What will be the impact of parasite resistance to antimalarial drugs on death in the population? Malaria is one of the few diseases for which we can predict the impact of the loss of drugs without an alternative form of control. We obtain these estimates of past and future malarial mortality from the frequencies of certain genes observed today.

J. B. S. Haldane (1) was the first to propose that infectious diseases were the main selective force for human evolution during the past 5000 years. In a recent study of diversity at the molecular level, Murphy (2) compared sequences of genes common between rodents and humans. It was found that host defense genes were more diverse than all other classes of proteins, suggesting that selection in mice and humans resulted from exposure to different microorganisms. In Europeans, tuberculosis has been a major selective force in evolution; in Africans, malaria was one of the major selective forces in their evolution and, as a result, many genes are known to confer a survival advantage. One of the best studied is the gene for hemoglobin S. From the frequency of the gene for hemoglobin S, it is possible to estimate the mortality from malaria by using the Hardy–Weinberg equation (3). It is assumed that mortality from malaria is the sole selective force for the gene. The mortality of hemoglobin SS in West Africa is 100% in childhood. In malaria-endemic areas, SA heterozygotes have a survival advantage compared with hemoglobin AA children. This selection of a deleterious gene by survival advantage for another disease (e.g., malaria) is referred to as a balanced polymorphism. In some areas of Africa, the mortality from malaria must have been as high as 25% to account for the hemoglobin S gene frequencies that we see today.

Another example of balanced polymorphism is a mutation in erythrocyte band 3, which causes a certain form of erythrocyte membrane defect known as Melanesian ovalocytosis. This mutation is a 27-base-pair (9 amino acid) deletion in band 3 (4). It is particularly common in Papua New Guinea, the only other area of the world with transmission of malaria to equal that seen in Africa. The ovalocytic erythrocyte is partially resistant to invasion by malaria parasites. Homozygosity for this mutation is 100% lethal during fetal development, the price that is paid for a deleterious gene that helps survival in heterozygous children.

The broader implications of the above studies are as follows. (i) Definitive studies on the population genetics of this disease were impossible before identification of the genetic defect because there are a number of causes of abnormally shaped erythrocytes in Papua New Guinea. It only now has been possible to study its gene frequency and the impact of the mutant allele on intrauterine lethality of the homozygote.

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