traits to appear in fairly high numbers to begin with? Why are there differences between different ethnic groups for these and other diseases? We are finding out that the answers to these two questions reside in the fact that for many recessive diseases there is a heterozygous advantage to carrier individuals.
The classic case is that of a disease we already mentioned in chapter 3, sickle-cell anemia. Recall in the last chapter that the incidence of sickle-cell anemia is much higher (about 1 in 400) among African Americans than among Caucasian Americans, who show a frequency of around 1 in 2,500. Why is there such a disparity between these two ethnic groups? The answer lies in the genetic history of these two populations. African Americans came from tropical regions with high incidence of malaria, whereas most Caucasian Americans came from temperate regions in Europe, where malaria was not prevalent.
Individuals who are heterozygous for the sickle-cell trait do not, of course, exhibit sickle-cell anemia because the trait is recessive. However, these heterozygous individuals, it turns out, are more resistant to malaria. Malaria is a microbial infection spread by mosquitoes that carry the malaria parasite. When mosquitoes carrying parasites bite a person, the parasites enter the blood stream and the red blood cells of this individual. The parasites infecting the red blood cells make the inside of the cells acidic. This does not affect normal P-hemoglobin in the red blood cells of a person homozygous for the normal P-hemoglobin gene. As a result, the red blood cells of this person retain their normal shape, and infection by the parasite can continue. Death results if the infection is left untreated. However, if the red blood cells of an individual heterozygous for the sickle-cell trait becomes acidic, the red blood cell takes on a sickle shape due to the mutated P-hemoglobin. The abnormal shape of the red blood cells signals the body to eliminate them. Thus, the malaria infection cannot proceed and the infected person survives.
This mutation, then, in the heterozygous state, provides a selective advantage to people living in areas where malaria is prevalent. Of course, it does not provide any advantage to people who do not experience malaria. The sickle-cell trait is debilitating to homozygous individuals and is thus a selective disadvantage. The selective advantage it provides to heterozygous individuals offsets this disadvantage and maintains a higher proportion of sickle-cell trait in the population than one would otherwise expect. This is a classic example of heterozygous advantage that maintains a disease gene in a population.
More recently, a mutation in another gene called G6PD (glucoses-phosphate dehydrogenase), which codes for an enzyme necessary for red blood cells to obtain energy from glucose, has also been found to exhibit heterozygous advantage. Certain mutations in G6PD, which in the homozygous state causes anemia, also provide resistance to malaria infection in the heterozygous state. Similarly, mutations in other genes for proteins found in red blood cells are thought to confer selective advantage in resistance to malaria. Malaria may have been quite prevalent for a long time and thus a strong selective force acting on the genetic makeup of peoples from tropical regions.
A last example of heterozygous advantage is that of PKU, a disease you have heard about already in chapters 3 and 10. As with sickle-cell anemia, homozygous, recessive individuals are highly disadvantaged.
However, again as with sickle-cell anemia, scientists postulate that the PKU trait provides a selective advantage to heterozygous individuals. The mild, damp climate of the British Isles is conducive to the growth of molds in grains and other stored foods. These areas also suffered repeated widespread famines. When one is starving, moldy food is better than no food. Molds have toxins that, among other things, cause spontaneous abortion. However, women heterozygous for the PKU trait appear to have had a lower spontaneous-abortion rate than women homozygous for the normal gene. Thus, the presence of the PKU trait in a heterozygous condition could have favored the survival of offspring from heterozygous women who resorted to eating toxic, moldy food. This would have favored the persistence of the PKU gene in populations where a combination of periodic starvation and moldy foods existed.
As we understand more about the evolution of genetic traits in humans, other recessive genetic diseases for which there is heterozygous advantage may be recognized. For example, cystic fibrosis is another disease that is postulated to confer heterozygous advantage in areas with diarrheal diseases.
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