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EDITS TO SICKLE CELL DISEASE PAGE UNDER GENETICS SECTION:

Over time, at least 3 separate populations in Africa have evolved the sickle cell gene by different mutational events [31]. The malarial environment, along with the disease that displays over dominance (or heterozygote advantage) has led to stabilizing selection of the βs gene in certain geographical areas. The heterozygote form of the gene leads to an increased fitness and thus has led to a balanced polymorphism for the trait in these malaria hot spots. As mentioned earlier, people that have both βs alleles have SCD and a much lower fitness. However, individuals that have one copy of the allele have a much higher fitness in malarious regions than normal individuals that do not possess a βs allele. When there is no malaria in a population, there is no selection pressure to carry the βs trait, which is deleterious in the absence of malaria. The only way this gene stays part of an isolated population in the highlands of Africa is likely due to gene flow with a malarious population. Multiple studies have shown evidence that it arose independently in separate areas of Africa and other malaria-burdened regions of the world, making it an analogous trait. In order to assess the DNA taken from separate populations in Africa, haplotype β-globin gene clusters were examined and sorted based on certain “variable segments” with specific repeats that could be used to identify differences in each geographic βs gene [32]. These DNA sequences were compared to human and monkey DNA, which are highly variable in these positions. However, in these individual populations, it is unlikely caused by recombination due to the high degree of homogeneity discovered. These findings indicate that each specific geographic area shares a unique mutation of the β-globin gene, thus suggesting that there are multiple origins of the βs allele in Africa. A study done by Pagnier et al includes one additional location of the βs allele in Algeria [33]. From their results, they have found that the Algerian version of the βs gene most likely came from Benin as the two are very closely related.

https://en.wikipedia.org/wiki/Sickle-cell_disease

PAPER STARTS HERE:

