Malaria is a deadly disease that, according to the World Health Organization, infects roughly 200 million people annually and kills more than half a million. It has thus become a powerful force of natural selection, helping shape the evolution of its human host.

Most famously, malaria selects for the allele (i.e., a particular version of a gene) that causes sickle-cell anemia. The full-blown disease, a serious condition that greatly shortens lifespan, occurs in people who carry two copies of the allele. However, those who possess only a single copy display partial resistance to malaria. Malaria, therefore, has helped maintain the presence of this otherwise undesirable allele in the human population.

Malaria's influence on the human genome does not end there. It was previously known that people with blood type A were particularly susceptible to developing a severe form of malaria, while people with type O blood were not. Now, a team of Scandinavian researchers thinks it knows why.

When a person contracts malaria, his red blood cells (RBCs) become infected with the parasite. Eventually, the RBCs express malarial proteins on their surfaces. One of these proteins, called PfEMP1, is involved in RBC "rosetting" -- the tendency of RBCs to clump together like petals on a flower. Rosetting is dangerous because clumps of cells block blood vessels and contribute to severe manifestations of the disease.

What the Scandinavian team discovered is that PfEMP1 isn't the only protein responsible for rosetting. They determined this by treating malaria-infected RBCs with trypsin, an enzyme that digests certain kinds of proteins, including PfEMP1. Then, they mixed these treated cells with type A and type O blood and measured the amount of rosetting. (See chart.)

As predicted, high concentrations of trypsin greatly reduced the amount of rosetting. However, notice that type A blood continued to form rosettes at a greater frequency than type O blood. This indicates that there is some other trypsin-resistant malarial protein on the surface of infected RBCs that causes rosetting, and this unidentified protein prefers to bind to blood type A.

The team's subsequent investigation led them to a diverse group of malarial proteins called RIFINs. They expressed malarial RIFIN proteins in hamster cells and discovered that these cells were much likelier to form rosettes with type A blood than with type O. Going a step further, the authors showed that type A blood, when treated with an enzyme that converts it to type O blood, largely loses its ability to bind the RIFIN-expressing cells.

Mystery solved: Malaria causes more severe illness in patients with type A blood because its RIFIN proteins prefer binding to the unique glycoprotein marker found exclusively on type A red blood cells.

This likely has evolutionary consequences. Specifically, we should observe a decrease in the number of people with type A blood in malaria-infested locations and an increase in the number of people with type O blood. Obviously, investigating that would be a good next step for evolutionary biologists and epidemiologists.

Source: Suchi Goel, et al. "RIFINs are adhesins implicated in severe Plasmodium falciparum malaria." Nature Medicine. Published online: 09-March-2015. doi:10.1038/nm.3812

(AP photo: Red blood cells)