Heterozygote advantage is the superior fitness often seen in hybrids, the cross between two dissimilar parents. A heterozygote is an organism with two different alleles , one donated from each parent. Fitness means the ability to survive and have offspring. Heterozygote advantage also refers more narrowly to superior fitness of an organism that is heterozygous for a particular gene, usually one governing a disease.
Inbreeding is the practice of repeatedly crossing a single variety of organism with itself, in order to develop a more uniform variety. During this process, the organism becomes homozygous for many genes, meaning that its two gene copies are identical. This is often accompanied by loss of vigor: slower growth, less resistance to disease, and other signs of decreased fitness. This is known as inbreeding depression. Breeding with another variety ("outcrossing") produces offspring that are heterozygous for many genes, and is often accompanied by an increase in size and vigor. This phenomenon had been known to farmers and plant breeders for many years, and was given the name "heterosis" by the U.S. geneticist George Shull in 1916. It is also known as hybrid vigor or, more commonly, as heterozygote advantage.
Hybrid vigor has had a profound impact on agriculture. Yields of hybrid corn are much greater than those of nonhybridized, "open-pollinated" varieties. This of course means that the hybrid "seed corn" must be produced each generation by crossing two distinct, inbred lines. This in turn has given employment to several generations of teenagers who, in summer, detassel corn plants, that is, remove the pollen from one of the parental plants to prevent self-pollination and assure cross-hybridization with the desired variety.
In domesticated animals used for meat or milk production, selection of the best producers to produce high-yielding offspring has been in effect for centuries and has produced dramatic results. In this case, however, essentially all crossing is performed within the same breed and usually involves inbreeding. No serious attempts are made to outcross among different breeds, which would take advantage of heterozygote advantage. Early experiments suggested that outcrossing does not yield favorable results and thus is avoided to this day.
Hypotheses of Heterozygote Advantage
There are two plausible explanations for heterozygote advantage and inbreeding depression, which may both act in a single organism on different genes. No single hypothesis is likely to explain all cases of heterozygote superiority.
The first hypothesis is known as the favorable dominance hypothesis. It is based on the fact that recessive alleles are very often deleterious in the homozygous condition, often because recessives code for a defective form of the protein. Thus, possessing at least one dominant allele is favored. Under this hypothesis, the two inbred parents are each homozygous recessive for one or more (different) traits, and each has decreased fitness. Hybridization creates heterozygote offspring that have a dominant (functional) allele for each trait, thus increasing their fitness or vigor. In this hypothesis, heterozygotes are superior to the homozygous recessive condition, but not the homozygous dominant condition.
The other explanation for heterosis is that the heterozygote is superior to both homozygotes. This is usually referred to as the overdominance hypothesis. Hybrid vigor in corn is due to overdominance rather than favorable dominance. Overdominance may help explain why harmful recessive alleles remain in the gene pool. Despite the disadvantage of possessing two copies, possessing one copy is advantageous. The molecular explanation for overdominance is less simple, and may be different for different genes (see discussion below).
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.
see also Hardy-Weinberg Equilibrium; Hemoglobinopathies; Inheritance Patterns; Population Genetics.
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.
"Heterozygote Advantage." Genetics. . Encyclopedia.com. (January 22, 2019). https://www.encyclopedia.com/medicine/medical-magazines/heterozygote-advantage
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