The disadvantage of homozygotes coexisting with the advantage of heterozygotes —therefore called a balanced polymorphism — had been already well characterized in Drosophila 11 and in other model systems: with the S gene it became clear that balanced polymorphism was a reality also in the human species. Theoretical and real life examples in the epidemiology of the sickle cell trait and of sickle cell anaemia.
In essence, the following points have emerged. These data from clinical epidemiology 14 are consistent with increased fitness of AS heterozygotes in an environment with malaria there would be no advantage in an environment without malaria ; at the same time, they tell us clearly that Hb S is not an absolute impediment to the malaria parasite.
Therefore, the mechanism for the increased fitness of AS heterozygotes is not failure of invading red cells see Table 2 : rather, it must be based in something that takes place subsequently. Beet 15 first suggested that the phenomenon of sickling may be responsible; and subsequently it was shown by quantitative in vitro studies that the rate of sickling of AS red cells that had been parasitized in vivo was significantly higher than that of non-parasitized red cells within the very same blood sample.
Cartoon illustration of how AS heterozygotes are relatively protected from severe P falciparum malaria. The upper part of the cartoon is a schematic diagram of what happens in red cells in a normal Hb AA person with malaria: after invasion of a red cell by a merozoite , this becomes a ring form , and this starts multiplying schizogony ; when a schizont is mature the infected red cell essentially bursts and releases new merozoites, each one of which can invade a new red cell.
The lower part of the cartoon is a schematic diagram of what happens in red cells in an AS heterozygote with malaria: the red cell, which appears normal at the time of invasion, once infected undergoes sickling probably as a result of deoxygenation and lowering pH caused by the parasite , and thus it falls easy prey to macrophages in the spleen, in other organs and even in the peripheral blood Phagocytosis of a parasitized red cells clearly interrupts the schizogonic cycle and thus the parasitaemia can be kept under control.
Protective mechanisms against malaria deployed by polymorphic genes expressed in red cells. This mechanism is consistent with in vitro culture studies that have shown normal growth of P falciparum in AS red cells and even in SS red cells, 17 , 18 clearly indicating that it is not Hb S per se that hinders parasite development: it must be something downstream of the parasite cycle, such as phagocytosis of sickled cells. In fact, although it is often stated that the mechanism of protection against malaria of AS heterozygotes is not clear, over the past 40 years there has not been any evidence contrary to the sickling-phagocytosis model; and increased phagocytosis of AS parasitized red cells has been confirmed.
The impaired cytoadherence seems to result from altered display on the red cell surface of the P falciparum erythrocyte membrane protein 1 PfEMP Protection against malaria by the S gene has been also demonstrated in a mouse model, and attributed to accelerated breakdown of haeme by haeme oxygenase 26 however, the pathophysiology of P berghei malaria in mouse is very different from that of P falciparum in humans, and therefore it is difficult to know whether this interesting phenomenon observed in the former is relevant to the latter.
Acquired immunity is a major determinant of the clinical outcome of malarial infection. Several studies have suggested that AS heterozygotes have accelerated acquisition of immunity, 27 , 28 although the matter is still controversial. This confirms the notion 20 that the main advantage of AS heterozygotes in areas with heavy malaria endemicity consists in their increased probability of surviving until acquired immunity is sufficient to protect them, as well as others, regardless of their haemoglobin type Figure 2.
In an area of heavy malaria Abeokuta, SW Nigeria the P falciparum parasite density is significantly reduced in AS versus AA children, specifically between the age of 3 and 5. Protection from life-threatening levels of parasitaemia is crucially important in this age group for the survival of AS heterozygotes, because subsequently acquired immunity can protect AA subjects as well.
If AS heterozygotes were protected from malaria through failure of infection, one might expect protection to be at least as effective in SS homozygotes, i. They have a prototype congenital haemolytic anaemia and are susceptible to malaria, which is a prototype acquired haemolytic anaemia.
Clinical experience has shown that, not surprisingly, this combination is highly dangerous. Of special note is the fact that normally the spleen plays an important role in filtering and removing parasitized red cells: but patients with SCA regularly have an impaired splenic function: often to the extent of functional asplenia, and sometimes the functional asplenia evolves to anatomical atrophy of the spleen from multiple infarcts so-called auto-splenectomy.
In an era of evidence-based medicine it is still not uncommon that hypothetical propositions are stated as facts. By contrast, it is quite remarkable that the protective effect of the Hb S gene against malaria is still portrayed as a hypothesis when it is, in fact, one of the best documented examples in the human species of balanced polymorphism, in which the severe disease of homozygotes SS or SCA is balanced by the advantage of AS heterozygotes.
