A. The Unique Geographic Distribution Pattern of Sickle-Cell Anemia

Almost as soon as sickle cell anemia was recognized as a blood-based disease, its higher frequency in families of African descent was noted. However, the first reports of cases in Africa itself did not come until the 1920s. In 1925 a 10-year old Arab boy was admitted to a hospital in Omdurman in the Sudan (on the Upper Nile, East central Africa, near Ethiopia) with severe weakness; later he was ascertained to have sickle cell disease (anemia). In 1944 R. Winston Evans, a pathologist at the West African Military Hospital, studied the blood of 600 men from Gambia, the Gold Coast, Nigeria and the Cameroons (all in western Africa on the Gulf of Guinea). He found about 20% of the population affected by the sickle-cell condition (disease + trait). However, a striking observation became apparent: while the frequency of sickle-cell trait in Africa was three times that in the United States, sickle cell disease was much less common. Even as late as the 1950s it was still unclear why this discrepancy existed. Three hypotheses existed at the time:

(a) Adult Africans are healthier than those living in urban America and thus do not show the effects of the disease as readily;

 

(b) Infant mortality, especially for Hb^SHb^S children, is much higher in Africa than in the U.S., so that homozygous recessive children never reach adulthood

 

(c) By chance fewer homozygous recessive individuals are conceived in Africa than in the United States.

In-Text Question 6: Which of these options do you think might explain the discrepancy?

Tutorial Answer 6

In certain parts of Africa today, the frequency of the mutant gene for sickle-cell (Hb^S) is very high (5-20%) as shown in the distribution map below:

How can we account for this very high frequency of a gene for a condition that can leave up to 25% of the population severely debilitated (with sickle cell disease)? It is logical to think that natural selection would have eliminated the gene from the population, especially since selection against homozygous recessive individuals has been almost 100% in the past (i.e., those individuals never lived to reproductive age). That it has not done so (apparently) became a major question for both geneticists and medical epidemiologists by the 1950s. The matter was all the more puzzling since the frequency of the HbS gene in the United States is less than that in Africa: 0.05 in the U.S. compared to 0.1-0.2 in central west Africa, even those most U.S. blacks came from those very populations in central west Africa where sickle cell anemia is so prevalent.

B. The Malarial Connection

In 1946 E.A. Beet, an MD in Northern Rhodesia noted that of a population of patients in his hospital, 15.3% of those who had normal blood had malaria, while only 9.8% of those with sickle cell (trait or disease) had the disease. Anthony C. Allison, a British medical doctor who had also taken a degree in biochemistry and genetics at Oxford shortly after World War II, studied the African situation closely in the early 1950s and published an important paper in 1954 outlining his hypothesis for why the African frequencies of the Hb^S gene were so high (he had found that in some tribes up to 40% of the individuals were heterozygous for sickle-cell trait). He reasoned that if natural selection were working to eliminate the recessive mutant gene, it would be necessary to invoke a mutation rate (from Hb^A to Hb^S) 1000 times higher than known for any other human gene in order to explain the continued high frequencies of HbS in the popluation. This seemed so unlikely he reasoned that some other forces must be at work.

Allison thought it was significant that the frequency distribution of the sickle-cell condition mapped out very closely to the distribution map for the most severe forms of malaria, those caused by the protozoan Plasmodium falciparum, as shown in the map below:

Borrowing the concept of balanced polymorphism from his teacher E.B. Ford at Oxford, Allison hypothesized that children in these regions who are heterozygous for HbS (i.e., HbAHbS) have an advantage in combatting the effects of malaria over individuals with normal hemoglobin (i.e., HbAHbA). Homozygous recessive individuals (HbSHbS) may also have an advantage against malaria, but they have all the other problems associated with sickle cell disease, and hence are severely selected against and seldom reproduce.The situation in which the heterozygote in any population is selectively favored over either homozygote is what is known as balanced polymorphism. It works to maintain a high frequency of the recessive mutant gene even though that gene is highly deleterious in the homozygous recessive form. At the time Allison did not know how the presence of sickle-cell hemoglobin conferred selective protection against malaria, but the connection seemed clear to him. In a non-malarial environment such as the United States, the heterozygotes would not have a selective advantage, and hence both hetero- and homo-zygote recessives would be selected against. Thus, in accordance with the data, sickle-cell was lower in frequency in the U.S. because there was no advantage to the heterozygote or the homozygote recessive.

An American geneticist, James V. Neel, also studied sickle cell frequencies and concluded that in malarial environments, heterozygotes (with sickle-cell trait) have an increased fitness (chance of leaving offspring) of 15% over those with normal hemoglobin.

C. How Does Sickle-Cell Help Combat Malaria?

The exact mechanism by which resistance to malaria is conferred by sickle cell hemoglobin in still unknown, but at least one part of the process seems clear. As shown in the life cycle of Plasmodium in the figure below, an asexual stage of the organism lives in red blood cells in humans, while a sexual phase develops in the mosquito. The asexually-reproducing forms, or merozoites, develop within red blood cells, breaking out of old cells and reinfecting new cells. It is during the period when the merozoites are breaking out of old red blood cells that the infected person develops a very high temperature (followed several hours later by a lowering of the temperature and the sensation of "chills").

"Life cycle of the malarial parasite Plasmodium. falciparum, the major and most severe form of malaria-causing protozoans."

There are at least three other Plasmodium species that produce milder forms of malaria. P. falciparum infection remains one of the major causes of human deaths in the world today.

While reproducing asexually inside the red blood cells, the merozoites have a high metabolic rate, and consequently consume lots of oxygen. If the individual is heterozygous for sickle-cell trait, half their hemoglobin is Hb^AHb^S, and thus will sickle when the oxygen tension becomes very low inside the red blood cells (recall that sickling does occur in heterozygous individuals, only at a lower oxygen tension than for homozygotes). These sickled cells are removed from the body by the spleen, along with the merozoites inside of them. Thus heterozygotes on the average remove merozoites from their body before the microorganisms have a chance to produce a large infectious population inside the body. It is this sleective advantage of the heterozyote that maintains the Hb^S gene at a higher level in malarial than in non-malarial environments.

In Biology 3051 you will return to a study of sickle-cell anemia in a more mathematically sophisticated context. It is an important case study in the way in which selective forces in evolution work to maintain different gene frequencies in different environments. What is selectively advantageous in one environment can be non-advantageous or even disadvantageous in another.