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Human Malaria Parasite's Evolution Refined by Genomes of Great Ape Pathogens

NEW YORK (GenomeWeb) – By sequencing a family of malaria parasites that infect gorillas and chimpanzees, a team from the UK, France, Kenya, and Gabon got a glimpse at the evolutionary history and virulence-related adaptations of the human malaria pathogen Plasmodium falciparum, which split from the other parasites and is in the same sub-genus.

"We estimated when Plasmodium falciparum and its relatives diverged," co-senior author Matthew Berriman, leader of the Wellcome Trust Sanger Institute's parasite genomics group, said in a statement, "and found evidence that the recent expansion of modern humans created the home in which the parasites irreversibly evolved into a human-specific form."

Berriman and his colleagues sequenced the genomes of 19 genotypes representing malaria-causing parasites in the Laverania — a sub-genus of African great ape-infecting parasites from a lineage that led to P. falciparum — using isolates from infected gorillas and chimpanzees at a wildlife sanctuary in Gabon. Based on the predominant genotype for each species, they put together de novo reference genome assemblies for half a dozen Plasmodium species, using syntenic sequences, phylogenetics, and comparative genomics to retrace the advent of crucial P. falciparum adaptations. 

"To investigate the evolutionary history of all known members of the Laverania sub-genus and to address the question why P. falciparum is the only extant species to have adapted successfully to humans," the authors wrote in Nature Microbiology, "we sequenced multiple genotypes of all known Laverania species."

After tracking down parasite-positive blood samples from four gorillas and seven chimps with a PCR-based approach, the researchers used a combination of Illumina MiSeq or HiSeq 2000 short reads and Pacific Biosciences long reads to sequence genomic DNA from 19 parasite genotypes spanning six species: P. praefalciparum, P. blacklocki, P. adleri, P. billcollinsi, P. gaboni, and P. reichenowi.

Using new reference genomes for each species and available sequences for the human parasite P. falciparum, they tracked down 4,350 orthologous genes shared by seven species.

The team's analyses of genome synteny, genetic diversity, mutation rate patterns, and other parasite genome sequences made it possible to retrace past population patterns in P. falciparum and the non-human primate-infecting species. For example, the investigators saw evidence that the P. falciparum lineage began splitting from the lineage leading to P. praefalciparum roughly 40,000 to 60,000 years ago.

But the evidence suggests the parasite took on adaptations that make it adept at infecting humans more recently. Its population size started to decline roughly 11,000 years ago, the researchers reported, dipping to an effective population size of just a few thousand individuals.

"In our analysis, we have shown that the successful infection of humans by P. falciparum occurred recently and involved numerous parasites rather than one as previously proposed," the authors wrote. "After the establishment in its new host, the parasite population went through a bottleneck around 5,000 years ago during the period of rapid human population expansion because of farming."

The team also retraced the ways genes shuttled between parasite clades, producing the fodder for virulent parasites capable of consistently infecting humans, including a locus containing a gene called rh5 that codes for an essential component of red blood cell invasion.

"The movement of a single cluster of genes was an early crucial event that enabled the malaria parasites to infect the red blood cells of a new host species," co-first author Thomas Otto, a former Sanger researcher who is currently based at the University of Glasgow, said in a statement. "After reconfiguring and fine-tuning the repertoires of genes that interact with the host and the vector, the parasites were able to establish long-term, transmissible infections in humans."