[BojanaL]

Single gene disorders and selective pressure

Single gene disorders represent a large group of inherited disorders. So far, over 10 000 genetic disorders are identified as a result of a single gene defect. Despite being familiar with mechanism of inheritance (autosomal, X-linked, dominant, recessive…), single gene disorders can’t be prevented unless genetic testing is performed before or during pregnancy. Pathology behind most diseases is well known, but it still remains unknown why nature tolerate “errors” in genetic material that are very harmful for the carriers/diseased? Answer to that question may be associated with sickle cell anemia, a well known single gene disorder, and ability of their carriers to tolerate malaria. Molecular mechanism behind this protective effect has been clarified recently.

Single cell anemia will develop as a consequence of point mutation in the beta hemoglobin gene located on the chromosome 11. Instead of glutamine, amino-acid valine will be inserted and altered beta chains will be formed. Mutated beta chains and unchanged alpha chains will form hemoglobin S. This type of hemoglobin will aggregate when person become exposed to low oxygen level, which will lead to formation of sickle shaped red blood cell. Sickle erythrocytes have decreased elasticity, which is required for optimal function of the red blood cells and their wriggling through narrow blood vessels, such as capillaries. Without elasticity and ability to return to the normal shape, sickle red blood cells will occlude smallest blood vessels and induce ischemia. Besides inability to perform normal function in the body, these type of red blood cells have very short lifespan and bone marrow can’t compensate their loss easily, especially because hemoglobin A (made of alpha and beta chains) represent the majority of hemoglobin types in the body (96-97%). People diagnosed with sickle cell anemia live between 42-48 years, but with proper therapy, life can be prolonged beyond 50 years.

Sickle cell anemia is most commonly recorded in tropic and sub-tropic areas of sub-Saharan areas (three quarters of all world cases). In the mid of the last century, scientists focused on sickle cell anemia discovered that carriers of mutated allele can survive malaria and that selective pressure increases the number of people carrying mutation in areas endemic for malaria. Today 10-40% of people in Africa carry mutation for hemoglobin S. Sickle cell anemia is example of genetic disorder that has heterozygous advantage: although 25% of the offspring has a chance to develop disease in case that both parent have impaired allele, carriers of the mutation will not develop classical diseased phenotype and they will be resistant to malaria.

Malaria is transmitted by mosquitoes that carry blood parasite Plasmodium falciparum. This protozoan species inhabit liver and red blood cells where it divides and increase its number. Classical symptoms of malaria (chills and fever) are associated with rupture of infected erythrocytes. Cerebral malaria is a dangerous complication of the malaria disease that usually affects children and may induce irreversible consequences in the neuronal functioning even after malaria is cured. It can end fatally. People who have sickle cell anemia are resistant to malaria, while those that carry just a single allele develop less severe symptoms of disease when they become infected. Scientific community was eager to discover mechanism that provides resistance against malaria, because without mechanism - proper medication can't be developed. Many believed that sickle shape of the erythrocytes prevents Plasmodium from entering the cell, but latest experiments discovered another factor that might contribute to the resistance against malaria. When researchers infected mouse with mutation in hemoglobin gene with Plasmodium, they noted that mouse doesn’t develop cerebral malaria (just like people with one impaired allele). Number of available normally shaped erythrocytes prevents Plasmodium to increase its number which reduces severity of infection immediately. Previous studies showed that carbon monoxide provides protection against cerebral malaria and in experiment with mice, researchers discovered that sickle cells produce increased amount of heme oxygenase-1, an enzyme responsible for carbon monoxide production. Increased level of carbon monoxide doesn’t interrupt Plasmodium’s cycle, but prevents brain damage typical for people with normal erythrocytes. Exact mechanism of carbon monoxide protection remains to be discovered, but it can be concluded that persons with hemoglobin S mutation develop lesser symptoms of disease due to lower number of parasites and their inability to induce cerebral damage (prevented by increased carbon monoxide production via enzymatic activity of sickle cells).

Mutations happen all the time and they shape evolution of all living creatures on the Earth: bad mutation will be eliminated, beneficial will remain in the population. Sometimes, mutation has two faces, good and bad. In that case, nature will select where and when mutation will spread. Just like with sickle cell anemia.