The Evolution of the Sickle Cell Gene Sickle Cell Disease (SCD) is an autosomal recessive disorder that affects hemoglobin production and red blood cell shape in humans (Delicat-Loembet, 2014). This disease displays characteristics of incomplete dominance – where there are three different phenotypes for each of the three individual genotypes – and can be harmful and even cause death in many cases. Because individuals affected with SCD have decreased production of hemoglobin, they often suffer from anemia, or a shortage of oxygen in the blood. In addition, the sickle-shaped cells are much more likely to cause blockages in blood vessels, causing hypoxia and/or ischemia (Mitchell, 1999). Symptoms may be much more mild in the heterozygous condition of the disease, called sickle cell trait (SCT), and are usually not life-threatening. What makes this disease so interesting is the fact that being heterozygous (having SCT) is linked to a much higher survival rate for malaria, one of the deadliest diseases in Africa (Arif et al., 2007). What scientists are discovering is that malaria has forced strong selection on the gene responsible for SCD (Penman et al, 2012) and that over time, at least 3 separate populations in Africa have evolved the sickle cell gene by different mutational events (Pagnier et al., 1984). To understand the origin of sickle cell gene, it is important to first understand the disease that put it under heavy selection. Malaria has been declared by the World Health Organization as “the 4th leading cause of death in children across developing countries” (Arif et al., 2007). It has lead to surplus of one million deaths per year from the disease. Scientists estimate that the β-globin allele originated 1.5 million years ago (Chebloune et al., 1998) and that the βs mutation responsible for SCT evolved a few thousand years ago (Edelstein, 1986). This mutation likely arose due to severe environmental pressures put on populations that were at a high risk of contracting malaria. The malarial environment, along with the disease that displays over dominance (or heterozygote advantage) has led to stabilizing selection of the βs gene in certain geographical areas. The heterozygote form of the gene leads to an increased fitness and thus has led to a balanced polymorphism for the trait in these malaria hot spots. Other malarial defense mechanisms involving red blood cell mutations have also been selected for, such as thalassemia and G-6-PD deficiency (Daar et al., 2000). These alleles are not the focus of this paper, however, and will not be discussed in much detail. Malaria is a vector-borne bacterial disease caused by different forms of the Plasmodium bacteria, which is spread by mosquitoes. Areas are only at risk if they harbor populations of mosquitoes known for being carriers of the Plasmodium bacteria. The majority of malaria cases worldwide come from Africa, south of the Saharan Desert, however it is found in all over in tropical and subtropical environments where mosquitoes are present. It is said that malaria was an unfortunate consequence of economical development, from which large confined populations were in close contact with the presence of still water (Daar et al., 2000). The mosquitoes that carry malaria rely on these stagnant pools of water to breed. Before the agricultural boom in Africa and other tropical regions, populations of humans were much more spread out and there weren’t as many potential breeding grounds for mosquitoes that came along with irrigation systems for agriculture. The combination of stagnant pools of water and increased population density led to Malaria becoming endemic in certain populations. In order to combat malaria, the sickle cell gene, or βs most likely arose via a mutation in the β-globin gene (Chebloune et al., 1988). As mentioned earlier, people that have both βs alleles have SCD and a much lower fitness. However, individuals that have one copy of the allele have a much higher fitness in malarious regions than normal individuals that do not possess a βs allele. This gene in the heterozygous condition does not prevent malarial infection, rather it substantially increases an individual’s chance of survival. The parasite malaria, which infects red blood cells in humans, is quickly destroyed when it attacks a sickled cell in a person with SCT (Arif et al., 2007). Although people with SCT have a mix of normal and sickled erythrocytes, once malaria is exposed the blood cells are much more likely to sickle and prevent the infection from severely affecting an individual (Roth et al., 1978). Although the βs mutation is seen across west and central Africa, certain highlands populations either do not have it in their gene pools or have it in a very low frequency (Arif et al., 2007). This is most likely due to the lack of malaria in these cooler, drier climates that are not habitable by the mosquitoes that carry it. When there is no malaria in a population, there is no selection pressure to carry the βs trait, which is deleterious in the absence of malaria. This is also why the βs gene is so much less common in parts of the world that are not affected by malaria. The only way this gene stays part of an isolated population in the highlands of Africa is likely due to gene flow with a malarious population. In contrast, in populations that are under high selection pressure for malaria, individuals that have SCT have a much higher fitness than individuals who have SCD and those that do not have any βs gene. In populations affected by malaria, individuals that have SCT have higher fertility rates and a better chance of producing more offspring than the normal population (Wiesenfeld, 1967). SCD individuals also have a lower fertility rate because not nearly as many make it to reproductive age. Normal individuals also have higher mortality rates than SCT individuals, adding another advantage to having SCT in a malaria-ridden environment. Finding the origin of the βs gene in our evolutionary history has been a challenge, but through the use of S1 nuclease mapping of DNA, scientists believe that the allele may not have one specific geographic origin. Instead, they have concluded that it arose independently in separate areas of Africa and other malaria-burdened regions of the world, making it an analogous trait. Homologous traits are ones that are present in two different species that were inherited from a common ancestor, while analogous traits are shared by two different species but not due to evolutionary descent. In order to assess the DNA taken from separate populations in Africa, haplotype β-globin gene clusters were examined and sorted based on certain “variable segments” with specific repeats that could be used to identify differences in each geographic βs gene (Chebloune et al., 1988). These DNA sequences were compared to human and monkey DNA, which are highly variable in these positions. However, in these individual populations, it is unlikely caused by recombination due to the high degree of homogeneity discovered. These findings indicate that each specific geographic area shares a unique mutation of the β-globin gene, thus suggesting that there are multiple origins of the βs allele in Africa. A study done by Pagnier et al includes one additional location of the βs allele in Algeria (Pagnier et al., 1984). From their results, they have found that the Algerian version of the βs gene most likely came from Benin as the two are very closely related. These studies all point to there being three separate points of origin of the βs gene in Africa. Although the sickle cell gene has had arguably the biggest impact on Africa as a continent, other places with tropical weather have also had to develop a way to fight malaria. In Mediterranean populations, thalassemia and βs have both evolved as an aid to combat malaria (Penman et al., 2012). It is common belief that SCD made its way into Europe via trade with and migration from Africa, which resulted in gene flow between the two populations. What is interesting particularly about Italy and Greece is that they show a high prevalence of thalassemia, but no longer have much of the βs gene in the population. For the most part, the βs gene is almost completely absent, but in certain sickle cell “hotspots”, the gene’s allele frequency is nearly what it is in parts of Africa with endemic malaria. In order for this to happen, two things may occur (although they are not certain). The first being limited gene flow. Metapopulations that fail to breed with distant populations do not introduce new alleles to the population as frequently, and can likely maintain a particular allele in the population for extended periods of time. Such is the case with the βs gene, which may be at a high frequency in some areas in the Mediterranean, but absent from surrounding populations. The second factor that may affect the frequency of the βs allele in the Mediterranean is negative epistasis that occurs between alpha thalassemia and SCT (Penman et al., 2012). Individuals that inherit both lose their protection from malaria due to epistasis and are much more likely to contract malaria. Because of this negative selection, it is believed that SCT has severely decreased in many Mediterranean populations. Populations without a high frequency of alpha thalassemia that do not have much gene flow are generally the populations with a higher frequency of βs. In conclusion, there is a very high amount of evidence supporting a multicentric origin of SCT in Africa. At present, scientists have identified three unique versions of the βs gene responsible for phenotypic display of SCT and SCD (Chebloune et al., 1988). These unique strands have likely evolved independently of each other due to high selective pressure put on humans in Africa by malaria. The evolution of SCT likely occurred in the past few millennia, as malaria was not a huge concern for human beings until the rise of agriculture and economic development (Daar et. al., 2000). As the βs gene spread from Africa to surrounding portions of the globe affected by malaria, the trait was often lost from the gene pool due to better malaria prevention and the possibility of epistasis and/or gene flow between populations without the βs gene (Penman et al., 2012). This just goes to show that the gene is only effective against fighting malaria and is deleterious when there is no malaria present.

