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Key Virulence Factors of Human Malaria Parasite Much More Ancient Than Thought; Intact Gene Segments Were Exchanged and Evolved in Plasmodium Sub-Genus in Apes Before Emergence of Human Malaria Parasiste (P. falciparum)

The malaria parasite (Plasmodium falciparum) (image) molecules associated with severe disease and death--those that allow the parasite to escape recognition by the immune system--have been shown to share key gene segments with chimp and gorilla malaria parasites, which are separated by several millions of years of evolution, according to a new study led by researchers at the Harvard T.H. Chan School of Public Health. This new information about the origin and genetics of human malaria virulence factors could aid in basic understanding of the causes of malaria and provide targets for drugs and vaccines. The study was published online on October 12, 2015 in an open-access article in Nature Communications. The article is titled “ "Ape Parasite Origins of Human Malaria Virulence Genes.” "The evolution of these key virulence determinants doesn't occur in the same way as in other pathogens. Instead of gradually changing by mutation, as the flu virus, these malaria parasites exchange intact gene segments, like shuffling a deck of cards," said Caroline Buckee, Ph.D., Assistant Professor of Epidemiology at Harvard’s Chan School and senior author of the study. Malaria kills more than 500,000 people a year, mostly children in Sub-Saharan Africa. Severe disease syndromes in human malaria--including severe malarial anemia, pregnancy-associated malaria, and cerebral malaria--have been linked with the malaria parasite's ability to cause infected red blood cells to bind to the inner lining of blood vessels. This ability of the infected cells to adhere in this way--which is key to malaria's virulence--is linked with certain genes called var genes. Looking at hundreds of var sequence fragments using network analysis, the researchers discovered that short segments of these genes are shared across many different malaria parasites affecting humans, apes, and chimps. These segments are not recent adaptations, but rather reflect an ancient genomic structure. "Astonishingly, we have found the very same shared sequence mosaics in these highly divergent species, implying that these short mosaic sequences, in spite of continual diversification, have an ancient origin," Dr. Buckee said. "The origin of human malaria virulence factors is actually much older than previously thought."

More specifically, in their abstract, the authors said they used network analysis to show that var architecture and mosaicism are conserved at multiple levels across the Laverania subgenus (sub Plasmodium), based on var-like sequences from eight single-species and three multi-species Plasmodium infections of wild-living or sanctuary African apes.

Using select whole-genome amplification, they also found evidence of multi-domain var structure and synteny in Plasmodium gaboni, one of the ape Laverania species most distantly related to P. falciparum, as well as a new class of Duffy-binding-like domains.

These findings, they said, indicate that the modular genetic architecture and sequence diversity underlying var-mediated host-parasite interactions evolved before the radiation of the Laverania subgenus, long before the emergence of P. falciparum.

Lead author of the study was Daniel B. Larremore, Ph.D., former postdoctoral fellow in the Center for Communicable Disease Dynamics at Harvard Chan School and now an Omidyar fellow at the Santa Fe Institute.

Institutions collaborating with the Harvard School of Public Health on this study, included the Perelman School of Medicine (University of Pennsylvania), The Wellcome Trust Sanger Institute, the University of Colorado, Santa Fe Institute, and the University of Edinburgh.

[Press release] [Nature Communications article]