Exam 5: Single-Gene Disorders: Inheritance Patterns, Phenotype Variability, and Allele Frequencies

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Some recessive disorders are common in the population as a result of a type of balancing selection in which a mutant allele is simultaneously subject to purifying selection in homozygotes and positive selection in heterozygotes. As, a result, heterozygotes with one mutant allele and one normal allele have a higher biological fitness than both mutant homozygotes (who are affected) and normal homozygotes. This situation where heterozygotes actively benefit from having a mutant allele is known as heterozygote advantage.
Some of the best examples of heterozygote advantage come from the high incidence of certain types of blood disorder that are found in populations who are exposed (or were recently exposed) to a high risk of contracting malaria. Sickle-cell anemia provides a classic example. It is very common in populations in which malaria caused by the Plasmodium falciparum parasite is endemic (or was endemic in the recent past) but is absent from populations in which malaria has not been frequent. In some malaria-infested areas of West Africa, the sickle- cell anemia allele has reached a frequency of 0.15-far too high to be explained by recurrent mutation.
Sickle-cell heterozygotes have red blood cells that are inhospitable to the malarial parasite (which spends part of its life cycle in red blood cells). As a result, they are comparatively resistant to falciparum malaria. Normal homozygotes, however, frequently succumb to malaria and are often severely, sometimes fatally, affected. Heterozygotes therefore have a higher fitness than both normal homozygotes and disease homozygotes (who have a fitness close to zero because of their hematological disease).
Heterozygote advantage through comparative resistance to malaria has also been invoked for certain other autosomal recessive disorders that feature hemolytic anemia, such as the thalassemias and glucose-6- phosphate dehydrogenase deficiency. The high incidence of cystic fibrosis in northern European populations and Tay-Sachs disease in Ashkenazi Jews is also likely to have originated from heterozygote advantage, possibly through a greater resistance of carriers to infectious disease.