Abstract
Plasmodium parasites exerted a strong selective pressure on primate genomes and mutations in genes encoding erythrocyte cytoskeleton proteins (ECP) determine protective effects against Plasmodium infection/pathogenesis. We thus hypothesized that ECP-encoding genes have evolved in response to Plasmodium-driven selection. We analyzed the evolutionary history of 15 ECP-encoding genes in primates, as well as of their Plasmodium-encoded ligands (KAHRP, MESA and EMP3). Results indicated that EPB42, SLC4A1, and SPTA1 evolved under pervasive positive selection and that episodes of positive selection tended to occur more frequently in primate species that host a larger number of Plasmodium parasites. Conversely, several genes, including ANK1 and SPTB, displayed extensive signatures of purifying selection in primate phylogenies, Homininae lineages, and human populations, suggesting strong functional constraints. Analysis of Plasmodium genes indicated adaptive evolution in MESA and KAHRP; in the latter, different positively selected sites were located in the spectrin-binding domains. Because most of the positively selected sites in alpha-spectrin localized to the domains involved in the interaction with KAHRP, we suggest that the two proteins are engaged in an arms-race scenario. This observation is relevant because KAHRP is essential for the formation of “knobs”, which represent a major virulence determinant for P. falciparum.
Highlights
Malaria is annually responsible for hundreds of thousands of deaths and millions of illnesses per year (WHO, http://www.who.int/malaria/publications/world-malaria-report-2016/)
We first aimed to comprehensively analyze the selective pressure acting on primate genes that encode erythrocyte cytoskeleton proteins (ECP)
We focused our attention on genes encoding ECPs that are involved in the remodeling of red blood cells (RBCs) during Plasmodium infection[3,4]
Summary
Malaria is annually responsible for hundreds of thousands of deaths and millions of illnesses per year (WHO, http://www.who.int/malaria/publications/world-malaria-report-2016/) It is caused by protozoan parasites of the genus Plasmodium, and, there are about 30 Plasmodium species that infect primates[1], only five (P. falciparum, P. vivax, P. malariae, P. knowlesi, and P. ovale) cause malaria in humans. P. falciparum achieves these changes in the iRBC structure by exporting parasite proteins into the erythrocytes Some of these proteins interact with host components of the cytoskeleton and plasma membrane and lead to the formation of cytoadhesive and antigenic supramolecular protrusions (“knobs”) at the iRBC surface[3,4]. All these molecules form direct interactions with human erythrocyte cytoskeleton proteins (ECP)[3,4]. Genetic variants in genes encoding ECPs can affect the infection success or pathogenesis of malaria caused by Plasmodium parasites other than P. falciparum
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