Heterozygote advantage
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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 exists on any given allele. Major genes almost always have multiple effects, 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.
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An example of heterozygote advantage in flies
This sort of selection can be seen in all kinds of populations: human and non-human. In the fly Drosophila melanogaster, there is an autosomal, completely recessive gene that expresses ebony body-color. When there is a fly with two copies of the recessive allele, this homozygote expresses the dark ebony color, but is also terribly weak, and is placed at a harsh reproductive disadvantage. If this were the only effect of the gene, and only conveyed disadvantages, we would expect selection to weed out this gene until it became extinct from the population. However, the same gene also conveys some advantages, by providing improved viability. This advantage is dominant, and conveyed in the heterozygote. So, in this case, the homozygote ebony color fly gene will be at a distinct disadvantage due to weakness; the heterozygote will express none of the disadvantages of weakness, and will gain improved viability from its mutant allele; and the homozygote wild-type will be perfectly healthy, but will not possess the improved viability of the heterozygote, and will be at a disadvantage in survivorship and reproduction.
This gene, which at first blush appears to harm its carrier, confers enough of an advantage that makes it beneficial to remain in the gene pool. In a study conducted by Kalumus in 1945, flies containing the ebony gene were introduced to a wild-type population; the ebony gene persisted throughout the many fly generations of the study. The genotype frequency of the ebony varied from 8% to 30%, in which the ebony gene was more prevalent and thereby advantageous in low, dry temperatures, and less so in warm, moist temperatures.
Heterozygote advantage and sickle-cell anemia
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.
Since 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 anemia 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 every thirteen 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 greater allele frequencies, as well. As modern medical technology has become and continues to become available to malaria-stricken populations, we can expect the allele frequency for SCA to decrease.
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 possession of the CF disease can increase 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 when they ingested water slower than their body passed it. Those with CF, or carriers of the allele, were much less likely to suffer this fate. Due to this increased resistance to disease, the CF allele in low frequencies was beneficial to the gene pool. Even today, approximately one in twenty-five people of European descent is a carrier for the disease, and one in every 2500 children born is affected by cystic fibrosis.
Possible existence of heterozygote advantage with Tay-Sachs disease
An issue of debate is whether Tay-Sachs, the genetic disorder, may have long ago provided a heterozygote advantage in the Ashkenazi Jewish population. The disease is autosomal recessive and starts affecting the individual in infancy with developmental retardation. Paralysis, dementia, blindness and death are also common within the first few years after birth. Approximately one in every forty-five Morrocan Jews is a carrier of Tay-Sachs and the allele frequency is comparable for North American Jews.
Heterozygote advantage seems a likely explanation for this allele, which conveys no benefit at all to the homozygous recessive individual. Some studies have given reason to the belief that the TSD gene’s persistence is due to founder effect, genetic drift, and unique immigration patterns. Others have indicated heterozygous advantage as a likely cause, citing evidence that TSD carriers have an increased resistance to Tuberculosis. One such study found that death rates from tuberculosis were much lower for grandparents of Jews that had died from TSD than those that had no descendents with TSD. This difference was also shown to be statistically significant.
This correlation is not proof that selection took place, but there is pressure to explain why such selection would have occurred in Jewish populations and not in other Europeans. One explanation offered is that Jews were confined to tubercular urban areas, and were under much more extreme selective pressures to evolve resistance to the disease. Urban populations of other ethnic groups had much more gene flow with rural populations, and these populations also moved more from urban to rural and vice-versa, whereas Jewish populations stayed in dense urban settings for many generations. It still remains to be seen whether the persistence of TSD is due to a complicated array of selective forces or whether other evolutionary forces were at play.