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Heterozygote Advantage

Heterozygote Superiority In Humans

Is hybrid vigor a common phenomenon in humans? Do traits such as birth weight, height, and other factors improve with outcrossing? In a large, welldesigned study of interracial crosses in Hawaii, Newton Morton and his colleagues found no significant beneficial effects among the offspring of an inter-racial cross when compared to offspring whose parents were from the same racial group. Other studies have found some beneficial effects of outbreeding but, in general, these studies tended to be flawed and are thus unreliable.

In a small number of cases, humans do show a heterozygote advantage, in which the fitness of the heterozygote is superior to either homozygote. The best known example is the β-hemoglobin locus and its relationship to sickle cell disease. Adult hemoglobin is composed of four polypeptides: two α chains and two β chains, coded for by different genes. The β chain is a sequence of 146 amino acids, with glutamic acid in position 6. This normal hemoglobin is referred to as type A. In sickle cell disease, a mutation causes glutamic acid to be replaced by valine at position 6 and is referred to as hemoglobin S. Individuals who are homozygous for the S allele (SS) have sickle cell disease. Untreated, this condition is lethal, and affected individuals do not survive to be old enough to have offspring.

If there were no selective advantage to the recessive allele, we would expect it to slowly be removed from the gene pool, and the frequency of individuals with sickle cell disease should approximate the mutation rate of the normal A allele to the S allele, which is extremely rare. The disease, however, is relatively common in western and central Africa, where the frequency of S allele can be over 15 percent. The reason for this high frequency is due to the heterozygote AS being resistant to the malarial parasite Plasmodium falciparum. Thus in areas where malaria is common, AS individuals, who possess one sickling allele, have an advantage over AA individuals, who possess none. Copies of the S allele are lost from the gene pool when they occur in individuals affected with sickle cell disease since they do not reproduce, but more copies are created in the offspring of AS individuals since they are resistant to a severe parasitic disease, namely malaria. This advantage compensates for the loss of individuals with sickle cell disease, and therefore keeps the S gene at a relatively high frequency in western and central African populations. Other hemoglobin abnormalities, including hemoglobin C and E, also seem to have the same effect as sickle cell disease, though the effect is not as pronounced.

Thalassemia is another hemoglobin disorder that causes severe anemia. There are two types, α and β, which are due to mutations at the α and β hemoglobin loci respectively. The disease has its highest frequency in areas bordered by the Mediterranean Sea, especially Sardinia, Greece, Cyprus, and Israel. Similar to sickle cell disease, the disorder is fatal at an early age and the heterozygotes are resistant to malaria.

The same is true for a deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) deficiency, which has a similar geographic distribution as thalassemia. The disease is X-linked, thus affecting boys. Its persistence in this case is due to heterozygous females being resistant to malaria. Other proposed cases of heterozygote superiority in humans are more speculative, and have not been confirmed by repeated studies.

P. Michael Conneally


Cavalli-Sforza, L. L., and W. F. Bodmer. The Genetics of Human Populations. Mineola, NY: Dover Publications, 1999.

Hartl, D. L., and A. G. Clark. Principles of Population Genetics, 3rd ed. Stamford, CT: Sinauer, 1997.

Li, Ching Chun. First Course in Population Genetics. Pacific Grove, CA: Boxwood Press, 1976.

Morton, Newton E., Chin S. Chung, and Ming-Pi Mi. Genetics of Interracial Crosses in Hawaii. New York: S. Karger, 1967.

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Medicine EncyclopediaGenetics in Medicine - Part 2Heterozygote Advantage - Agricultural Significance, Hypotheses Of Heterozygote Advantage, Heterozygote Superiority In Humans