Heterozygote advantage
A heterozygote advantage describes the case in which the heterozygous genotype has a higher relative fitness than either the homozygous dominant or homozygous recessive genotype. Loci exhibiting heterozygote advantage are a small minority of loci.[1] The specific case of heterozygote advantage due to a single locus is known as overdominance.[2][3] Overdominance is a rare[4] condition in genetics where the phenotype of the heterozygote lies outside of the phenotypical range of both homozygote parents, and heterozygous individuals have a higher fitness than homozygous individuals.
Polymorphism can be maintained by selection favoring the heterozygote, and this mechanism is used to explain the occurrence of some kinds of genetic variability. A common example is the case where the heterozygote conveys both advantages and disadvantages, while both homozygotes convey a disadvantage. A well-established case of heterozygote advantage is that of the gene involved in sickle cell anaemia.
Often, the advantages and disadvantages conveyed are rather complicated, because more than one gene may influence a given trait or morph. Major genes almost always have multiple effects (pleiotropism), which can simultaneously convey separate advantageous traits and disadvantageous traits upon the same organism. In this instance, the state of the organism's environment will provide selection, with a net effect either favoring or working in opposition to the gene, until an environmentally determined equilibrium is reached.
Heterozygote advantage is a major underlying mechanism for heterosis, or "hybrid vigor", which is the improved or increased function of any biological quality in a hybrid offspring. Previous research, comparing measures of dominance, overdominance and epistasis (mostly in plants), found that the majority of cases of heterozygote advantage were due to complementation (or dominance), the masking of deleterious recessive alleles by wild-type alleles, as discussed in the articles Heterosis and Complementation (genetics), but there were also findings of overdominance, especially in rice.[3] More recent research, however, has established that there is also an epigenetic contribution to heterozygote advantage, primarily as determined in plants,[5][6] though also reported in mice.[7]
In theory[edit]
When two populations of any sexual organism are separated and kept isolated from each other, the frequencies of deleterious mutations in the two populations will differ over time, by genetic drift. It is highly unlikely, however, that the same deleterious mutations will be common in both populations after a long period of separation. Since loss-of-function mutations tend to be recessive (given that dominant mutations of this type generally prevent the organism from reproducing and thereby passing the gene on to the next generation), the result of any cross between the two populations will be fitter than the parent.
This article deals with the specific case of fitness overdominance, where the fitness advantage of the cross is caused by being heterozygous at one specific locus alone.
Experimental confirmation[edit]
Cases of both homozygote and heterozygote advantage have been demonstrated in several organisms, including humans.[8][9] The first experimental confirmation of heterozygote advantage was with Drosophila melanogaster, a fruit fly that has been a model organism for genetic research. In a classic study on the ebony mutation, Kalmus demonstrated how polymorphism can persist in a population through heterozygote advantage.[10]
If weakness were the only effect of the mutant allele, so it conveyed only disadvantages, natural selection would weed out this version of the gene until it became extinct from the population. However, the same mutation also conveyed advantages, providing improved viability for heterozygous individuals. The heterozygote expressed none of the disadvantages of homozygotes, yet gained improved viability. The homozygote wild type was perfectly healthy, but did not possess the improved viability of the heterozygote, and was thus at a disadvantage compared to the heterozygote in survival and reproduction.
This mutation, which at first glance appeared to be harmful, conferred enough of an advantage to heterozygotes to make it beneficial, so that it remained at dynamic equilibrium in the gene pool. Kalmus introduced flies with the ebony mutation to a wild-type population. The ebony allele persisted through many generations of flies in the study, at genotype frequencies that varied from 8% to 30%. In experimental populations, the ebony allele was more prevalent and therefore advantageous when flies were raised at low, dry temperatures, but less so in warm, moist environments.
Heterozygote disadvantage occurs when "a heterozygote has a lower overall fitness than either homozygote."[11] Heterozygote disadvantage occurs in mammals, birds, and insects.[12]
In human genetics[edit]
Sickle-cell anemia[edit]
Sickle-cell anemia (SCA) is a genetic disorder caused by the presence of two incompletely recessive alleles. When a sufferer's red blood cells are exposed to low-oxygen conditions, the cells lose their healthy round shape and become sickle-shaped. This deformation of the cells can cause them to become lodged in capillaries, depriving other parts of the body of sufficient oxygen. When untreated, a person with SCA may suffer from painful periodic bouts, often causing damage to internal organs, strokes, or anemia. Typically, the disease results in premature death.