High rate of adaptation of mammalian proteins that interact with Plasmodium and related parasites

Plasmodium parasites, along with their Piroplasm relatives, have caused malaria-like illnesses in terrestrial mammals for millions of years.Several Plasmodium-protective alleles have recently evolved in human populations, but little is known about host adaptation to blood parasites over deeper evolutionary timescales.In this work, we analyze mammalian adaptation in ~500 Plasmodium-or Piroplasm-interacting proteins (PPIPs) manually curated from the scientific literature.We show that (i) PPIPs are enriched for both immune functions and pleiotropy with other pathogens, and (ii) the rate of adaptation across mammals is significantly elevated in PPIPs, compared to carefully matched control proteins.PPIPs with high pathogen pleiotropy show the strongest signatures of adaptation, but this pattern is fully explained by their immune enrichment.Several pieces of evidence suggest that blood parasites specifically have imposed selection on PPIPs.First, even non-immune PPIPs that lack interactions with other pathogens have adapted at twice the rate of matched controls.Second, PPIP adaptation is linked to high expression in the liver, a critical organ in the parasite life cycle.Finally, our detailed investigation of alpha-spectrin, a major red blood cell membrane protein, shows that domains with particularly high rates of adaptation are those known to interact specifically with P. falciparum.Overall, we show that host proteins that interact with Plasmodium and Piroplasm parasites have experienced elevated rates of adaptation across mammals, and provide evidence that some of this adaptation has likely been driven by blood parasites. Author summaryMalaria caused by the parasite Plasmodium falciparum remains the third-most deadly infectious disease of humans.Over the last 75,000 years, partial genetic resistance to malaria has evolved several times, earning malaria the title of "one of the strongest selective forces on the human genome."Yet, these human adaptations are only the most recent maneuvers in an ancient evolutionary war between host and parasite.Relatives of