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Researchers Explore Population Patterns in Zoonotic Malaria Parasite

NEW YORK (GenomeWeb) – Researchers have identified genetically diverse sub-species of Plasmodium knowlesi, a malaria-causing parasite that can infect humans but is best known for affecting long-tailed macaques and pig-tailed macaques.

An international research team sequenced and compared genome sequences for four dozen P. knowlesi isolates from Malaysian Borneo to one another and to lab lines originating from the Philippines and the Malaysian peninsula that have been grown in rhesus macaques since the 1960s.

Results of the analysis, published online this week in the Proceedings of the National Academy of Sciences, revealed three genetically distinct and diverse P. knowlesi clusters, including two clinical sub-populations of the parasite.

Within the larger of the clinical isolate clusters, the researchers uncovered signals of selection that differ from those found in the Plasmodium parasites that typically infect humans in other parts of the world.

"Overall genome-wide nucleotide diversity was much higher than has been seen in the worldwide samples of either of the major endemic malaria parasite species Plasmodium falciparum and Plasmodium vivax," the study's authors wrote.

"A remarkable sub-structure is revealed within P. knowlesi," they added, "consisting of two major sympatric clusters of the clinical isolates and a third cluster comprising the laboratory isolates."

Although P. falciparum and P. vivax parasites are the most common malaria culprits, Southeast Asia has recently seen a rise in zoonotic malaria cases caused by P. knowlesi, the team noted. The parasite, which also causes malaria in long-tailed macaques and pig-tailed macaques, can be transmitted by vectors such as the Anopheles latens mosquitoes and mosquitoes of the Anopheles leucosphyrus species.

"Human populations have grown very rapidly in the Southeast Asian region and encroach on most of the wild macaque habitats," the study's authors explained, "so it is vital to know if P. knowlesi parasites are adapting to human hosts or to an anthropophilic mosquito vector species, either of which could cause human-mosquito-human transmission."

To delve into such questions, the researchers used Illumina paired-end sequencing to generate genome sequence data for 48 clinical isolates, along with five P. knowlesi lab lines.

The team sequenced the lab strains to average depths of 120-fold genome coverage, while the clinical isolate sequences covered the 23.5 megabase P. knowlesi reference genome to average depths of 36-fold.

The team found that P. knowlesi had significantly higher genetic diversity than that described in Plasmodium parasites more often implicated in human disease: P. falciparum and P. vivax.

Within the clinical and lab isolates of P. knowlesi, the researchers uncovered more than 975,000 high-quality SNPs, with nearly half of those turning up in the minor allele form in a single P. knowlesi isolate.

While two lab lines were closely related to one another — and to the strain used to produce the P. knowlesi reference genome — most of the isolates were genetically distinct from one another.

Nevertheless, the team saw two clinical isolate clusters, one involving 38 isolates and another with 10 isolates, with nearly 9,300 fixed SNP differences between these two P. knowlesi sub-populations.

The researchers' subsequent analyses indicated that the first of these clusters has undergone population growth stretching back over long periods of time and contains signals of selection on distinct genes from those that have been subject to selection in P. falciparum and P. vivax.

"The absence of any signature of positive selection on the P. knowlesi orthologs of drug-resistance genes is consistent with the hypothesis that most selection on these parasites occurs in macaque rather than human hosts, specifically in the long-tailed macaques for the cluster 1 population," the study's authors concluded.