II. Selection in the past.

III. Present-day selection.

Terms

I. Natural selection may favor a heterozygote rather than either homozygote. This creates a balanced polymorphism. At equilibrium, the number of alleles lost from lack of fitness of one homozygote equals the number of alleles lost from lack of fitness of the other homozygote. Deviation from an equilibrium value for the allele frequences is offset by selection against the excess homozygotes.

Example: Sickle cell anemia is one of several diseases maintained in tropical areas by heterozygote advantage in the presence of falciparum malaria. There are a number of polymorphic markers in the vicinity of the beta-globin locus. The Hb S mutation occurs on four of the large number of marker combinations (haplotypes). This suggests that the Hb S mutation has occurred independently at least four times, and each mutation has expanded enormously in frequency because of greater fitness.

A. Diabetes mellitus type II has been suggested as a "thrifty genotype" under the feast-or-famine conditions that must have existed in primitive hunting-and-gathering societies. The disadvantage associated with late-onset diabetes at that time would not have been large, since the average life span of adults was short because of competing causes of death.

B. Such major epidemics as the Black Death (bubonic plague) in the Middle Ages could have had significant impact on the frequencies of any alleles that made individuals more sensitive or more resistant to infection or to the physiological effects of infection. Typhoid fever and malaria are other examples of infectious diseases thought to have been agents of natural selection.

A. The frequencies of dominant detrimental alleles are extremely low because of the efficiency of selection against them. Rare dominant traits are generally rare for good reason.

B. Falciparum malaria has been a strong selective agent in the tropics. Hb S, Hb C, Hb E, Hb Constant Spring, thalassemias, G6PD deficiency are all maintained as balanced polymorphisms.

C. In Africa, vivax malaria has favored an allele at the Duffy blood group locus (parasite receptor) that confers resistance to vivax malaria. Non-African populations have the two alleles, Fy^a and Fy^b. Africans have a third allele, Fy^o, at frequencies near 100%.

D. It has been argued that other high frequency inherited diseases, such as cystic fibrosis, Tay-Sachs disease, and schizophrenia are maintained as balanced polymorphisms, but there is little direct evidence. Recently, transgenic mice that are homozygous for cystic fibrosis proved to be resistant to the detrimental effects of cholera and typhoid. Heterozygotes were less strongly affected. It was suggested that human heterozygotes for cystic fibrosis may have an advantage in epidemics of typhoid fever.

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