Heterozygote advantage

A heterozygote advantage (heterozygous advantage or overdominance) describes the case in which the heterozygote genotype has a higher relative fitness than either the homozygote dominant or homozygote recessive genotype. This selection favoring the heterozygote is one of the mechanisms that maintain polymorphism and help to explain some kinds of genetic variability. There are several cases in which the heterozygote conveys certain advantages and some disadvantages while both versions of homozygotes are only at disadvantages. 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 (biology) or morph (zoology). 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 in theory
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 prevalent 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
Cases of heterozygote advantage have been demonstrated in several organisms, including humans. 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, Kalmus demonstrated how polymorphism can persist in a population through heterozygote advantage.

Kalmus discovered a mutant allele of an autosomal gene that expressed ebony body color and other selective advantages in a pattern that was autosomal dominant. The same allele also conveyed harsh disadvantages in a pattern that was completely recessive. When a fly inherited two copies of the mutation (homozygous), it expressed the dark ebony color, but it was also particularly weak, and was placed at a harsh reproductive disadvantage.

If weakness were the only effect of the mutant allele, so that 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 individuals that were heterozygotes. 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 advantage in human genetics
Sickle-cell anemia (SCA) is a genetic disorder that is 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-shape. This deformation of the cells can cause them to become lodged in capillaries, depriving other parts of the body of precious 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.

Because the genetic disorder is incompletely recessive, a person with only one SCA allele and one unaffected allele will have a "mixed" phenotype: The sufferer will not experience the ill effects of the disease, yet will still possess a sickle cell trait, whereby some of the red blood cells undergo benign effects of SCA, but nothing severe enough to be harmful. Those afflicted with sickle-cell trait are also known as carriers: If two carriers have a child, there is a twenty-five percent chance that their child will have SCA, a fifty percent chance that their child will be a carrier, and a twenty-five percent chance that the child will neither have SCA nor be a carrier. Were the presence of the SCA allele to confer only negative traits, we would expect its allele frequency to decrease generation after generation, until its presence were completely eliminated by selection and by chance.

However, there is convincing evidence indicating that, in areas with persistent malaria outbreaks, individuals with the heterozygous state have a distinct advantage. Those with the benign sickle trait possess a resistance to malarial infection. The pathogen that causes the disease spends part of its cycle in the red blood cells, and those with sickle cells effectively stop the pathogen in its tracks, until the immune system destroys the foreign bodies. These individuals have a great immunity to infection and have a greater chance of surviving outbreaks. However, those with two alleles for SCA may survive malaria but will typically die from their genetic disease unless they have access to advanced medical care. Those of the homozygous normal or wild-type case will have a greater chance of passing on their genes successfully, in that there is no chance of their offspring's suffering from SCA; yet, they are more susceptible to dying from malarial infection before they have a chance to pass on their genes.

This resistance to infection is the main reason that we still see the SCA allele and SCA disease. It is found in greatest frequency in populations where malaria was and often still is a serious problem. Approximately one in 13 African-Americans is a carrier, as their recent ancestry is from malaria-stricken regions. Other populations in Africa, India, the Mediterranean and the Middle East have higher allele frequencies as well. As effective anti-malarial treatment becomes increasingly available to malaria-stricken populations, we can expect the allele frequency for SCA to decrease, so long as SCA treatments are unavailable or only partially effective. If effective Sickle-cell anemia treatments become available to the same degree, we can expect allele frequencies to remain at their present levels in these populations. In this context, 'treatment effectiveness' refers to the reproductive fitness that it grants, rather than the degree of suffering alleviation.

Heterozygote advantage and cystic fibrosis
Cystic fibrosis, or CF, is an autosomal recessive hereditary disease of the lungs, sweat glands and digestive system. The disorder is caused by the malfunction of the CFTR protein, which controls inter-membrane transport of chloride ions, which is vital to maintaining equilibrium of water in the body. The malfunctioning protein causes viscous mucus to form in the lungs and intestinal tract. Before modern times, children born with CF would have a life expectancy of only a few years, but modern medicine has made it possible for these people to live into adulthood. However, even in these individuals, male and female, CF typically causes sterility. It is the most common genetic disease among people of European descent.

The presence of a single CF mutation may influence survivorship of people affected by diseases involving loss of body fluid, typically due to diarrhea. The most common of these maladies is cholera, which throughout history has killed many Europeans. Those with cholera would often die of dehydration due to intestinal water losses. A mouse model of CF was used to study resistance to cholera, and the results were published in Science in 1994 (Gabriel, et al). The heterozygote (carrier) mouse had less secretory diarrhea than normal, non-carrier mice. Thus it appeared for a time that resistance to cholera explained the selective advantage to being a carrier for CF and why the carrier state was so frequent.

This theory has been called into question. Hogenauer, et al (American Journal of Human Genetics. 67:1422-7, 2000) have challenged this popular theory with a human study. Prior data were based on solely on mouse experiments. These authors found that the heterozygote state was indistinguishable from the non-carrier state. Many experts in the field have discarded the cholera theory as a result.

Another theory for the prevalence of the CF mutation is that it provides resistance to tuberculosis. Tuberculosis was responsible for 20% of all European deaths between 1600 and 1900, so even partial protection against the disease could account for the current gene frequency.

As of 2007, the selective pressure for the high gene prevalence of CF mutations is still uncertain. Approximately 1 in 25 persons of European descent is a carrier of the disease, and 1 in 2500 to 3000 children born is affected by cystic fibrosis.

Heterozygote advantage and Triose Phosphate Isomerase
Triose Phosphate Isomerase (TPI) is a central enzyme of glycolysis, the main pathway for cells to obtain energy metabolizing carbon sugars. In humans, certain mutations within this enzyme which affect the dimerisation of this protein are causal for a rare disease, Triose Phosphate Isomerase deficiency. Other mutations, which inactivate the enzyme (= null alleles) are lethal when inherited homozygously (two defect copies of the TPI gene), but have no obvious effect as heterozygotes (one defect and one normal copy). However, the frequency of heterozygous null-alleles is much higher than expected, indicating a heterozygous advantage for TPI null alleles as well. The reason is unknown, however, new scientific results are suggesting that cells having reduced TPI activity are more resistant against oxidative stress PlosOne, Dec. 2006