Malaria and sickle cell anaemia are still major challenges to infectious disease medicine and to haematology respectively, and both are also major public health problems. One might have hoped that what we have learnt about the of advantage of AS heterozygotes with respect to malaria would enable us to protect from malaria mortality other people as well. That this has not yet happened is disappointing but perhaps not surprising, because the key is sickling of red cells, and this is a unique phenomenon.
It cannot be a straightforward task to mimic sickling by a pharmacological approach in subjects who do not have Hb S, and in a way that would act selectively only on parasitized red cells.
We can still hope that human imagination will evolve novel approaches that can match the power of mutation and selection in biological evolution. In the meantime SCA remains a source of great suffering to patients, especially in those developing countries where the numbers are staggering see Table 1.
It is urgent that more is done in order to offer to these patients a better way of life: this ought to include optimal management of pain, often hydroxyurea and, especially in Africa, 34 protection against the potentially fatal threat of P falciparum malaria. If, as doctors, we have a professional obligation towards all of our patients, for those with SCA we have an added human obligation, if we consider that they carry the genetic burden that has helped human populations to survive in malaria-endemic regions of the world.
I am taking this opportunity to thank all patients with sickle cell anemia from whom I have learnt about the disease through their Hospital and Clinic visits in Ibadan, London, New York and Firenze.
Competing interests: The author has declared that no competing interests exist. National Center for Biotechnology Information , U. Mediterr J Hematol Infect Dis. Published online Oct 3. Lucio Luzzatto. Author information Article notes Copyright and License information Disclaimer. Correspondence to: Prof. This example illustrates how a single mutation can have a large effect, in this case, both a positive and a negative one. But in many cases, evolutionary change is based on the accumulation of many mutations, each having a small effect.
Whether the mutations are large or small, however, the same chain of causation applies: changes at the DNA level propagate up to the phenotype. The effects of mutations.
Mutations are random. Subscribe to our newsletter. Sickle cell disease is a group of disorders that affects hemoglobin , the molecule in red blood cells that delivers oxygen to cells throughout the body. People with this disease have atypical hemoglobin molecules called hemoglobin S, which can distort red blood cells into a sickle , or crescent, shape. Signs and symptoms of sickle cell disease usually begin in early childhood. Characteristic features of this disorder include a low number of red blood cells anemia , repeated infections, and periodic episodes of pain.
The severity of symptoms varies from person to person. Some people have mild symptoms, while others are frequently hospitalized for more serious complications. The signs and symptoms of sickle cell disease are caused by the sickling of red blood cells. When red blood cells sickle, they break down prematurely, which can lead to anemia. Anemia can cause shortness of breath, fatigue, and delayed growth and development in children.
The rapid breakdown of red blood cells may also cause yellowing of the eyes and skin, which are signs of jaundice. Painful episodes can occur when sickled red blood cells, which are stiff and inflexible, get stuck in small blood vessels. These episodes deprive tissues and organs, such as the lungs, kidneys, spleen, and brain, of oxygen-rich blood and can lead to organ damage. A particularly serious complication of sickle cell disease is high blood pressure in the blood vessels that supply the lungs pulmonary hypertension , which can lead to heart failure.
Pulmonary hypertension occurs in about 10 percent of adults with sickle cell disease. Sickle cell disease affects millions of people worldwide.
What was puzzling was why sickle cell anemia was so prevalent in some African populations. How could a "bad" gene -- the mutation that causes the sometimes lethal sickle cell disease -- also be beneficial? On the other hand, if it didn't provide some survival advantage, why had the sickle gene persisted in such a high frequency in the populations that had it?
The sickle cell mutation is a like a typographical error in the DNA code of the gene that tells the body how to make a form of hemoglobin Hb , the oxygen-carrying molecule in our blood. Every person has two copies of the hemoglobin gene.
Usually, both genes make a normal hemoglobin protein. When someone inherits two mutant copies of the hemoglobin gene, the abnormal form of the hemoglobin protein causes the red blood cells to lose oxygen and warp into a sickle shape during periods of high activity. These sickled cells become stuck in small blood vessels, causing a "crisis" of pain, fever, swelling, and tissue damage that can lead to death.
This is sickle cell anemia. But it takes two copies of the mutant gene, one from each parent, to give someone the full-blown disease.
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