Last week, I discussed the genetic basis of cancer risk, specifically breast cancer. This week I want to start talking about direct genetic diseases, starting with a disease that has an interesting connection with malaria: sickle-cell anemia. Sickle-cell anemia affects millions of people worldwide, and it is particularly common in people with African or Mediterranean ancestry. Individuals with two sickle-cell disease (SCD) genes (one from their mother and one from their father) develop sickle-cell anemia, which causes their red blood cells to become warped and “sickle” shaped. These sickle cells are stiff and they tend to build up in the blood vessels causing blockages and pain. Additionally, sickle cells die very quickly, leaving the body with a shortage of red blood cells (anemia) that starves the body of oxygen. Despite how harmful it is, the sickle-cell gene persists because its relationship with malaria. Individuals with only one SCD gene (and one normal gene) are considered carriers of the sickle-cell trait, but they do not suffer any of the negative symptoms associated with the disease. And, it turns out, individuals who are carriers of the sickle-cell trait are significantly less likely to die from malaria. Therefore, SCD genes stick around, especially in populations where malaria is a persistent problem. People who live in, or had ancestors who lived in, Africa, the Mediterranean, India, South America, and the Caribbean are more likely to inherit an SCD gene since those areas have more malaria-carrying mosquitos. Sickle-cell anemia demonstrates how a gene with negative consequences can actually be favored by natural selection due to environmental forces.
On average, a healthy adult has about 5 liters of blood containing 25 trillion red blood cells. Normal red blood cells are shaped like a flattened disk with a thumbprint indentation. They are about 7-8 microns across (for comparison you could lay over 2 thousand red blood cells across the diameter of a dime). In humans, red blood cells do not have a nucleus, but they do have up to 250 million molecules of hemoglobin. Hemoglobin is a protein made up of four subunits, each of which carries an iron atom. Each iron atom acts as a magnet for an oxygen atom, allowing the red blood cell to carry oxygen from the lungs to the various tissues of the body where that oxygen can be converted to energy. Hemoglobins can also pick up carbon dioxide (a byproduct of the cell’s conversion of oxygen into energy) from the tissues and transport it back to the lungs to be exhaled. Rhythmic contractions from the heart keep the blood circulating, bringing oxygenated blood cells from the lungs to the tissues and returning the blood cells to the lungs with carbon dioxide waste.
Individuals who inherit the gene for the sickle cell hemoglobin variant (HbS) form abnormal hemoglobin molecules. The difference in structure is fairly small, but it causes a large change in how the hemoglobin functions. When no oxygen is attached to the HbS molecule it tends to crystallize with other HbS molecules in long chains that stretch and deform the red blood cell into the sickle shape. The deoxygenated sickle cells become dehydrated, rigid, and irreversibly deformed. Over time they break down completely, leaving the blood depleted of oxygen-carrying blood cells. The sickled cells also tend to stick to each other causing blood clots and episodes of severe pain (referred to as a sickle cell crisis).
Sickle-cell trait (SCT) carriers, individuals with only one inherited sickle-cell gene, have a certain amount of normal hemoglobin (HbA) that disrupts the crystallization of HbS. The presence of HbA lowers the probability of hemoglobin crystallization, which allows most carriers to live their lives free of clinical sickle-cell symptoms. But carriers who suffer from oxygen starvation (hypoxia—can occur with lung damage or even asthma), high blood acidity (acidosis—can be due to chest trauma or certain metabolic disorders), or dehydration are at a higher risk of sickle-cell formation. Carriers who regularly exert themselves, like athletes, may suffer from exercise collapse associated with SCT (ECAST). ECAST can cause serious muscle death (rhabdomyolysis—try saying that five times fast), but it is easy for carriers to avoid this with enough hydration and oxygenation.
In addition to being relatively safe from the negative effects of sickle-cell disease, SCT carriers gain functional protection from malaria. Individuals with some of the HbS variant, are not protected from contracting malaria, but they are far less likely to die from the disease than individuals with completely normal HbA hemoglobin. Since malaria deaths are most common in children, SCT carriers are more likely to live long enough to have children and pass on the SCT gene. This strong environmental selection allows the SCT gene to predominate despite the debilitating effects of sickle-cell anemia.
But how does the SCT gene protect against malaria? Malaria is a parasite carried by mosquitos. It infects a red blood cell, reproduces, and then destroys the cell. This life cycle repeats, creating a horde of the parasitic invaders that continue to destroy red blood cells and release toxic materials into the bloodstream that can induce life-threatening symptoms. It turns out that, while HbS hemoglobin doesn’t prevent parasitic infection in a red blood cell, it does prevent the parasite from reproducing and spreading to more cells. Like I said above, SCT carriers still have the potential of forming sickled red blood cells. And when a red blood cell is sickled, cells from the immune system seek to destroy it. This is the mechanism that prevents the malaria parasite from reproducing and spreading from red blood cell to red blood cell. Invasion by the parasite leads to deoxygenation and high blood acidity, two of the factors that promote the crystallization of HbS and red blood cell sickling. And sickling of the red blood cell promotes cell degradation, which destroys the parasite before it can continue to spread. This mechanism, which can cause painful or fatal symptoms for some, protects SCT carriers from the potentially fatal effects of malaria.
So, the SCT gene experiences selective pressure from both sides in regions where malaria is prevalent. On one hand, the presence of the SCT gene in a population increases the probability of an individual inheriting two SCT genes and suffering from the debilitating life-long condition of sickle-cell anemia. On the other hand, the presence of the SCT gene in a population can prevent individuals in that population from dying of malaria. These pressures work against each other to keep a base level of the SCT gene prevalent in populations at risk of malaria.
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