References Arif, SH. "Sickle Cell Disease and Malaria." Indian Journal of Hematology & Blood Transfusion : an Official Journal of Indian Society of Hematology and Blood Transfusion. 23 (2007): 3-4. Print. Aydinok, Y. (2012). Thalassemia. Hematology, 1728-31. doi:10.1179/102453312X13336169155295 Chebloune, Y., Pagnier, J., Trabuchet, G., Faure, C., Verdier, G., Labie, D., & Nigon, V. (January 01, 1988). Structural analysis of the 5' flanking region of the beta-globin gene in African sickle cell anemia patients: further evidence for three origins of the sickle cell mutation in Africa. Proceedings of the National Academy of Sciences of the United States of America, 85, 12, 4431-5. Daar, Shahina, H M. Hussain, David Gravell, Ronald L. Nagel, and Rajagopal Krishnamoorthy. "Genetic Epidemiology of Hbs in Oman: Multicentric Origin for the Βs Gene." American Journal of Hematology. 64.1 (2000): 39-46. Print. Delicat-Loembet et al. "Prevalence of the Sickle Cell Trait in Gabon: a Nationwide Study." Infection, Genetics and Evolution. 25 (2014). Print. Edelstein, S. J. (1986) in The Sickled Cell (Harvard Univ. Press, Cambridge, MA), pp. 44-64. Mitchell, R. "Sickle Cell Anemia." The American Journal of Nursing. 99.5 (1999): 36-7. Print. Pagnier, J, JG Mears, O Dunda-Belkhodja, KE Schaefer-Rego, C Beldjord, RL Nagel, and D Labie. "Evidence for the Multicentric Origin of the Sickle Cell Hemoglobin Gene in Africa." Proceedings of the National Academy of Sciences of the United States of America. 81.6 (1984): 1771-3. Print. Penman, B. S., Gupta, S., & Buckee, C. O. (October 01, 2012). The emergence and maintenance of sickle cell hotspots in the Mediterranean. Infection, Genetics and Evolution, 12, 7, 1543-1550. Roth JR, EF, Friedman M, Ueda Y, Tellez I, Trager W Nagel RL (1978) Sickling rates of humans AS red cells infected in vitro with Plasmodium falciparum malaria. Science 202: 650-652. Wiesenfeld, SL. "Sickle-cell Trait in Human Biological and Cultural Evolution. Development of Agriculture Causing Increased Malaria Is Bound to Gene-Pool Changes Causing Malaria Reduction." Science (new York, N.y.). 157.3793 (1967): 1134-40. Print.

The Evolution of the Sickle-Cell Gene: How It Started and How it Has Lived On

Solomon, E, and WF Bodmer. "Evolution of Sickle Variant Gene." Lancet. 1.8122 (1979). Print.

Nigon, V. "Structural Analysis of the 5 Prime Flanking Region of The. Beta. Globin Gene in African Sickle Cell Anemia Patients: Further Evidence for Three Origins of the Sickle Cell Mutation in Africa." (1988). Print.

Lerner, Barron H. "In a Lifetime of Sickle Cell, the Evolution of a Disease." New York Times. (2007). Print.

"Prevalence of the Sickle Cell Trait in Gabon: a Nationwide Study." Infection, Genetics and Evolution. 25 (2014). Print.

Pagnier, J, JG Mears, O Dunda-Belkhodja, KE Schaefer-Rego, C Beldjord, RL Nagel, and D Labie. "Evidence for the Multicentric Origin of the Sickle Cell Hemoglobin Gene in Africa." Proceedings of the National Academy of Sciences of the United States of America. 81.6 (1984): 1771-3. Print.

SUGGESTED EDITING FOR ANOTHER ARTICLE ASSIGNMENT:

Web Page: https://en.wikipedia.org/wiki/Sickle-cell_disease

Suggestions for editing:

https://en.wikipedia.org/wiki/Sickle-cell_disease

---In this article, it states that "the estimated mean survival for sickle-cell patients was 53 years old for men and 58 years old for women with homozygous SCD." Throughout the entire article it also talks about much lower life expectancies are for individuals that have SCD. My question is, should this life expectancy be compared to the typical European/American life expectancies (which would be relatively high) or the life expectancy of people living in areas where SCD is much more common? These areas are typically much more impoverished and likely have much lower life expectancies as it is. In this case, 53 years of age for men and 58 years of age for women does not seem like it would be too far removed from the life expectancies of the people living in these traditionally malaria-stricken countries. Their average life expectancy at least be given in order to have a good reference point for how people with SCD compare.

---The name of the area that has the highest frequency of persons infected with SCD is called the "Sicklemic Belt" (Lehman and Huntsman, 1974). I think this needs to be mentioned, as the particular region does have a more specific name.

---In the article, it says that "Sickle-cell gene mutation probably arose spontaneously in different geographic areas, as suggested by restriction endonuclease analysis. These variants are known as Cameroon, Senegal, Benin, Bantu and Saudi-Asian." A study done in 1988 only traces the origins of mutation back to three places, namely Benin, Senegal, and Central African Republic (Nigon, 1988). This is information appears to be inconsistent with what is known about the origin of SCD.

Added citation:

---The majority of children in impoverished countries that do not have access to proper treatment die before the age of five (Delicat-Loembet, 2014)

"Prevalence of the Sickle Cell Trait in Gabon: a Nationwide Study." Infection, Genetics and Evolution. 25 (2014). Print.